Sheng Deng

Identification of TMEM230 mutations in familial Parkinson's disease

Parkinsons disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinsons disease or parkinsonian disorders. The pathogenesis of Parkinsons disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body–confirmed Parkinsons disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinsons disease, with implications for understanding the pathogenic mechanism of Parkinsons disease and for developing rational therapies.

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.

LINGO1 rs9652490 variant in Parkinson disease patients

Essential tremor (ET) has been hypothesized to be a risk factor for the development of Parkinson disease (PD). Recently, rs9652490 variant in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was found to be associated with ET susceptibility. To evaluate whether the same variant is associated also with PD susceptibility, we investigated the association between the LINGO1 rs9652490 variant and PD phenotype in Caucasian and Chinese PD subjects. We found no significant differences in genotypic and allele distribution between patients and control subjects (χ(2)=1.931, p=0.381 for genotypic distribution; χ(2)=0.001, p=0.973 for allele distribution), suggesting this variant is not associated with PD.

A Novel COL4A5 Mutation Identified in a Chinese Han Family Using Exome Sequencing

Alport syndrome (AS) is a monogenic disease of the basement membrane (BM), resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and ocular anomalies. It is caused by mutations in the collagen type IV alpha-3 gene (COL4A3), the collagen type IV alpha-4 gene (COL4A4), and the collagen type IV alpha-5 gene (COL4A5), which encodes type IV collagen α3, α4, and α5 chains, respectively. To explore the disease-related gene in a four-generation Chinese Han pedigree of AS, exome sequencing was conducted on the proband, and a novel deletion mutation c.499delC (p.Pro167Glnfs*36) in the COL4A5 gene was identified. This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family. Neither sensorineural hearing loss nor typical COL4A5-related ocular abnormalities (dot-and-fleck retinopathy, anterior lenticonus, and the rare posterior polymorphous corneal dystrophy) were present in patients of this family. The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD). Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

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.

Systematic Genetic Analysis of the SMPD1 Gene in Chinese Patients with Parkinson's Disease.

To examine the association between the sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) gene, and Parkinson’s disease (PD) in Han Chinese from Central South part of Mainland China, we performed systematic genetic analysis in 502 Chinese Han patients with PD and 637 gender-, age-, and ethnicity-matched normal controls from Central South part of the Mainland China. We identified 11 single nucleotide variants and Leu-Ala (Val) repeat variants in the SMPD1 gene in our large cohort. Two novel missense variants, c.638A > C (p.H213P) and c.1673T > C (p.L558P), and a rare known missense variant, c.1805G > A (p.R602H, rs370129081), were identified in three sporadic PD cases. None of these three variants were observed in controls. Additionally, case-control analysis showed association between Leu-Ala (Val) repeat variants in SMPD1 and Chinese Han patients with PD (P = 0.015, χ2 = 8.451). Our data provide supportive evidence that some genetic variants in SMPD1 increase the risk of PD in the Chinese Han population.

Genetic analysis of the NEUROG2 gene in patients with Parkinson's disease.

The proneural protein Neurogenin 2 (NEUROG2) is a transcription factor of importance for the differentiation and survival of midbrain dopaminergic neurons. To determine whether genetic variation in the coding region of the NEUROG2 gene plays a role in the etiology of Parkinsons disease (PD), we screened DNA samples from 202 PD patients and 201 normal controls. No mutation in the NEUROG2 gene was identified in our PD cohort, except that novel compound heterozygous variants (Gly56Arg and Asp206Glu) were found in a 91-year normal male, suggesting that mutations in the coding region of the NEUROG2 gene play little or no role in the development of PD.

A Missense Variant p.Ala117Ser in the Transthyretin Gene of a Han Chinese Family with Familial Amyloid Polyneuropathy

Familial amyloid polyneuropathy (FAP) is a dominantly inherited disorder. This study aims to explore the genetic features of a Han Chinese family with FAP, characterized by bloating, alternating diarrhea and constipation, and weakness in his feet. Amyloid presented histologically in the vessel walls of hepatic portal area and nerves of the surgically excised liver specimens from the proband by hematoxylin and eosin staining. Amyloid deposition was further confirmed with Congo red treatment. A c.349G>T transversion (p.Ala117Ser) in TTR gene exon 4 was identified in the proband with typical autonomic neuropathy and peripheral motor neuropathy, as well as in his asymptomatic son. The variant was not detected in 200 normal ethnically matched controls. These findings provide new insights into FAP cause and diagnosis and have implications for genetic counseling.

Identification of a novel collagen type IV alpha-4 (COL4A4) mutation in a Chinese family with autosomal dominant Alport syndrome using exome sequencing

Background & objectives: Alport syndrome (AS) is an inherited disorder characterized by glomerulonephritis and end-stage renal disease (ESRD). The aim of this study was to identify the gene responsible for the glomerulopathy in a Chinese family with autosomal dominant AS using exome sequencing. Methods: A 4-generation, 30-member Chinese Han family was enrolled in this study. Exome sequencing was conducted in the proband of the family, and then direct sequencing was performed in family members of the pedigree and 100 normal controls. Results: A novel frameshift mutation, c.3213delA (p.Gly1072Glufs*69), in the collagen type IV alpha-4 gene (COL4A4) was found to be the genetic cause. Neither sensorineural hearing loss nor ocular abnormalities were present in the patients of this family. Other clinical features, such as age of onset, age of ESRD occurring and disease severity, varied among the patients of this family. Interpretation & conclusions: A novel frameshift mutation, c.3213delA (p.Gly1072Glufs*69) in the COL4A4 gene, was identified in the Chinese pedigree with autosomal dominant AS. Our findings may provide new insights into the cause and diagnosis of AS and also have implications for genetic counselling.