The history of medical genetics is briefly reviewed. It is evident that medical genetics with its inseparable part, clinical genetics, started out as a cfinical science from the very beginning. Its robust development ...The history of medical genetics is briefly reviewed. It is evident that medical genetics with its inseparable part, clinical genetics, started out as a cfinical science from the very beginning. Its robust development in the developed countries is the result of a close interaction between the basic sciences and clinical genetics. In China, however, clinical genetics has not received due emphasis and medical genetics is still not recognized as one of the medical specialties. This is in marked contrast to the situation in the West. It is high time to acknowledge that medical genetics is a medical specialty and to promote clinical genetics service in qualified hospitals in our country.展开更多
This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and f...This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and further analysis identified seven novel mutants.The preponderance of variants was observed in exon 1 and exon 4,specifically within the nicotinamide adenine dinucleotide phosphate(NADPH)-binding region.Among the entire cohort,53 patients underwent initial surgery at Sichuan Provincial People’s Hospital(Chengdu,China).The external genitalia scores(EGS)of these participants varied from 2.0 to 11.0,with a mean of 6.8(standard deviation[s.d.]:2.5).Thirty patients consented to hormone testing.Their average testosterone-todihydrotestosterone(T/DHT)ratio was 49.3(s.d.:23.4).Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome;and their T/DHT ratios were below the diagnostic threshold.Furthermore,assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants.These mechanisms include interference with NADPH binding(c.356G>C,c.365A>G,c.492C>G,and c.662T>G)and destabilization of the protein structure(c.727C>T).The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts.Seven novel variations were identified,and the variant database for the SRD5A2 gene was expanded.These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.展开更多
Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion...Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.Results:In our model,the number of CAG repeats remained stable during transmission,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impairment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropathological phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant differences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.展开更多
The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease （IBD） are due to an overly aggressi...The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease （IBD） are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/ or barrier function, with onset triggered by environmental stimuli. These factors and their interactions may also be important determinants of disease phenotype and disease progression. The emergence of immunogenetic phenotypes lends support to the proposed hypothesis that susceptibility genes regulate distinct immune processes, driven by luminal antigens, expressed as specific immune phenotypes which in turn influence clinical phenotypes in IBD patient.展开更多
Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that ...Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that become unstable beyond a critical length whentransmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells(diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.展开更多
Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In recent years, several genome-wide single-nucleotide polymorphism （SNP） association studies （GWAS） have been performed on a...Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In recent years, several genome-wide single-nucleotide polymorphism （SNP） association studies （GWAS） have been performed on azoospermia and/or oligozoospermia in different populations including two GWAS on nonobstructive azoospermia in China; however, the association of SNPs with idiopathic male infertility, especially asthenozoospermia and oligozoospermia, and their correlation with semen parameters are still not clear. To investigate genetic variants associated with idiopathic male infertility （asthenozoospermia, oligozoospermia, and oligoasthenozoospermia） in Chinese Han people, 20 candidate SNPs were selected from GWAS results and genotyped using the Sequenom MassARRAY assay. A total of 136 subfertile men and 456 healthy fertile men were recruited, rs6476866 in SLCIA1 （P = 1.919E-4, OR = 0.5905, 95% Ch 0.447-0.78） and rs10129954 in DPF3 （P = 0.0023, OR = 2.199, 95% Ch 1.311-3.689） were strongly associated with idiopathic male infertility. In addition, positive associations were observed between asthenozoospermia and rs215702 in LSM5 （P= 0.0016, OR = 1.479, 95% CI： 1.075-2.033） and between oligoasthenozoospermia and rs2477686 in PEXIO （P= 0.0011, OR = 2.935, 95% Ch 1.492-5.775）. In addition, six SNPs （rs215702 in LSMS, rs6476866 in SLCIA1, rs10129954 in DPF3, rs1801133 in MTHFR, rs2477686 in PEXIO, and rs10841496 in PED3A） were significantly correlated with semen quality alterations. Our results suggest that idiopathic male infertility in different ethnic groups may share the same mechanism or pathway. Cohort expansion and further mechanistic studies on the role of genetic factors that influence spermatogenesis and sperm progressive motility are suggested.展开更多
