Lamei Yuan

EIF4G1 Ala502Val and Arg1205His variants in Chinese patients with Parkinson disease

Growing evidences show that genetic abnormalities play an important role in the etiopathogenesis of Parkinson disease (PD). At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. Recently, the p.Ala502Val and p.Arg1205His variants in the eukaryotic translation initiation factor 4-gamma 1 gene (EIF4G1) were found to be associated with PD. To evaluate whether the EIF4G1 p.Ala502Val and p.Arg1205His variants are related to PD in Chinese Han population, we conducted genetic examination of these two variants in 425 PD patients from Mainland China and none was found in our patients. We did identify a known non-pathogenic polymorphism c.3660C>T (p.Ala1220Ala, rs143852330) in a 73-year-old male patient. Our results, consistent with other recent reports, suggest that the EIF4G1 p.Ala502Val and p.Arg1205His variants are a rare cause of PD, at least in Chinese population.

Genetic analysis of the RAB39B gene in Chinese Han patients with Parkinson's disease.

Parkinsons disease (PD) is a common neurodegenerative disorder of complex etiology. Mounting evidence indicates that genetic abnormalities play an important role in the pathogenesis of PD. To date, at least 20 genetic loci and 15 disease-causing genes for parkinsonism have been identified, as well as some susceptibility genes conferring risk to PD. More recently, mutations in the RAB39B gene (RAB39B, member RAS oncogene family) have been reported to cause X-linked intellectual disability and early-onset PD with α-synuclein pathology. To evaluate whether variants in the RAB39B gene are related to PD in Chinese Han population, we conducted genetic analysis of the RAB39B gene in 502 patients with PD from Mainland China. No pathogenic mutation or variant was identified in the coding region or exon-intron boundaries of the gene. Our results suggest that mutation(s) in the coding region of the RAB39B gene plays little or no role in the development of PD in Chinese population.

Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing.

Abstract Familial hypophosphatemic rickets (HR), the most common inherited form of rickets, is a group of inherited renal phosphate wasting disorders characterized by growth retardation, rickets with bone deformities, osteomalacia, poor dental development, and hypophosphatemia. The purpose of this study was to identify the genetic defect responsible for familial HR in a four-generation Chinese Han pedigree by exome sequencing and Sanger sequencing. Clinical features include skeletal deformities, teeth abnormalities, hearing impairments and variable serum phosphate level in patients of this family. A novel deletion mutation, c.1553delT (p.F518Sfs*4), was identified in the X-linked phosphate regulating endopeptidase homolog gene (PHEX). The mutation is predicted to result in prematurely truncated and loss-of-function PHEX protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in HR, a disorder with genetic and clinical heterogeneity. The findings may also provide new insights into the cause and diagnosis of HR, and have implications for genetic counseling and clinical management.

Identification of a novel COL4A5 mutation in a Chinese family with X-linked Alport syndrome using exome sequencing

Alport syndrome (AS) is an inherited disorder and clinically characterized by glomerulonephritis and end-stage kidney disease (ESRD). The aim of this study was to identify the gene responsible for glomerulopathy in a 4-generation Chinese pedigree. Exome sequencing was conducted in four patients of the family, and then direct sequencing was performed in other members of the pedigree. A novel missense mutation c.368G>A (p.Gly123Glu) in the collagen type IV alpha-5 gene (COL4A5) was found to be the genetic cause. The p.Gly123Glu mutation occurs prior to Gly-X-Y repeats in the alpha-5 chain of type IV collagen. Neither sensorineural hearing loss nor ocular abnormalities were present in patients of this family. Other clinical features, such as age of onset, age of ESRD, disease severity and complications, varied among patients of this family. Our finding may provide new insights into the cause and diagnosis of AS, and also have implications for genetic counseling.

Genetic analysis of the S100B gene in Chinese patients with Parkinson disease

There is growing evidence that genetic abnormalities play an important role in the pathogenesis of Parkinson disease (PD). At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. The S100 calcium-binding beta (S100B), which is expressed and secreted by astrocytes, has been found to be associated with PD. To evaluate whether the S100B variants are related to PD in Chinese Han population, we conducted genetic examination of the S100B gene in 502 PD patients from Mainland China. We did identify two known variants c.279+4T>C (rs187503470) and c.99C>G (p.Leu33Leu, rs1051169) in our patients. Neither of these two variants is predicted to change amino acid or splice site, indicating that they are not pathogenic mutations. Our results suggest that mutations in the coding region or intron/exon boundaries of the S100B gene play little or no role in the development of PD in Chinese population.

Identification of a novel GJA3 mutation in congenital nuclear cataract.

