BACKGROUND Although numerous single nucleotide polymorphism in multiple genes involve in the risk of type 2 diabetes mellitus(T2D),the single gene defects of T2D with strong family history is not clear yet.SPTLC1 are ...BACKGROUND Although numerous single nucleotide polymorphism in multiple genes involve in the risk of type 2 diabetes mellitus(T2D),the single gene defects of T2D with strong family history is not clear yet.SPTLC1 are causative for hereditary sensory and autonomic neuropathy,which is clinical overlapping with diabetic peripheral neuropathy.Mice with adipocyte-specific deletion of SPTLC1 had impaired glucose tolerances and insulin sensitivity.Thus,it is necessary to investigate the SPTLC1 mutations in adult-onset T2D with strong family history.AIM To analyze the role of SPTLC1 mutation on adult-onset T2D with strong family history.METHODS By whole-exome sequence analysis of a patient with T2D and his family members,an uncertain variant in SPTLC1 was identified.Bioinformation analysis was used to evaluate the influence of mutation,rare variant gene-level associations for SPTLC1 in T2D,and the relationship between SPTLC1 mRNA and T2D in human islets from GSE25724.The effect of G371R of SPTLC1 on the characteristics of inflammatory cytokines and apoptosis was also tested on human embryonic kidney(HEK)293 cells.RESULTS A single nucleotide variation in SPTLC1(c.1111G>A:p.G371R)was identified in a family with T2D.The deleterious variant was predicted by functional analysis through hidden Markov models and mendelian clinically applicable pathogenicity software.This pathogenicity might be derived from the different amino acid properties.In HEK 293T cells,p.G371R of SPTLC1 induced the expression of tumor necrosis factor-αand the percent of apoptosis.Meanwhile,rare variant gene-level associations for SPTLC1 also refer to the high risk of T2D(the overall odds ratio=2.4968,P=0.0164).Data from GSE25724 showed that SPTLC1 mRNA was lower in pancreatic islets from T2D human islets(P=0.046),and was as sociated with the decreased level of insulin mRNA expression(Spearman r=0.615,P=0.025).CONCLUSION The study classified SPTLC1 p.G371R mutation as the likely pathogenic mutation from an adult-onset T2D patients with strong family history T2D.展开更多
目的研究人源血清类粘蛋白1(orosomucoid 1,ORM1)通过丝氨酸棕榈酰转移酶长链碱基亚基1(serine palmitoyltransferase long chain base subunit 1,SPTLC1)对干眼症鞘脂代谢的影响,为干眼症的发病机制提供新的研究方向。方法通过皮下注...目的研究人源血清类粘蛋白1(orosomucoid 1,ORM1)通过丝氨酸棕榈酰转移酶长链碱基亚基1(serine palmitoyltransferase long chain base subunit 1,SPTLC1)对干眼症鞘脂代谢的影响,为干眼症的发病机制提供新的研究方向。方法通过皮下注射氢溴酸东莨菪碱构建干眼症模型,通过晶状体注射腺相关病毒过表达ORM1。行泪液分泌量检测,杯状细胞检测,角膜荧光素染色,泪膜破裂时间检测,HE检测评估角膜结膜损伤,泪液质量,以及组织病理变化。通过生化试剂盒检测神经酰胺和鞘磷脂含量,通过qPCR和WB检测ORM1和SPTLC1的表达。结果(1)ORM1可增加干眼症模型的泪液分泌(P<0.0001);(2)ORM1可增加干眼症模型的眼表泪膜稳定性(P<0.001);(3)ORM1可改善干眼症模型的角膜上皮损伤(P<0.0001);(4)ORM1可增加干眼症模型的角膜组织中杯状细胞数量(P<0.001);(5)过表达ORM1后,角膜组织上皮层变厚,基底层细胞排列较为紧密,细胞层数变多,空泡减少;(6)ORM1可抑制干眼症模型的炎症基因表达(P<0.01);(7)ORM1可促进总神经酰胺和鞘磷脂含量(P<0.01);(8)ORM1可促进SPTLC1的mRNA和蛋白表达(P<0.001)。结论ORM1可通过调控SPTLC1参与调控干眼症鞘脂代谢,为探讨干眼症的发生发展机制和寻找有效且安全的治疗方案提供新的视角。展开更多