We studied the allelic frequency distributions and statistical forensic parameters of 21 new short tandem repeat(STR)loci and the amelogenin locus,which are not included in the combined DNA index system(CODIS),in a Ru...We studied the allelic frequency distributions and statistical forensic parameters of 21 new short tandem repeat(STR)loci and the amelogenin locus,which are not included in the combined DNA index system(CODIS),in a Russian ethnic minority group from the Inner Mongolia Autonomous Region,China.A total of 114 bloodstain samples from unrelated individuals were extracted and co-amplified with four fluorescence-labeled primers in a multiplex polymerase chain reaction(PCR)system.Using capillary electrophoresis,the PCR products of the 21 STR loci were separated and genotyped.A total of 161 alleles were observed in the Russian ethnic minority group,and corresponding allelic frequencies ranged from 0.0044 to 0.5965.The 21 non-CODIS STR loci of the Russian ethnic minority group were characterized by high genetic diversity and therefore may be useful for elucidating the population's genetic background,for individual identification,and for paternity testing in forensic practice.展开更多
Several studies have reported a relationship between the length of the CAG-repeat in the polymerase y （POLG） gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-...Several studies have reported a relationship between the length of the CAG-repeat in the polymerase y （POLG） gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-CAG-repeat length was analyzed in 535 healthy individuals from six Chinese Han populations living in different provinces. The frequencies of IO-CAG alleles and genotypes were high （97.38 and 94.13%, respectively）, with no significant difference among the six Chinese Han populations. Furthermore, we determined the distribution of the POLG-CAG-repeat in 150 infertile men and 126 fertile men. Our study suggested that the distributions of POLG-CAG-repeat alleles and genotypes were not significantly different between infertile （95.67 and 92.67%, respectively） and fertile men （97.22 and 94.44%, respectively）. In a subsequent meta-analysis, combining our data with data from previous studies, a comparison of the CAG-repeat alleles in fertile versus infertile men showed no obvious risk for male infertility associated with any particular allele （pooled odds ratio （0R）=0.94; 95% confidence interval （CI）： 0.60-1.48）. The significance level was not attained with any of the following genetic models： homozygote comparison （not lO/not 10 versus 10110： OR= 1.34; 95% Ch 0.66-2.72）, heterozygote comparison （lO/not 10 versus 10/10： OR= 1.04; 95% Ch 0.78-1.38）, dominant model comparison （not lO/not 10＋ 101 not 10 versus 10110. OR= 1.08; 95% Ch 0.79-1.47） and recessive genetic comparison （not lO/not 10 versus lO/not 10＋ 10/10- OR= 1.31; 95% Ch 0.68-2.55）. In conclusion, there is no significant difference of the frequencies of POLG-CAG-repeat variants among six Chinese Han populations, and this polymorphism may not be associated with Chinese male infertility. On the basis of a meta-analysis, there is no obvious association between CAG-repeat variants of the POLG gene and male infertility.展开更多
Juvenile X-linked retinoschisis（XLRS, MIM#312700） belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mu...Juvenile X-linked retinoschisis（XLRS, MIM#312700） belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography（SD-OCT） images. The mean central foveal thickness was 569.7 μm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio（〈1.0） in all patients. RS1（NM_000330.3） gene coding exons Sanger sequencing was performed. RS1 c.599 G〉T（p.R200 L） mutation was detected in one case, showing to be pathogenic in silico analysis. c.（92_97） ins C（p.W33 fs） mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422 C〉G（p.R141 H）, HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.展开更多
A Chinese scientist, Jiankui He, and his creation of the world ' s first genetically altered baby made headlines recently. As a newly developed gene-editing technique, the CRISPR/Cas system should not be applied t...A Chinese scientist, Jiankui He, and his creation of the world ' s first genetically altered baby made headlines recently. As a newly developed gene-editing technique, the CRISPR/Cas system should not be applied to human beings for reproductive purposes until it has been extensively tested. However, numerous experimental research studies in human somatic, germline cells, and even in embryos, have been conducted, which have shown CRISPR/Cas to be a useful tool for human genome editing and a potential therapeutic method for future clinical use.展开更多
Conductive hearing loss is the impairment in the mechanical transduction of sound wave through the external ear and the middle ear.Although most cases are sporadic due to acquired causes such as infections(otitis medi...Conductive hearing loss is the impairment in the mechanical transduction of sound wave through the external ear and the middle ear.Although most cases are sporadic due to acquired causes such as infections(otitis media and otitis externa),cerumen obstruction,and injuries,congenital structural defects are uncommon for significant etiologies to recognize.Stapes ankylosis is characterized by conductive hearing loss.It may be difficult to differentiate from otosclerosis,the most common cause of progressive conductive hearing loss,by audiologic evaluation,when the diagnosis is delayed.Skeletal anomalies may be subtle,such that the syndrome may not be recognized(Brown et al.,2002).展开更多