Purpose Congenital cataract is a visual impairment that needs correction as early as possible after birth. This study aimed to identify whether genetic defects exist in a Chinese Han pedigree with congenital nuclear cataract. Methods A family consisting of six members and three patients with nuclear cataract spanning three generations and 100 unrelated ethnically matched normal subjects were recruited in this study. Exome sequencing was performed in the 24-year-old proband, and Sanger sequencing was then conducted in other family members and 100 normal controls. Results A novel missense variant, c.428G>A (p.G143E), in the gap junction protein-alpha 3 gene (GJA3) was identified in three patients of the family but unidentified in three family members without lens opacity and 100 normal controls. Conclusions A novel missense mutation, c.428G>A (p.G143E), in the GJA3 gene, localized to the cytoplasmic loop, was suggested to be the genetic cause of congenital nuclear cataract, which further expands the gene mutation spectrum. Our findings suggest that exome sequencing is a powerful and cost-effective tool to discover mutation(s) in disorders with high genetic and clinical heterogeneity. Further functional studies in the GJA3 gene mutations may help uncover pathogenic mechanisms of congenital cataract and therefore provide a possible genetic therapy for this disorder.

Association of the MTHFR rs1801131 and rs1801133 variants in sporadic Parkinson’s disease patients

Parkinsons disease (PD) is a common age-dependent neurodegenerative movement disorder related to multiple factors, and genetic factors play an important role in the pathogenesis of PD. Variants in the methylenetetrahydrofolate reductase gene (MTHFR), a gene encoding a folate-dependent enzyme that is involved in homocysteine metabolism, have been reported to be associated with PD. To explore the role of the MTHFR gene in the development of PD in Chinese Han population, we analyzed two MTHFR variants (rs1801131 and rs1801133) in a patient cohort consisting of 512 patients with PD from mainland China and a control cohort consisting of 512 age, gender and ethnicity matched normal subjects. Statistically significant differences in genotypic and allelic frequencies were detected in the MTHFR variant rs1801133 (P=0.022 and 0.007, respectively; odds ratio=0.780, 95% confidence interval=0.651-0.934). In addition, the A-T haplotype of rs1801131-rs1801133 showed a protective role against PD development (P=0.007, odds ratio=0.779, 95% confidence interval=0.650-0.933). Our results suggested that the T allele of rs1801133 variant and A-T haplotype of rs1801131-rs1801133 in the MTHFR gene may decrease the risk of developing PD in Chinese Han population from mainland China.

Identification of a Novel Mutation in the COL2A1 Gene in a Chinese Family with Spondyloepiphyseal Dysplasia Congenita.

Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short-trunk dwarfism, skeletal and vertebral deformities. Exome sequencing and Sanger sequencing were performed in a Chinese Han family with typical SEDC, and a novel mutation, c.620G>A (p.Gly207Glu), in the collagen type II alpha-1 gene (COL2A1) was identified. The mutation may impair protein stability, and lead to dysfunction of type II collagen. Family-based study suggested that the mutation is a de novo mutation. Our study extends the mutation spectrum of SEDC and confirms genotype-phenotype relationship between mutations at glycine in the triple helix of the alpha-1(II) chains of the COL2A1 and clinical findings of SEDC, which may be helpful in the genetic counseling of patients with SEDC.

Identification of a Novel Mutation in the Titin Gene in a Chinese Family with Limb-Girdle Muscular Dystrophy 2J

Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of genetic myopathies characterized by progressive proximal pelvic and/or shoulder girdle muscle weakness, with the onset ages ranging from early childhood to late adulthood. The identification of these dystrophies through genetic testing will not only inform long-term prognosis but will also assist in directing care more efficiently, including more frequent cardiorespiratory monitoring and prophylactic treatments. The aim of this study was to identify the responsible gene in a five-generation Chinese Han pedigree with autosomal recessive LGMD. Exome sequencing was conducted and a novel mutation c.107788T>C (p.W35930R) in the titin gene (TTN) was identified. The mutation co-segregated with the disorder in the family and was absent in normal controls. Our discovery broadens the mutation spectrum of the TTN gene associated with LGMD2J.

Exome Sequencing of a Pedigree Reveals S339L Mutation in the TLN2 Gene as a Cause of Fifth Finger Camptodactyly

Camptodactyly is a digit deformity characterized by permanent flexion contracture of one or both fifth fingers at the proximal interphalangeal joints. Though over 60 distinct types of syndromic camptodactyly have been described, only one disease locus (3q11.2-q13.12) for nonsyndromic camptodactyly has been identified. To identify the genetic defect for camptodactyly in a four-generation Chinese Han family, exome and Sanger sequencings were conducted and a missense variant, c.1016C>T (p.S339L), in the talin 2 gene (TLN2) was identified. The variant co-segregated with disease in the family and was not observed in 12 unaffected family members or 1,000 normal controls, suggesting that p.S339L is a pathogenic mutation. Two asymptomatic carriers in the family indicated incomplete penetrance or more complicated compensated mechanism. Most of p.S339L carriers also have relatively benign cardiac phenotypes. Expression of wild and mutant TLN2 in HEK293 cells suggested the predominant localization in cytoplasm. Our data suggest a potential molecular link between TLN2 and camptodactyly pathogenesis.