Hereditary sensory neuropathy type I is an autosomal dominant disorder that affects the sensory neurons. Three missense mutations in serine palmitoyltransferase long chain subunit 1 cause hereditary sensory neuropathy...Hereditary sensory neuropathy type I is an autosomal dominant disorder that affects the sensory neurons. Three missense mutations in serine palmitoyltransferase long chain subunit 1 cause hereditary sensory neuropathy type I. The endoplasmic reticulum, where the serine palmitoyltransferase long chain subunit 1 protein resides, and mitochondria are both altered in hereditary sensory neuropathy type I mutant cells. Employing a transfected neuronal cell line (ND15), we have identified and confirmed altered protein expression levels of ubiquinol cytochrome C, Hypoxia Up regulated Protein 1, Chloride Intracellular Channel Protein 1, Ubiqutin-40s Ribosomal Protein S27a, and Coactosin. Additionally, further 14 new proteins that exhibited altered expression within V144D, C133W and C133Y mutants were identified. These data have shown that mutations in SPTLC1 alter the expression of a set of proteins that may help to establish a causal link between the mitochondria and ER and the “dying back” process of dorsal root ganglion neurons that occurs in HSN-I.展开更多
Background: The variable clinical features of hereditary sensory and autonomi c neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory ne uropathy could be caused by missense mutations of SPTLC1 a...Background: The variable clinical features of hereditary sensory and autonomi c neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory ne uropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be rec ognised as familial. Objective: To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7. Patients: DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients w ith idiopathic sensory neuropathy were also screened for known mutations of thes e genes. Results: Of the 25 kindreds, only one had a mutation (SPTLC1 399T→ G). This kindred, and 10 without identified mutations, had prominent mutilating foo t injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity w ith injuries but no weakness, one had restless legs and burning feet, and one ha d dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neur opathy. Conclusions: Adult onset HSAN I is clinically and genetically heterogene ous and further work is required to identify additional genetic causes. Known SP TLC1 or RAB7 mutations were not found in idiopathic sensory neuropathy.展开更多
Background: Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS....Background: Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS. SPTLC1 was recently identified as a disease-causative gene for JALS, which has rarely been reported in Asian populations. Little is known regarding the difference in clinical features between JALS patients carrying FUS and SPTLC1 mutations. This study aimed to screen mutations in JALS patients and to compare the clinical features between JALS patients with FUS and SPTLC1 mutations. Methods: Sixteen JALS patients were enrolled, including three newly recruited patients between July 2015 and August 2018 from the Second Affiliated Hospital, Zhejiang University School of Medicine. Mutations were screened by whole-exome sequencing. In addition, clinical features such as AAO, onset site and disease duration were extracted and compared between JALS patients carrying FUS and SPTLC1 mutations through a literature review. Results: A novel and de novo SPTLC1 mutation (c.58G>A, p.A20T) was identified in a sporadic patient. Among 16 JALS patients, 7/16 carried FUS mutations and 5/16 carried respective SPTLC1 , SETX , NEFH , DCTN1 , and TARDBP mutations. Compared with FUS mutation patients, those with SPTLC1 mutations had an earlier AAO (7.9 ± 4.6 years vs. 18.1 ± 3.9 years, P < 0.01), much longer disease duration (512.0 [416.7-607.3] months vs. 33.4 [21.6-45.1] months, P < 0.01), and no onset of bulbar. Conclusion: Our findings expand the genetic and phenotypic spectrum of JALS and help to better understand the genotype-phenotype correlation of JALS.展开更多