The ataxin-2 （ATXN2） gene is located on human chromo-some 12q24.1. In normal individuals, the coding region in exon 1 of this gene has fewer than 31 CAG repeats （Yu et al., 2005： Laffita-Mesa et al., 2012）. Howev...The ataxin-2 （ATXN2） gene is located on human chromo-some 12q24.1. In normal individuals, the coding region in exon 1 of this gene has fewer than 31 CAG repeats （Yu et al., 2005： Laffita-Mesa et al., 2012）. However, an abnormal expansion of CAG trinucleotide repeats results in the aggre-gation of polyglutamine （polyQ）, which causes spinocer-ebellar ataxia type 2 （SCA2） （Pulst et al., 1996）. The expanded alleles have more than 32 repeats in the affected individuals, and generally there is an inverse correlation between CAG repeat length and age of onset （Pulst et al., 1996）. SCA2 is an autosomal dominant inheritance neurodegenerative disease, whose major clinical feature is progressive cerebellar ataxia. Atrophies of the brainstem and frontal lobe have been frequently detected by magnetic resonance imaging （MRI） （Yamamoto-Watanabe et al., 2010）. This disease has the strong effect on sensory and motor control.展开更多
Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clin...Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.展开更多
Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifthmetacarpals. In the previous publication, we first identified a heterozygous missense mutation Q...Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifthmetacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) ofHOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlyingpathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed togenerate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly andpartial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes.Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limbdevelopment, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud atE10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibitednotable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involvedin various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopicexpression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both theanterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascadeultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations inhomozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may beresponsible for the manifestation of human SDTY5.展开更多
Background: Febrile seizures (FSs) are the most common form of childhood seizures, and genetic factors play a role in susceptibility to FS. Objective: To identify novel loci and genes associated with susceptibility to...Background: Febrile seizures (FSs) are the most common form of childhood seizures, and genetic factors play a role in susceptibility to FS. Objective: To identify novel loci and genes associated with susceptibility to FS. Methods: Study participants were the FS probands and family members of 59 Japanese nuclear families (223 members including 112 affected children). Forty- eight of these families had at least two affected children for which genome- wide linkage screening was carried out. The Genehunter software was used to perform nonparametric multipoint linkage analysis. Mutational and association analyses were conducted in all 59 Japanese FS families. Results: Genotyping data of 407 microsatellite markers suggested linkage of FSs to chromosome 18p11.2 (non- parametric linkage score = 3.68, p = 0.0001). This region includes the IMPA2 gene, which encodes myo- inositol monophosphatase (IMPase) 2. In the phosphatidylinositol- signaling pathway, IMPase is inhibited by lithium, which has a proconvulsant effect, and is stimulated by carbamazepine, an anticonvulsant. A systematic search was performed for mutations in IMPA2 in 24 unrelated randomly selected Japanese FS patients; seven variants were detected. Haplotype analysis revealed an association of a common haplotype in IMPA2 with FSs (p = 0.0009). Conclusion: The authors found a novel locus on chromosome 18p11.2 for febrile seizures (FSs). IMPA2 is likely to be an FS susceptibility gene.展开更多
Background:The liver is fundamental for keeping up the entire body’s homeostasis.The liver hepatocytes have been shown to undergo genomic instability with aging.The stability of the hepatocytes depends on its nuclear...Background:The liver is fundamental for keeping up the entire body’s homeostasis.The liver hepatocytes have been shown to undergo genomic instability with aging.The stability of the hepatocytes depends on its nuclear architecture.Calorie restriction has been shown to extend life-span favorably and this may be through the reorganization of the nuclear structure.Objective:To study the effect of cyclic feeding regime on the chromatin assembly anchored to the nuclear membrane scaffold of rat models hepatocytes nuclei.Method:Rats models underwent cyclic feeding regime,after which nuclei were isolated;then,we investigated the chromatin decondensation and nuclear membrane disintegration of the hepatocytes using fluorescence imaging methods.Results:In 60 seconds,protease decondensed the chromatin and disintegrated the nuclear membrane structure of controls.After the first fasting,the time increased to 145 seconds in 3-month-old rats.The first refeeding increased the time to 156 seconds with a further rise to 340 seconds following the second fasting,then dropped to 116 seconds by the second refeeding.20 months old rats showed 186 seconds increase in the time of chromatin decondensation and nuclear membrane disintegration after the first fasting,with a decrease to 140 seconds observed after first refeeding.The second fasting increased the time to 165 seconds,which then slightly decreased to 163 seconds after the second refeeding.Conclusion:These results show that intermittent fasting may have acted on chromatin histone interactions and the structural lamin networks of the nuclear membranes in bringing about nuclear stability,which is essential for normal cellular function.展开更多
