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Mutations in the human VPS13 genes are responsible for neurodevelopmental and neurodegenerative disorders including chorea acanthocytosis (VPS13A) and Parkinson's disease (VPS13C). The mechanisms of these diseases are unknown. Genetic studies in yeast hinted that Vps13 may have a role in lipid exchange between organelles. In this study, we show that the N-terminal portion of VPS13 is tubular, with a hydrophobic cavity that can solubilize and transport glycerolipids between membranes. We also show that human VPS13A and VPS13C bind to the ER, tethering it to mitochondria (VPS13A), to late endosome/lysosomes (VPS13C), and to lipid droplets (both VPS13A and VPS13C). These findings identify VPS13 as a lipid transporter between the ER and other organelles, implicating defects in membrane lipid homeostasis in neurological disorders resulting from their mutations. Sequence and secondary structure similarity between the N-terminal portions of Vps13 and other proteins such as the autophagy protein ATG2 suggest lipid transport roles for these proteins as well. Show less

Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM₀₀₁₁₂₇₂₂₂.1: c.7261₇₂₆₂delinsGT, p.Pro2421Val), REEP4 (NM₀₂₅₂₃₂.3: c.109C>T, p.Arg37Trp), TOR2A (NM₁₃₀₄₅₉.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM₀₀₅₁₇₃.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM₀₂₂₄₆₀.3: c.94C>A, p.Gly32Cys) and GNA14 (NM₀₀₄₂₉₇.3: c.989₉₉₀del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns. Show less

A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls. Significant associations with PD were observed in the variants of SIPA1L2 (p = 0.001) and VPS13C (p = 0.007), where the T (odd ratio [OR] = 1.484, 95% confidence interval [CI] 1.186-1.858) and A (OR = 1.362, 95% CI 1.087-1.707) alleles serve as the risk alleles, respectively. The genotype distributions in the SIPA1L2 and VPS13C variants were also different between the patients and controls (p = 0.002 and p = 0.023, respectively). In contrast, no significant association with PD was found in the variants of MIR4697, GCH1, and DDRGK1 either in allele or genotype frequencies. Noteworthy, a followed meta-analysis of East Asian studies suggested an association of the GCH1 variant with PD (p = 0.04, OR 1.08, 95% CI 1.00-1.16), while the other results are in line with those of our cohort. In conclusion, our study together with meta-analyses demonstrates that the variants of SIPA1L2 and VPS13C, potentially GCH1, but not of MIR4697 and DDRGK1, are associated with PD susceptibility in East Asians. Show less

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095. Show less

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at Show less

Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies. Show less

This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes. Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. Mutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson's disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD. Show less

A large meta-analysis recently identified six new loci associated with risk of PD, but subsequent studies have given discrepant results. Here we conducted a case-control study in a Han Chinese population in an attempt to clarify risk associations in Chinese. Among the four single-nucleotide polymorphisms (SNPs) that we examined - VPS13C-rs2414739, MIR4697-rs329648, GCH1-rs11158026, and SIPA1L2- rs10797576 we detected a significant association between rs329648 and risk of developing PD in a recessive model. This association remained significant after adjusting for gender and age (OR 1.87, 95%CI 1.295-2.694, p=8.21×10 Show less

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression. Show less

Large-scale meta-analysis of genome-wide association data has identified six new risk loci (SIPA1L2, INPP5F, MIR4697, GCH1, VPS13C, and DDRGK1) for Parkinson's disease (PD). However, the characteristics of those loci in a Han Chinese population from mainland China are unknown. We examined genetic associations of VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 with PD susceptibility in a Han Chinese population of 1028 sporadic PD patients and 1109 healthy controls. All subjects were genotyped for these loci using the Sequenom iPLEX Assay. We also conducted further stratified analysis according to age at onset and compared the clinical characteristics between minor allele carriers and non-carriers for each locus. However, we did not observe any significant difference in genotype distribution between PD patients and controls for the four loci, even after being stratified by age at onset. Besides, minor allele carriers cannot be distinguished from non-carriers based on their clinical features. Our findings first demonstrated that VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 do not confer a significant risk for PD in Chinese population. Additional replication studies in other populations and functional studies are warranted to better validate the role of the four new loci in PD risk. Show less

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Prevalence of PD increases steadily with age. A recent meta-analysis of genome-wide association studies has identified six new loci to be linked with PD. Here we investigated the association of four of these new loci, SIPA1L2, MIR4697, GCH1 and VPS13C with PD in an Iranian population. Through a case-control study a total of 1800 subjects comprising 600 PD patients and 1200 unrelated healthy controls were recruited. Rs10797576, rs329648, rs11158026 and rs2414739 related to SIPA1L2, MIR4697, GCH1 and VPS13C loci respectively, were genotyped in all subjects. The difference of genotype and allele frequencies between case and control groups were investigated using chi-square test and logistic regression models with R software. Genotype and allele frequencies were significantly different in PD patients and control group for rs329648, rs11158026 and rs2414739 (p-value=0.018, 0.025, and 0.009 respectively for allele frequency differences). There was no difference in genotype nor allele frequencies between the two groups for rs10797576. We replicated the association of three new loci which are proposed for PD. More studies in other populations and also functional analysis are required to clear the role of these variants in PD. Show less

Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13c(fl/fl):Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca(2+) were significantly increased in islets from female KO mice, suggesting impaired Ca(2+) sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved. Show less

Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue disease in 2009. However, WS is limited in stratifying adult dengue patients at early infection (Day 1-3 post fever), who require close monitoring in hospitals to prevent severe dengue. The aim of this study is to identify and validate prognostic models, built with differentially expressed biomarkers, that enable the early identification of those with early dengue infection that require close clinical monitoring. RNA microarray and protein assays were performed to identify differentially expressed biomarkers of severity among 92 adult dengue patients recruited at early infection from years 2005-2008. This comprised 47 cases who developed WS after first presentation and required hospitalization (WS+Hosp), as well as 45 controls who did not develop WS after first presentation and did not require hospitalization (Non-WS+Non-Hosp). Independent validation was conducted with 80 adult dengue patients recruited from years 2009-2012. Prognostic models were developed based on forward stepwise and backward elimination estimation, using multiple logistic regressions. Prognostic power was estimated by the area under the receiver operating characteristic curve (AUC). The WS+Hosp group had significantly higher viral load (P<0.001), lower platelet (P<0.001) and lymphocytes counts (P = 0.004) at early infection compared to the Non-WS+Non-Hosp group. From the RNA microarray and protein assays, the top single RNA and protein prognostic models at early infection were CCL8 RNA (AUC:0.73) and IP-10 protein (AUC:0.74), respectively. The model with CCL8, VPS13C RNA, uPAR protein, and with CCL8, VPS13C RNA and platelets were the best biomarker models for stratifying adult dengue patients at early infection, with sensitivity and specificity up to 83% and 84%, respectively. These results were tested in the independent validation group, showing sensitivity and specificity up to 96% and 54.6%, respectively. At early infection, adult dengue patients who later presented WS and require hospitalization have significantly different pathophysiology compared with patients who consistently presented no WS and / or require no hospitalization. The molecular prognostic models developed and validated here based on these pathophysiology differences, could offer earlier and complementary indicators to the clinical WHO 2009 WS guide, in order to triage adult dengue patients at early infection. Show less

Galectin-12, a member of the galectin family of β-galactoside-binding animal lectins, is preferentially expressed in adipocytes and required for adipocyte differentiation in vitro. This protein was recently found to regulate lipolysis, whole body adiposity, and glucose homeostasis in vivo. Here we identify VPS13C, a member of the VPS13 family of vacuolar protein sorting-associated proteins highly conserved throughout eukaryotic evolution, as a major galectin-12-binding protein. VPS13C is upregulated during adipocyte differentiation, and is required for galectin-12 protein stability. Knockdown of Vps13c markedly reduces the steady-state levels of galectin-12 by promoting its degradation through primarily the lysosomal pathway, and impairs adipocyte differentiation. Our studies also suggest that VPS13C may have a broader role in protein quality control. The regulation of galectin-12 stability by VPS13C could potentially be exploited for therapeutic intervention of obesity and related metabolic diseases. Show less

Recently, a large-scale meta-analysis of genome-wide association study (GWAS) data identified several new risk loci that can modulate the risk of Parkinson's disease (PD). These associations have yet to be examined in PD patients in Chinese or Asian population. Because ethnic-specific effect is an important concern for GWAS analysis, we genotyped single-nucleotide polymorphisms in the new genetic loci, GCH1 (rs11158026), SIPA1L2 (rs10797576), VPS13C (rs2414739), and MIR4697 (rs329648), to investigate their associations with risk of PD in Taiwan. Another single-nucleotide polymorphism GCH1 rs7155501, previously identified by GWAS listed at the top 20 genes in PDGene database was also included. A total of 1151 study subjects comprising 598 patients with PD and 553 unrelated healthy controls were recruited. The frequency of minor allele (C allele) of GCH1 rs11158026 was found to be significantly higher in PD cases than in controls (p = 0.003). The CC genotype of rs11158026 increased PD risk compared to TT genotype (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.09, 1.53, p = 0.004). Under additive model, the GCH1 rs11158026 increased the risk of developing PD (OR = 1.30, 95% CI = 1.10, 1.54, p = 0.002). In recessive model, the genotype TT of MIR4697 rs329648 marginally decreased the PD risk (OR = 0.62, 95% CI = 0.43, 0.90, p = 0.01). The PD patients demonstrated similar genotypic and allelic frequencies in GCH1 rs7155501, SIPA1L2 rs10797576, and VPS13C rs2414739 with the controls. These findings suggest that the GCH1 and MIR4697 but not SIPA1L2 and VPS13C are genetic loci influencing risk of PD in Taiwan. Show less