文摘BACKGROUND Although numerous single nucleotide polymorphism in multiple genes involve in the risk of type 2 diabetes mellitus(T2D),the single gene defects of T2D with strong family history is not clear yet.SPTLC1 are causative for hereditary sensory and autonomic neuropathy,which is clinical overlapping with diabetic peripheral neuropathy.Mice with adipocyte-specific deletion of SPTLC1 had impaired glucose tolerances and insulin sensitivity.Thus,it is necessary to investigate the SPTLC1 mutations in adult-onset T2D with strong family history.AIM To analyze the role of SPTLC1 mutation on adult-onset T2D with strong family history.METHODS By whole-exome sequence analysis of a patient with T2D and his family members,an uncertain variant in SPTLC1 was identified.Bioinformation analysis was used to evaluate the influence of mutation,rare variant gene-level associations for SPTLC1 in T2D,and the relationship between SPTLC1 mRNA and T2D in human islets from GSE25724.The effect of G371R of SPTLC1 on the characteristics of inflammatory cytokines and apoptosis was also tested on human embryonic kidney(HEK)293 cells.RESULTS A single nucleotide variation in SPTLC1(c.1111G>A:p.G371R)was identified in a family with T2D.The deleterious variant was predicted by functional analysis through hidden Markov models and mendelian clinically applicable pathogenicity software.This pathogenicity might be derived from the different amino acid properties.In HEK 293T cells,p.G371R of SPTLC1 induced the expression of tumor necrosis factor-αand the percent of apoptosis.Meanwhile,rare variant gene-level associations for SPTLC1 also refer to the high risk of T2D(the overall odds ratio=2.4968,P=0.0164).Data from GSE25724 showed that SPTLC1 mRNA was lower in pancreatic islets from T2D human islets(P=0.046),and was as sociated with the decreased level of insulin mRNA expression(Spearman r=0.615,P=0.025).CONCLUSION The study classified SPTLC1 p.G371R mutation as the likely pathogenic mutation from an adult-onset T2D patients with strong family history T2D.
文摘目的研究人源血清类粘蛋白1(orosomucoid 1,ORM1)通过丝氨酸棕榈酰转移酶长链碱基亚基1(serine palmitoyltransferase long chain base subunit 1,SPTLC1)对干眼症鞘脂代谢的影响,为干眼症的发病机制提供新的研究方向。方法通过皮下注射氢溴酸东莨菪碱构建干眼症模型,通过晶状体注射腺相关病毒过表达ORM1。行泪液分泌量检测,杯状细胞检测,角膜荧光素染色,泪膜破裂时间检测,HE检测评估角膜结膜损伤,泪液质量,以及组织病理变化。通过生化试剂盒检测神经酰胺和鞘磷脂含量,通过qPCR和WB检测ORM1和SPTLC1的表达。结果(1)ORM1可增加干眼症模型的泪液分泌(P<0.0001);(2)ORM1可增加干眼症模型的眼表泪膜稳定性(P<0.001);(3)ORM1可改善干眼症模型的角膜上皮损伤(P<0.0001);(4)ORM1可增加干眼症模型的角膜组织中杯状细胞数量(P<0.001);(5)过表达ORM1后,角膜组织上皮层变厚,基底层细胞排列较为紧密,细胞层数变多,空泡减少;(6)ORM1可抑制干眼症模型的炎症基因表达(P<0.01);(7)ORM1可促进总神经酰胺和鞘磷脂含量(P<0.01);(8)ORM1可促进SPTLC1的mRNA和蛋白表达(P<0.001)。结论ORM1可通过调控SPTLC1参与调控干眼症鞘脂代谢,为探讨干眼症的发生发展机制和寻找有效且安全的治疗方案提供新的视角。
文摘遗传性感觉自主神经病(hereditary sensory autonomic neuropathy,HSAN),是一组以感觉障碍为主的遗传性周围神经病,具有临床及遗传异质性。临床表现为四肢对称性感觉减退、肌无力和肌肉萎缩,伴有自主神经功能障碍[1-2]。遗传性感觉自主神经病1型(HSAN1)是一种罕见的常染色体显性遗传病,为HSAN最常见的类型,主要表现为肢体远端感觉功能障碍[3-4]。本文探讨一例SPTLC1(serine palmitoyltransferase long chain base subunit 1)基因突变所致HSAN1的临床、病理、电生理和遗传学特点,给予L-丝氨酸口服及足部正畸治疗随访观察,对其基因突变进行分析。