Aim:To study a possible defect in spermatogenesis of Fragile X syndrome(FXS)patients.Methods:Two different polymerase chain reaction(PCR)based methods were used for the molecular diagnosis of FXS.Sperm collection was ...Aim:To study a possible defect in spermatogenesis of Fragile X syndrome(FXS)patients.Methods:Two different polymerase chain reaction(PCR)based methods were used for the molecular diagnosis of FXS.Sperm collection was done mostly according to the laboratory manual of the World Health Organization.Results:We failed to collect sperm samples from five Fragile X subjects aged 18-60 years as a result of an unexpected erectile dysfunction(ED). Multiple examinations of the same subject at different times,and of different subjects from different provinces by different physicians,showed the same result consistently in all five subjects examined.Conclusion:Erectile reflex is an instinctive response in all healthy males.The absence of erection can be caused by hormonal,physical or neuronal malfunction.As hormonal profiles were reported to be generally normal in Fragile X men,we propose that an unknown physical factor or the neuronal circuit,or both,underlying the erection is compromised.The finding of ED in Fragile X patients may help better understand the clinical spectrum and pathogenesis of the disease.(Asian J Androl 2006 Jul;8:483-487)展开更多
Hereditary spherocytosis （HS）, the most common cause of congenital hemolytic anemia, is caused by deficiency of the ery- throcyte membrane proteins. Five causative genes （ANK1, SPTB, SPTA1, SLC4AI, and EPB42） have...Hereditary spherocytosis （HS）, the most common cause of congenital hemolytic anemia, is caused by deficiency of the ery- throcyte membrane proteins. Five causative genes （ANK1, SPTB, SPTA1, SLC4AI, and EPB42） have been identified. To date, molecular genetic studies have been performed in different populations, including the American, European, Brazilian, Japanese and Korean populations, whereas only a few studies have been described in the Chinese population. Here, by reanalysis of the exome data, we revealed causative mutations and established a definitive diagnosis of HS in all 38 Chinese families. We found 34 novel mutations and four reported mutations in three known HS-causing genes--17 in ANK1, 17 in SPTB and four in SLC4A1, suggesting that ANK1 and SPTB are the major genes in Chinese patients with HS. All of the ANK1 or SPTB mutations, scattered throughout the entire genes, are non-recurrent; and most of them are null mutations, which might cause HS via a hap-loinsufficiency mechanism. De novo mutations in ANK1 or SPTB often occur with an unexpected high frequency （87.5% and 64.2%, respectively）. Our study updates our knowledge about the genetic profile of HS in Chinese and shows that family-based, especially parent-offspring trio, sequencing analysis can help to increase the diagnostic power and improve diagnostic efficiency.展开更多
The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes,including ...The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes,including cell cycle arrest,apoptosis,senescence,DNA repair,and metabolic regulation.In response to diverse stresses,p53 undergoes multiple posttranslational modifications(PTMs)that coordinate with intimate interdependencies to precisely modulate its diverse properties in given biological contexts.Notably,PTMs can recruit‘reader’proteins that exclusively recognize specific modifications and facilitate the functional readout of p53.Targeting PTM–reader interplay has been developing into a promising cancer therapeutic strategy.In this review,we summarize the advances in deciphering the‘PTM codes’of p53,focusing particularly on the mechanisms by which the specific reader proteins functionally decipher the information harbored within these PTMs of p53.We also highlight the potential applications of intervention with p53 PTM–reader interactions in cancer therapy and discuss perspectives on the‘PTMomic’study of p53 and other proteins.展开更多
Osteogenesis imperfecta （01）, also known as brittle bone disease or Lobstein syndrome, is characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractur...Osteogenesis imperfecta （01）, also known as brittle bone disease or Lobstein syndrome, is characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures. Based on clinical, genetic, and radiological features, Sillence et al. classified the OI into four subtypes including type I： Mild, common, with blue sclera; type Ⅱ： Perinatal lethal form; type Ⅲ： Severe and age-related progressive detbrmity, with normal sclera; and type Ⅳ： Moderate severity with normal sclera.展开更多
文摘The history of medical genetics is briefly reviewed. It is evident that medical genetics with its inseparable part, clinical genetics, started out as a cfinical science from the very beginning. Its robust development in the developed countries is the result of a close interaction between the basic sciences and clinical genetics. In China, however, clinical genetics has not received due emphasis and medical genetics is still not recognized as one of the medical specialties. This is in marked contrast to the situation in the West. It is high time to acknowledge that medical genetics is a medical specialty and to promote clinical genetics service in qualified hospitals in our country.
基金supported by the Sichuan Science and Technology Program(No.2022JDZH0029 to JYY)the Special Fund for Clinical Research and Translational Medicine from Chinese Academy of Medical Sciences(No.2022-I2M-C&T-B-117 to JYY)the Sichuan Key Research and Development Project from the Department of Science and Technology of Sichuan Province(No.2022YFS0237 to YMT).