Vacuolar protein sorting plays crucial roles in the traffic of molecules between cellular organelles. Although involvement of vacuolar protein sorting proteins in cancer is known, genetic alterations of VPS genes have not been reported in cancers. We found that VPS4B, VPS13A, VPS13B, VPS13C, VPS33A, VPS35, VPS37B, VPS37D, VPS41, and VPS54 have mononucleotide repeats in their coding sequences. To see whether these genes are mutated in cancers with microsatellite instability, we analyzed the mononucleotide repeats in 30 gastric cancers with high microsatellite instability, 13 gastric cancers with low microsatellite instability, and 45 gastric cancers with stable microsatellites and 40 colorectal cancers with high microsatellite instability, 14 colorectal cancers with low microsatellite instability, and 45 colorectal cancers with stable microsatellites by single-strand conformation polymorphism. We found mutations of VPS13A, VPS13B, VPS13C, VPS33A, VPS35, VPS37B, VPS41, and VPS54 in 9, 3, 12, 3, 5, 9, 2, and 2 cancers, respectively, all in cancers with high microsatellite instability. The gastric cancers and colorectal cancers with high microsatellite instability harbored one or more mutations of the VPS genes in 53.3% and 50.0%, respectively. Loss of Vps13A expression was observed in 30% of the gastric cancers and 35% of the colorectal cancers, whereas loss of Vps35 was observed in 55% of the gastric cancers and 55% of the colorectal cancers. Our data indicate that frameshift mutations of VPS genes and losses of expression of Vps13A and Vps35 proteins are common in gastric cancers and colorectal cancers with high microsatellite instability and suggest that these alterations might contribute to development of cancers with high microsatellite instability by deregulating vacuolar protein sorting proteins. Show less

A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits. We genotyped the rs7172432 variant in the population-based Inter99 cohort (n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT. The diabetes-associated A allele was associated with 0.60 cm higher waist circumference (p = 0.004), 0.037 mmol/l higher fasting plasma glucose (p = 4 × 10(-5)) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT (p = 4 × 10(-4)). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin (β = -0.039, p = 2 × 10(-7)), insulinogenic index (β = -0.057, p = 1 × 10(-8)) and BIGTT-acute insulin release (β = -0.041, p = 9 × 10(-9)). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 (R (2) < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305. The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait. Show less

Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. Show less

In humans and great apes, CHRNA1 encoding the muscle nicotinic acetylcholine receptor alpha subunit carries an inframe exon P3A, the inclusion of which yields a nonfunctional alpha subunit. In muscle, the P3A(-) and P3A(+) transcripts are generated in a 1:1 ratio but the functional significance and regulation of the alternative splicing remain elusive. An intronic mutation (IVS3-8G>A), identified in a patient with congenital myasthenic syndrome, disrupts an intronic splicing silencer (ISS) and results in exclusive inclusion of the downstream P3A exon. We found that the ISS-binding splicing trans-factor was heterogeneous nuclear ribonucleoprotein (hnRNP) H and the mutation attenuated the affinity of hnRNP for the ISS approximately 100-fold. We next showed that direct placement of hnRNP H to the 3' end of intron 3 silences, and siRNA-mediated downregulation of hnRNP H enhances recognition of exon P3A. Analysis of the human genome suggested that the hnRNPH-binding UGGG motif is overrepresented close to the 3' ends of introns. Pursuing this clue, we showed that alternative exons of GRIP1, FAS, VPS13C and NRCAM are downregulated by hnRNP H. Our findings imply that the presence of the hnRNP H-binding motif close to the 3' end of an intron is an essential but underestimated splicing regulator of the downstream exon. Show less

Mutations in vacuolar protein sorting 13A (VPS13A) gene are responsible for chorea-acanthocytosis (ChAc). We previously determined the full-length sequence and exon-intron structure of mouse VPS13A and generated a ChAc model mouse by using the gene targeting technique. In the process, we found diverse 5' and 3' transcript variants. Since ChAc is a rare neurodegenerative disorder, the mouse model should be useful for investigation of ChAc molecular pathogenesis, and the model's brain specific variants of VPS13A will be indispensable in these investigations. In the present study, we investigated mouse VPS13A transcript variants. We found brain-specific variants of mouse VPS13A, which may be involved in the brain-specific pathology of ChAc. In addition, we identified for the first time mouse VPS13C cDNA sequences and brain-specific variants of VPS13C. Show less

The gene mutated in chorea-acanthocytosis (CHAC; approved gene symbol VPS13A) encodes chorein, a protein similar to yeast Vps13p. We detected several similar putative human proteins by BLAST analysis of chorein. We characterized the structure of three new genes encoding these CHAC-similar proteins, located on chromosomes 1p36, 8q22, and 15q21. The most similar gene in yeast to all four human genes is Vps13, and therefore the human genes were named VPS13A (CHAC, 9q21), VPS13B (8q22), VPS13C (15q21), and VPS13D (1p36). VPS13B has recently been reported as COH1, altered in Cohen syndrome. For each gene, we describe several alternative splicing variants; at least two transcripts per gene are major forms. The expression pattern of these genes is ubiquitous, with some tissue-specific differences between several transcript variants. Protein sequence comparisons suggest that intramolecular duplications have played an important role in the evolution of this gene family. Show less