文摘Hereditary sensory neuropathy type I is an autosomal dominant disorder that affects the sensory neurons. Three missense mutations in serine palmitoyltransferase long chain subunit 1 cause hereditary sensory neuropathy type I. The endoplasmic reticulum, where the serine palmitoyltransferase long chain subunit 1 protein resides, and mitochondria are both altered in hereditary sensory neuropathy type I mutant cells. Employing a transfected neuronal cell line (ND15), we have identified and confirmed altered protein expression levels of ubiquinol cytochrome C, Hypoxia Up regulated Protein 1, Chloride Intracellular Channel Protein 1, Ubiqutin-40s Ribosomal Protein S27a, and Coactosin. Additionally, further 14 new proteins that exhibited altered expression within V144D, C133W and C133Y mutants were identified. These data have shown that mutations in SPTLC1 alter the expression of a set of proteins that may help to establish a causal link between the mitochondria and ER and the “dying back” process of dorsal root ganglion neurons that occurs in HSN-I.
文摘Background: The variable clinical features of hereditary sensory and autonomi c neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory ne uropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be rec ognised as familial. Objective: To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7. Patients: DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients w ith idiopathic sensory neuropathy were also screened for known mutations of thes e genes. Results: Of the 25 kindreds, only one had a mutation (SPTLC1 399T→ G). This kindred, and 10 without identified mutations, had prominent mutilating foo t injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity w ith injuries but no weakness, one had restless legs and burning feet, and one ha d dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neur opathy. Conclusions: Adult onset HSAN I is clinically and genetically heterogene ous and further work is required to identify additional genetic causes. Known SP TLC1 or RAB7 mutations were not found in idiopathic sensory neuropathy.
基金supported by the National Natural Science Foundation(No.81671245).
文摘Background: Juvenile amyotrophic lateral sclerosis (JALS) is an uncommon form of amyotrophic lateral sclerosis whose age at onset (AAO) is defined as prior to 25 years. FUS mutations are the most common cause of JALS. SPTLC1 was recently identified as a disease-causative gene for JALS, which has rarely been reported in Asian populations. Little is known regarding the difference in clinical features between JALS patients carrying FUS and SPTLC1 mutations. This study aimed to screen mutations in JALS patients and to compare the clinical features between JALS patients with FUS and SPTLC1 mutations. Methods: Sixteen JALS patients were enrolled, including three newly recruited patients between July 2015 and August 2018 from the Second Affiliated Hospital, Zhejiang University School of Medicine. Mutations were screened by whole-exome sequencing. In addition, clinical features such as AAO, onset site and disease duration were extracted and compared between JALS patients carrying FUS and SPTLC1 mutations through a literature review. Results: A novel and de novo SPTLC1 mutation (c.58G>A, p.A20T) was identified in a sporadic patient. Among 16 JALS patients, 7/16 carried FUS mutations and 5/16 carried respective SPTLC1 , SETX , NEFH , DCTN1 , and TARDBP mutations. Compared with FUS mutation patients, those with SPTLC1 mutations had an earlier AAO (7.9 ± 4.6 years vs. 18.1 ± 3.9 years, P < 0.01), much longer disease duration (512.0 [416.7-607.3] months vs. 33.4 [21.6-45.1] months, P < 0.01), and no onset of bulbar. Conclusion: Our findings expand the genetic and phenotypic spectrum of JALS and help to better understand the genotype-phenotype correlation of JALS.