文摘This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and further analysis identified seven novel mutants.The preponderance of variants was observed in exon 1 and exon 4,specifically within the nicotinamide adenine dinucleotide phosphate(NADPH)-binding region.Among the entire cohort,53 patients underwent initial surgery at Sichuan Provincial People’s Hospital(Chengdu,China).The external genitalia scores(EGS)of these participants varied from 2.0 to 11.0,with a mean of 6.8(standard deviation[s.d.]:2.5).Thirty patients consented to hormone testing.Their average testosterone-todihydrotestosterone(T/DHT)ratio was 49.3(s.d.:23.4).Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome;and their T/DHT ratios were below the diagnostic threshold.Furthermore,assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants.These mechanisms include interference with NADPH binding(c.356G>C,c.365A>G,c.492C>G,and c.662T>G)and destabilization of the protein structure(c.727C>T).The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts.Seven novel variations were identified,and the variant database for the SRD5A2 gene was expanded.These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:CIFMS,2021-I2M-1-024The Joint Fund for the Department of Science and Technology of Yunnan Province-Kunming Medical University,Grant/Award Number:202201AY070001-007+1 种基金Open Research Fund Project of Yunnan Provincial Key Laboratory of Pharmacology of Natural Medicines,Grant/Award Number:YKLPNP-G2403The Science and Technology Leading Talent Program of Yunnan Province,Grant/Award Number:202405AB350002。
文摘Background:Spinocerebellar ataxia type 2(SCA2)is a neurodegenerative disease marked by significant clinical and genetic heterogeneity,primarily caused by expanded CAG mutations in the ATXN2 gene.The unstable expansion of CAG repeats disrupts the genetic stability of animal models,which is detrimental to disease research.Methods:In this study,we established a mouse model in which CAG repeats do not undergo microsatellite instability(MSI)across generations.A humanized ATXN2 cDNA with four CAA interruptions within 73 CAG expansions was inserted into the Rosa26 locus of C57BL/6J mice.A 23 CAG control mouse model was also generated to verify ATXN2 integration and expression.Results:In our model,the number of CAG repeats remained stable during transmission,with no CAG repeat expansion observed in 64 parent-to-offspring transmissions.Compared with SCA2-Q23 mice,SCA2-Q73 mice exhibited progressive motor impairment,reduced Purkinje cell count and volume(indicative of cell atrophy),and muscle atrophy.These observations in the mice suggest that the behavioral and neuropathological phenotypes may reflect the features of SCA2 patients.RNA-seq analysis of the gastrocnemius muscle in SCA2-Q73 mice showed significant changes in muscle differentiation and development gene expression at 56 weeks,with no significant differences at 16 weeks compared to SCA2-Q23 mice.The expression level of the Myf6 gene significantly changed in the muscles of aged mice.Conclusion:In summary,the establishment of this model not only provides a stable animal model for studying CAG transmission in SCA2 but also indicates that the lack of long-term neural stimulation leads to muscle atrophy.
文摘The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease （IBD） are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/ or barrier function, with onset triggered by environmental stimuli. These factors and their interactions may also be important determinants of disease phenotype and disease progression. The emergence of immunogenetic phenotypes lends support to the proposed hypothesis that susceptibility genes regulate distinct immune processes, driven by luminal antigens, expressed as specific immune phenotypes which in turn influence clinical phenotypes in IBD patient.
文摘Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences(mostly microsatellites) that become unstable beyond a critical length whentransmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells(diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.
文摘Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In recent years, several genome-wide single-nucleotide polymorphism （SNP） association studies （GWAS） have been performed on azoospermia and/or oligozoospermia in different populations including two GWAS on nonobstructive azoospermia in China; however, the association of SNPs with idiopathic male infertility, especially asthenozoospermia and oligozoospermia, and their correlation with semen parameters are still not clear. To investigate genetic variants associated with idiopathic male infertility （asthenozoospermia, oligozoospermia, and oligoasthenozoospermia） in Chinese Han people, 20 candidate SNPs were selected from GWAS results and genotyped using the Sequenom MassARRAY assay. A total of 136 subfertile men and 456 healthy fertile men were recruited, rs6476866 in SLCIA1 （P = 1.919E-4, OR = 0.5905, 95% Ch 0.447-0.78） and rs10129954 in DPF3 （P = 0.0023, OR = 2.199, 95% Ch 1.311-3.689） were strongly associated with idiopathic male infertility. In addition, positive associations were observed between asthenozoospermia and rs215702 in LSM5 （P= 0.0016, OR = 1.479, 95% CI： 1.075-2.033） and between oligoasthenozoospermia and rs2477686 in PEXIO （P= 0.0011, OR = 2.935, 95% Ch 1.492-5.775）. In addition, six SNPs （rs215702 in LSMS, rs6476866 in SLCIA1, rs10129954 in DPF3, rs1801133 in MTHFR, rs2477686 in PEXIO, and rs10841496 in PED3A） were significantly correlated with semen quality alterations. Our results suggest that idiopathic male infertility in different ethnic groups may share the same mechanism or pathway. Cohort expansion and further mechanistic studies on the role of genetic factors that influence spermatogenesis and sperm progressive motility are suggested.
基金Project supported by the Program for New Century Excellent Talents of the Ministry of Education,China (No. NECT-10-0687)the Fun-damental Research Funds for the Central University (No. 2011jdgz20)the Shaanxi Provincial Science and Technology Research and Development Project Fund (No. 2012K16-08-01),China
文摘We studied the allelic frequency distributions and statistical forensic parameters of 21 new short tandem repeat(STR)loci and the amelogenin locus,which are not included in the combined DNA index system(CODIS),in a Russian ethnic minority group from the Inner Mongolia Autonomous Region,China.A total of 114 bloodstain samples from unrelated individuals were extracted and co-amplified with four fluorescence-labeled primers in a multiplex polymerase chain reaction(PCR)system.Using capillary electrophoresis,the PCR products of the 21 STR loci were separated and genotyped.A total of 161 alleles were observed in the Russian ethnic minority group,and corresponding allelic frequencies ranged from 0.0044 to 0.5965.The 21 non-CODIS STR loci of the Russian ethnic minority group were characterized by high genetic diversity and therefore may be useful for elucidating the population's genetic background,for individual identification,and for paternity testing in forensic practice.
