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Genetic factors are thought to play an important role in the pathogenesis of Parkinson's disease (PD), particularly early-onset PD. The PRKN gene is the primary disease-causing gene for early-onset PD. The details of its functions remain unclear. This study identified novel compound heterozygous variants (p.T240K and p.L272R) of the PRKN gene in a Han-Chinese family with early-onset PD. This finding is helpful in the genetic diagnosis of PD and also the functional research of the PRKN gene. [ABSTRACT FROM AUTHOR]

Conclusion: This study demonstrates that the gap junction protein beta-2 gene (GJB2) p.R32C and p.L79Cfs*3 variants are associated to a consanguineous family with autosomal recessive non-syndromic hearing loss (ARNSHL). The p.R32C variant is found for the first time in the NSHL patients of Han Chinese origin. The finding sheds new light on the accurate genetic diagnosis and counseling for the family.Objective: ARNSHL is a highly heterogeneous genetic disease. ARNSHL usually displays non-progressive congenital or pre-lingual deafness. In this study, the aim is to detect the disease-causing mutation(s) in a Han family with ARNSHL.Methods: A consanguineous Han family with ARNSHL was enrolled. Two hundred ethnicity-matched unrelated subjects without any hearing impairments were used as normal controls. Exome sequencing and Sanger sequencing were applied to identify the causative mutation in the ARNSHL family.Results: Compound heterozygous variants c.94C > T (p.R32C) and c.235delC (p.L79Cfs*3) in theGJB2gene were identified in the two patients of the ARNSHL family, and the heterozygousGJB2c.94C > T and c.235delC variants were identified in his unaffected father and mother, respectively. The two variants in theGJB2gene were absent in the 200 unrelated controls. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous sensorineural disorder, generally manifested with prelingual hearing loss and absence of other clinical manifestations. The aim of this study is to identify the pathogenic gene in a four-generation consanguineous Chinese family with ARNSHL. A novel homozygous variant, c.9316dupC (p.H3106Pfs*2), in the myoxin XVa gene (MYO15A) was identified by exome sequencing and Sanger sequencing. The homozygous MYO15A c.9316dupC variant co-segregated with the phenotypes in the ARNSHL family and was absent in two hundred normal controls. The variant was predicted to interfere with the formation of the Myosin XVa-whirlin-Eps8 complex at the tip of stereocilia, which is indispensable for stereocilia elongation. Our data suggest that the homozygous MYO15A c.9316dupC variant might be the pathogenic mutation, and exome sequencing is a powerful molecular diagnostic strategy for ARNSHL, an extremely heterogeneous disorder. Our findings extend the mutation spectrum of the MYO15A gene and have important implications for genetic counseling for the family. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway. [ABSTRACT FROM AUTHOR]

Abstract: Tourette syndrome (TS), a neurological disorder with a reported prevalence frequency ranging from 0.7% to 4.2%, is manifested by motor and phonic tics and associated with a variety of behavioral abnormalities including impulsivity. Clinical, neuroimaging and other studies support dysfunction of the dopamine and 5-hydroxytryptamine neurotransmitter systems in TS. To determine whether TS is associated with mutation in the 5-hydroxytryptamine receptor 2B gene (HTR2B), which has been also implicated in impulsivity, we screened 132 Caucasian and 128 Chinese Han patients with TS. Two novel (c.188T>G, Met63Arg; c.1346G>A, Arg449Gln) and three known (rs61731726, Gly51Gln; rs200541113, Lys324Asn; rs61731723, Asn438Asn) nucleotide variants were found. Further analysis of sex, age, and ethnically matched normal controls (138 Caucasians and 248 Chinese Han individuals), as well as an affected family member, indicated that these variants may not be pathogenically relevant, suggesting that variants in the HTR2B gene may play little or no role in the development of TS. [Copyright &y& Elsevier]

Parkinson's 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. [ABSTRACT FROM AUTHOR]

Abstract: The F-box only protein 48 gene (FBXO48) is located in 2p13.3, the disease gene locus of Parkinson disease type 3 (PARK3), and it is one of the paralogs of the F-box only protein 7 gene (FBXO7), which is a causative gene of the Parkinson disease type 15 (PARK15; also known as Parkinsonian-pyramidal disease, PPD). To determine whether genetic mutation in the coding region of the FBXO48 gene plays a role in the etiology of PD, we screened DNA samples from 350 Chinese Han patients with PD. No mutation in the coding region of the FBXO48 gene was identified in our PD cohort, suggesting that mutations in the coding region of the FBXO48 gene play little or no role in the development of PD. [Copyright &y& Elsevier]

Abstract: 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 Parkinson''s 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. [Copyright &y& Elsevier]