尼曼-匹克病C型(Niemann-Pick disease type C,NPC)是常染色体隐性遗传的罕见病,以肝脾肿大和神经系统功能障碍为主要表现。本文报告1例35岁女性患者,因“渐进性双手抖动、动作笨拙23年,精神异常14年”就诊。患者12岁起病,因检查提示铜...尼曼-匹克病C型(Niemann-Pick disease type C,NPC)是常染色体隐性遗传的罕见病,以肝脾肿大和神经系统功能障碍为主要表现。本文报告1例35岁女性患者,因“渐进性双手抖动、动作笨拙23年,精神异常14年”就诊。患者12岁起病,因检查提示铜代谢指标异常及脾肿大被误诊为肝豆状核变性,口服青霉胺及苯海索症状改善。至21岁时出现精神异常,予以青霉胺与利培酮治疗后症状控制。本次入院发现患者虽有神经精神症状、脾大及铜生化异常,但始终未见角膜色素环,颅脑MRI亦缺乏特征性改变,最终经基因检测及骨髓细胞学检查确诊为NPC。口服麦格司他胶囊及利培酮,随访1年病情稳定。本病例提示,对于以神经精神症状起病并伴有脾肿大的患者,需高度警惕NPC的可能,避免误诊。展开更多
Wolfram syndrome(WS)is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness(often referred to as DIDMOAD),and overall severe neu...Wolfram syndrome(WS)is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness(often referred to as DIDMOAD),and overall severe neurodegenerative fallback.The global prevalence of this disease is estimated at 1 in 770,000(Lee et al.,2023).It is most commonly caused by biallelic(point)mutations in the Wolframin endoplasmic reticulum(ER)transmembrane glycoprotein(WFS1)gene(in case of WS type 1),but mutations in the CDGSH Iron Sulfur Domain 2(CISD2)are also linked to WS(type 2).The latter,however,often present with less severe pathological manifestations(Lee et al.,2023).WFS1 is located on chromosome 4p16.1 and spans over 33 kilobases.Many mutation variants have been identified in WFS1,encompassing missense,nonsense,and frameshift mutations.These mutations are spread across the coding region of WFS1,but certain regions,such as exon 8,the largest exon,appear particularly mutation-prone and associated with the classical WS type 1 phenotype(Lee et al.,2023).展开更多
Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.Ho...Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.展开更多
AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
Hereditary hemochromatosis (HH) is defined as an autosomal recessive iron metabolism disorder, typically characterized by excessive iron absorption leading to iron overload in multiple organs, particularly the liver, ...Hereditary hemochromatosis (HH) is defined as an autosomal recessive iron metabolism disorder, typically characterized by excessive iron absorption leading to iron overload in multiple organs, particularly the liver, heart, and endocrine glands. Clinical manifestations commonly include diabetes, skin pigmentation, cirrhosis, abdominal pain, arthralgia, and fatigue. Mutations in the HFEgene, located on chromosome 6p22, have been identified as the primary genetic basis of HH. This gene encodes a protein critical for iron absorption and metabolism. Studies indicate that HH is most prevalent in European populations but rare in Asians. Due to reduced iron accumulation from menstrual blood loss in females, the disease predominantly affects adult males, with females often developing symptoms post-menopause. This article reports a rare case of HHin a premenopausal Chinese female caused by a homozygous HFE gene mutation (c.340 + 4T > C). The patient presented with chronic fatigue, abdominal pain, and lower limb petechiae. Diagnosis was confirmed via clinical evaluation, laboratory tests, and genetic analysis. This study identifies a novel pathogenic mutation in the Chinese population, contributing to early diagnosis and treatment of HH.展开更多
文摘尼曼-匹克病C型(Niemann-Pick disease type C,NPC)是常染色体隐性遗传的罕见病,以肝脾肿大和神经系统功能障碍为主要表现。本文报告1例35岁女性患者,因“渐进性双手抖动、动作笨拙23年,精神异常14年”就诊。患者12岁起病,因检查提示铜代谢指标异常及脾肿大被误诊为肝豆状核变性,口服青霉胺及苯海索症状改善。至21岁时出现精神异常,予以青霉胺与利培酮治疗后症状控制。本次入院发现患者虽有神经精神症状、脾大及铜生化异常,但始终未见角膜色素环,颅脑MRI亦缺乏特征性改变,最终经基因检测及骨髓细胞学检查确诊为NPC。口服麦格司他胶囊及利培酮,随访1年病情稳定。本病例提示,对于以神经精神症状起病并伴有脾肿大的患者,需高度警惕NPC的可能,避免误诊。
基金Research into Wolfram syndrome in the De Groef team has been supported by the Eye Hope Foundation(Belgium),Wolfram UK(UK)and The Snow Foundation(USA).
文摘Wolfram syndrome(WS)is a rare autosomal rece s s i ve disease characte r i zed by the development of diabetes insipidus,diabetes mellitus,optic atrophy,and deafness(often referred to as DIDMOAD),and overall severe neurodegenerative fallback.The global prevalence of this disease is estimated at 1 in 770,000(Lee et al.,2023).It is most commonly caused by biallelic(point)mutations in the Wolframin endoplasmic reticulum(ER)transmembrane glycoprotein(WFS1)gene(in case of WS type 1),but mutations in the CDGSH Iron Sulfur Domain 2(CISD2)are also linked to WS(type 2).The latter,however,often present with less severe pathological manifestations(Lee et al.,2023).WFS1 is located on chromosome 4p16.1 and spans over 33 kilobases.Many mutation variants have been identified in WFS1,encompassing missense,nonsense,and frameshift mutations.These mutations are spread across the coding region of WFS1,but certain regions,such as exon 8,the largest exon,appear particularly mutation-prone and associated with the classical WS type 1 phenotype(Lee et al.,2023).
基金supported by the Fundamental Research Funds for the Central Universities(226-2022-00035)the National Natural Science Foundation of China(81600986).
文摘Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
文摘Hereditary hemochromatosis (HH) is defined as an autosomal recessive iron metabolism disorder, typically characterized by excessive iron absorption leading to iron overload in multiple organs, particularly the liver, heart, and endocrine glands. Clinical manifestations commonly include diabetes, skin pigmentation, cirrhosis, abdominal pain, arthralgia, and fatigue. Mutations in the HFEgene, located on chromosome 6p22, have been identified as the primary genetic basis of HH. This gene encodes a protein critical for iron absorption and metabolism. Studies indicate that HH is most prevalent in European populations but rare in Asians. Due to reduced iron accumulation from menstrual blood loss in females, the disease predominantly affects adult males, with females often developing symptoms post-menopause. This article reports a rare case of HHin a premenopausal Chinese female caused by a homozygous HFE gene mutation (c.340 + 4T > C). The patient presented with chronic fatigue, abdominal pain, and lower limb petechiae. Diagnosis was confirmed via clinical evaluation, laboratory tests, and genetic analysis. This study identifies a novel pathogenic mutation in the Chinese population, contributing to early diagnosis and treatment of HH.