文摘Several studies have reported a relationship between the length of the CAG-repeat in the polymerase y （POLG） gene and male infertility. However, other studies have not reproduced this result. In our study, the POLG-CAG-repeat length was analyzed in 535 healthy individuals from six Chinese Han populations living in different provinces. The frequencies of IO-CAG alleles and genotypes were high （97.38 and 94.13%, respectively）, with no significant difference among the six Chinese Han populations. Furthermore, we determined the distribution of the POLG-CAG-repeat in 150 infertile men and 126 fertile men. Our study suggested that the distributions of POLG-CAG-repeat alleles and genotypes were not significantly different between infertile （95.67 and 92.67%, respectively） and fertile men （97.22 and 94.44%, respectively）. In a subsequent meta-analysis, combining our data with data from previous studies, a comparison of the CAG-repeat alleles in fertile versus infertile men showed no obvious risk for male infertility associated with any particular allele （pooled odds ratio （0R）=0.94; 95% confidence interval （CI）： 0.60-1.48）. The significance level was not attained with any of the following genetic models： homozygote comparison （not lO/not 10 versus 10110： OR= 1.34; 95% Ch 0.66-2.72）, heterozygote comparison （lO/not 10 versus 10/10： OR= 1.04; 95% Ch 0.78-1.38）, dominant model comparison （not lO/not 10＋ 101 not 10 versus 10110. OR= 1.08; 95% Ch 0.79-1.47） and recessive genetic comparison （not lO/not 10 versus lO/not 10＋ 10/10- OR= 1.31; 95% Ch 0.68-2.55）. In conclusion, there is no significant difference of the frequencies of POLG-CAG-repeat variants among six Chinese Han populations, and this polymorphism may not be associated with Chinese male infertility. On the basis of a meta-analysis, there is no obvious association between CAG-repeat variants of the POLG gene and male infertility.
文摘Juvenile X-linked retinoschisis（XLRS, MIM#312700） belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography（SD-OCT） images. The mean central foveal thickness was 569.7 μm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio（〈1.0） in all patients. RS1（NM_000330.3） gene coding exons Sanger sequencing was performed. RS1 c.599 G〉T（p.R200 L） mutation was detected in one case, showing to be pathogenic in silico analysis. c.（92_97） ins C（p.W33 fs） mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422 C〉G（p.R141 H）, HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.
基金National Key Research and Development Program of China,Grant/Award Number:2016YFA0100103CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2016-I2M-3-002
文摘A Chinese scientist, Jiankui He, and his creation of the world ' s first genetically altered baby made headlines recently. As a newly developed gene-editing technique, the CRISPR/Cas system should not be applied to human beings for reproductive purposes until it has been extensively tested. However, numerous experimental research studies in human somatic, germline cells, and even in embryos, have been conducted, which have shown CRISPR/Cas to be a useful tool for human genome editing and a potential therapeutic method for future clinical use.
基金funded in part by the National Nature Science Foundation of China(81771013,81822011,and 81570914)Science and Technology Commission of Shanghai Municipality(17ZR1448600 and 18410712400)the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health in the United States(R03DC013866 and R01DC015052)
文摘Conductive hearing loss is the impairment in the mechanical transduction of sound wave through the external ear and the middle ear.Although most cases are sporadic due to acquired causes such as infections(otitis media and otitis externa),cerumen obstruction,and injuries,congenital structural defects are uncommon for significant etiologies to recognize.Stapes ankylosis is characterized by conductive hearing loss.It may be difficult to differentiate from otosclerosis,the most common cause of progressive conductive hearing loss,by audiologic evaluation,when the diagnosis is delayed.Skeletal anomalies may be subtle,such that the syndrome may not be recognized(Brown et al.,2002).
基金supported by the National Natural Science Foundation of China(No.30400264)the Natural Science Foundation of Yunnan Province,China(No.2008ZC068M)the Chinese National High Technology Research and Development Program(No.2012AA021802)
文摘The ataxin-2 （ATXN2） gene is located on human chromo-some 12q24.1. In normal individuals, the coding region in exon 1 of this gene has fewer than 31 CAG repeats （Yu et al., 2005： Laffita-Mesa et al., 2012）. However, an abnormal expansion of CAG trinucleotide repeats results in the aggre-gation of polyglutamine （polyQ）, which causes spinocer-ebellar ataxia type 2 （SCA2） （Pulst et al., 1996）. The expanded alleles have more than 32 repeats in the affected individuals, and generally there is an inverse correlation between CAG repeat length and age of onset （Pulst et al., 1996）. SCA2 is an autosomal dominant inheritance neurodegenerative disease, whose major clinical feature is progressive cerebellar ataxia. Atrophies of the brainstem and frontal lobe have been frequently detected by magnetic resonance imaging （MRI） （Yamamoto-Watanabe et al., 2010）. This disease has the strong effect on sensory and motor control.
基金funded in part by the Beijing Natural Science Foundation(JQ20032 to N.W.and to 7191007 to Z.W.)National Natural Science Foundation of China(81822030 and 82072391 to N.W.,81772299and 81930068 to Z.W.,81772301 and 81972132 to G.Q.,81672123and 81972037 to J.Z.)+7 种基金Capital's Funds for Health Improvement and Research(2020-4-40114 to N.W.)Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research ProgramNational Key Research and Development Program of China(2018YFC0910500 to N.W.and Z.W.,2016YFC0901501 to S.Z.)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(3332019052 to Y.M.)the CAMS Initiative Fund for Medical Sciences(2016-I2M-3-003 to G.Q.and N.W.,2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT320025 to N.W.)sponsored by GeneScience Pharmaceuticals Co.,Ltd.(Changchun,China)funded by the United States National Institutes of Health(UM1HG006542 and K08 HG008986)。
文摘Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
基金supported by grants from the National Key Research and Development Program of China(2022YFC2703700 and 2022YFC2703900)National Natural Science Foundation of China(30871367)CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-018 and CIFMS 2021-I2M-1-051).
文摘Syndactyly type V (SDTY5) is an autosomal dominant extremity malformation characterized by fusion of the fourth and fifthmetacarpals. In the previous publication, we first identified a heterozygous missense mutation Q50R in homeobox domain (HD) ofHOXD13 in a large Chinese family with SDTY5. In order to substantiate the pathogenicity of the variant and elucidate the underlyingpathogenic mechanism causing limb malformation, transcription-activator-like effector nucleases (TALEN) was employed togenerate a Hoxd13Q50R mutant mouse. The mutant mice exhibited obvious limb malformations including slight brachydactyly andpartial syndactyly between digits 2-4 in the heterozygotes, and severe syndactyly, brachydactyly and polydactyly in homozygotes.Focusing on BMP2 and SHH/GREM1/AER-FGF epithelial mesenchymal (e-m) feedback, a crucial signal pathway for limbdevelopment, we found the ectopically expressed Shh, Grem1 and Fgf8 and down-regulated Bmp2 in the embryonic limb bud atE10.5 to E12.5. A transcriptome sequencing analysis was conducted on limb buds (LBs) at E11.5, revealing 31 genes that exhibitednotable disparities in mRNA level between the Hoxd13Q50R homozygotes and the wild-type. These genes are known to be involvedin various processes such as limb development, cell proliferation, migration, and apoptosis. Our findings indicate that the ectopicexpression of Shh and Fgf8, in conjunction with the down-regulation of Bmp2, results in a failure of patterning along both theanterior-posterior and proximal-distal axes, as well as a decrease in interdigital programmed cell death (PCD). This cascadeultimately leads to the development of syndactyly and brachydactyly in heterozygous mice, and severe limb malformations inhomozygous mice. These findings suggest that abnormal expression of SHH, FGF8, and BMP2 induced by HOXD13Q50R may beresponsible for the manifestation of human SDTY5.
文摘Background: Febrile seizures (FSs) are the most common form of childhood seizures, and genetic factors play a role in susceptibility to FS. Objective: To identify novel loci and genes associated with susceptibility to FS. Methods: Study participants were the FS probands and family members of 59 Japanese nuclear families (223 members including 112 affected children). Forty- eight of these families had at least two affected children for which genome- wide linkage screening was carried out. The Genehunter software was used to perform nonparametric multipoint linkage analysis. Mutational and association analyses were conducted in all 59 Japanese FS families. Results: Genotyping data of 407 microsatellite markers suggested linkage of FSs to chromosome 18p11.2 (non- parametric linkage score = 3.68, p = 0.0001). This region includes the IMPA2 gene, which encodes myo- inositol monophosphatase (IMPase) 2. In the phosphatidylinositol- signaling pathway, IMPase is inhibited by lithium, which has a proconvulsant effect, and is stimulated by carbamazepine, an anticonvulsant. A systematic search was performed for mutations in IMPA2 in 24 unrelated randomly selected Japanese FS patients; seven variants were detected. Haplotype analysis revealed an association of a common haplotype in IMPA2 with FSs (p = 0.0009). Conclusion: The authors found a novel locus on chromosome 18p11.2 for febrile seizures (FSs). IMPA2 is likely to be an FS susceptibility gene.
基金funding agency in the public,commercial,or not-for-profit sectors.
文摘Background:The liver is fundamental for keeping up the entire body’s homeostasis.The liver hepatocytes have been shown to undergo genomic instability with aging.The stability of the hepatocytes depends on its nuclear architecture.Calorie restriction has been shown to extend life-span favorably and this may be through the reorganization of the nuclear structure.Objective:To study the effect of cyclic feeding regime on the chromatin assembly anchored to the nuclear membrane scaffold of rat models hepatocytes nuclei.Method:Rats models underwent cyclic feeding regime,after which nuclei were isolated;then,we investigated the chromatin decondensation and nuclear membrane disintegration of the hepatocytes using fluorescence imaging methods.Results:In 60 seconds,protease decondensed the chromatin and disintegrated the nuclear membrane structure of controls.After the first fasting,the time increased to 145 seconds in 3-month-old rats.The first refeeding increased the time to 156 seconds with a further rise to 340 seconds following the second fasting,then dropped to 116 seconds by the second refeeding.20 months old rats showed 186 seconds increase in the time of chromatin decondensation and nuclear membrane disintegration after the first fasting,with a decrease to 140 seconds observed after first refeeding.The second fasting increased the time to 165 seconds,which then slightly decreased to 163 seconds after the second refeeding.Conclusion:These results show that intermittent fasting may have acted on chromatin histone interactions and the structural lamin networks of the nuclear membranes in bringing about nuclear stability,which is essential for normal cellular function.
文摘Aim:To study a possible defect in spermatogenesis of Fragile X syndrome(FXS)patients.Methods:Two different polymerase chain reaction(PCR)based methods were used for the molecular diagnosis of FXS.Sperm collection was done mostly according to the laboratory manual of the World Health Organization.Results:We failed to collect sperm samples from five Fragile X subjects aged 18-60 years as a result of an unexpected erectile dysfunction(ED). Multiple examinations of the same subject at different times,and of different subjects from different provinces by different physicians,showed the same result consistently in all five subjects examined.Conclusion:Erectile reflex is an instinctive response in all healthy males.The absence of erection can be caused by hormonal,physical or neuronal malfunction.As hormonal profiles were reported to be generally normal in Fragile X men,we propose that an unknown physical factor or the neuronal circuit,or both,underlying the erection is compromised.The finding of ED in Fragile X patients may help better understand the clinical spectrum and pathogenesis of the disease.(Asian J Androl 2006 Jul;8:483-487)
基金supported by the National Key Research and Development Program of China (2016YFC0905100)the CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002)+3 种基金the National Natural Science Foundation of China (NSFC) (81230015)the Beijing Municipal Science and Technology Commission (Z151100003915078)the Medical Science and Technology Research Projects of Henan Provincial Health Bureau (201601019)the Scientific and Technological Projects of the Technology Bureau of Henan Provincial Technology (172102410010)
文摘Hereditary spherocytosis （HS）, the most common cause of congenital hemolytic anemia, is caused by deficiency of the ery- throcyte membrane proteins. Five causative genes （ANK1, SPTB, SPTA1, SLC4AI, and EPB42） have been identified. To date, molecular genetic studies have been performed in different populations, including the American, European, Brazilian, Japanese and Korean populations, whereas only a few studies have been described in the Chinese population. Here, by reanalysis of the exome data, we revealed causative mutations and established a definitive diagnosis of HS in all 38 Chinese families. We found 34 novel mutations and four reported mutations in three known HS-causing genes--17 in ANK1, 17 in SPTB and four in SLC4A1, suggesting that ANK1 and SPTB are the major genes in Chinese patients with HS. All of the ANK1 or SPTB mutations, scattered throughout the entire genes, are non-recurrent; and most of them are null mutations, which might cause HS via a hap-loinsufficiency mechanism. De novo mutations in ANK1 or SPTB often occur with an unexpected high frequency （87.5% and 64.2%, respectively）. Our study updates our knowledge about the genetic profile of HS in Chinese and shows that family-based, especially parent-offspring trio, sequencing analysis can help to increase the diagnostic power and improve diagnostic efficiency.
基金This work was supported by the National Key R&D Program of China(2019YFC1005200 and 2019YFC1005201)the National Natural Science Foundation of China(81872311 and 82073132)+1 种基金the Beijing Municipal Natural Science Foundation(7192126)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2017-I2M-1-008 and 2018-I2M-1-002).
文摘The genome guardian p53 functions as a transcription factor that senses numerous cellular stresses and orchestrates the corresponding transcriptional events involved in determining various cellular outcomes,including cell cycle arrest,apoptosis,senescence,DNA repair,and metabolic regulation.In response to diverse stresses,p53 undergoes multiple posttranslational modifications(PTMs)that coordinate with intimate interdependencies to precisely modulate its diverse properties in given biological contexts.Notably,PTMs can recruit‘reader’proteins that exclusively recognize specific modifications and facilitate the functional readout of p53.Targeting PTM–reader interplay has been developing into a promising cancer therapeutic strategy.In this review,we summarize the advances in deciphering the‘PTM codes’of p53,focusing particularly on the mechanisms by which the specific reader proteins functionally decipher the information harbored within these PTMs of p53.We also highlight the potential applications of intervention with p53 PTM–reader interactions in cancer therapy and discuss perspectives on the‘PTMomic’study of p53 and other proteins.
文摘Osteogenesis imperfecta （01）, also known as brittle bone disease or Lobstein syndrome, is characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures. Based on clinical, genetic, and radiological features, Sillence et al. classified the OI into four subtypes including type I： Mild, common, with blue sclera; type Ⅱ： Perinatal lethal form; type Ⅲ： Severe and age-related progressive detbrmity, with normal sclera; and type Ⅳ： Moderate severity with normal sclera.
