Identification of TMEM230 mutations in familial Parkinson's disease

Deng, Hua; Shi, Yongyong; Yang, Yi; Ahmeti, Kreshnik B.; Miller, Nimrod; Huang, Cao; Cheng, Lijun; Zhai, Hong; Deng, Sheng; Nuytemans, Karen; Corbett, Nicola J.; Kim, Myung Jong; Deng, Hao; Tang, Beisha; Yang, Ziquang; Xu, Yanming; Chan, Piu; Huang, Bo; Gao, Xiao; Song, Zhi; Liu, Zhenhua; Fecto, Faisal; Siddique, Nailah; Foroud, Tatiana; Jankovic, Joseph; Ghetti, Bernardino; Nicholson, Daniel A.; Krainc, Dimitri; Melen, Onur; Vance, Jeffery M.; Pericak‐Vance, Margaret A.; Yin, Chao; Rajput, Ali H.; Siddique, Teepu

doi:10.1038/ng.3589

Cited by 165 publications

(182 citation statements)

References 47 publications

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“…They also showed that TMEM230 encodes a transmembrane protein of synaptic vesicles in neurons and that disease-linked mutations impair synaptic vesicle trafficking. Presence of TMEM230 in alpha-synuclein-positive Lewy bodies and Lewy neurites in midbrain and neocortex sections from sporadic PD cases gave supporting evidence for a role of this gene in PD pathology (Deng et al, 2016). …”

Section: Introductionmentioning

confidence: 88%

“…In a recent publication, Deng et al showed genetic evidence linking a mutation in transmembrane protein 230 ( TMEM230 ) to autosomal dominant Parkinson’s disease (PD) in a large family from North America (Deng et al, 2016). Identification of an additional mutation in 7 small Chinese families supports their results and suggests that mutations in this gene may be a relatively common cause of PD in this population.…”

Section: Introductionmentioning

confidence: 99%

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Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population

Giri

Mok²,

Jansen

et al. 2017

Neurobiology of Aging

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Mutations in TMEM230 have recently been associated to Parkinson’s disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population

Giri

Mok²,

Jansen

et al. 2017

Neurobiology of Aging

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“…27 Unsurprisingly, there are numerous examples of variant TMEM proteins in human genetic disorders, [28][29][30][31][32][33][34] and in that context, we do gain pathomechanistic clues about the disorder. We have reported enrichment of TMEM domains in the ciliary proteome, 35 raising the possibility that the present constellation of phenotypes could be part of the ciliopathy spectrum.…”

Section: Renal Defectsmentioning

confidence: 99%

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Ta‐Shma

Khan

Vivante

et al. 2017

The American Journal of Human Genetics

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Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.Whole-exome and whole-genome sequencing (WES and WGS, respectively) have accelerated the expansion of the repertoire of human loci underscoring Mendelian phenotypes to account for~3,000 human genes (15%).1 Nonetheless, the diagnostic yield remains <50%, 2-4 suggesting that the majority of disease-causing lesions are yet to be identified and that a significant fraction of this genetic burden is likely to be contributed by ultra-rare or private mutations. To contribute to the saturation of the morbid human genome as a means of improving both diagnostic value and mechanistic insight, we undertook the systematic sequencing of families affected by suspected genetic disorders, with an emphasis on congenital syndromic traits. Here, we report the genetic and functional dissection of affected individuals with a genetically undiagnosed syndrome characterized by cardiac, CNS, renal, and digit abnormalities in two unrelated consanguineous pedigrees. We show that the likely molecular cause, homozygous truncating mutations in TMEM260, affect the functions of one of the two established isoforms transcribed from this locus, thereby demonstrating the necessity of the long isoform for the development of multiple tissues. We consulted family 1, a con...

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“…Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. Recent data provide evidence for new molecular pathways involving neurodevelopmental mechanisms [207,210], modulating the signaling processes at the endocytic pathway [142], synaptic vesicles endocytosis and trafficking in PD pathogenesis [202,206], maintaining the integrity of the cytoskeleton and axonal transport in neurons [192].…”

Section: Discussionmentioning

confidence: 99%

“…Very recently, another gene with role in synaptic vesicle trafficking involved in pathogenesis of PD was identified on chromosome 20pter-p12 [206]. TMEM230 codes for a transmembrane protein of secretory/recycling vesicles.…”

Section: Tmem230mentioning

confidence: 99%

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Popescu¹

2016

Med Clin Rev

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Parkinson's disease (PD) etiology is based upon interactions between genetic susceptibility and the environmental exposure. Multiple environmental factors inducing oxidative stress, mitochondrial damage, impairment of the neuroprotective and autophagic mechanisms are responsible for dopaminergic neurons death. Defining the contributions of genetic and environmental factors, may have important implications for understanding the pathogenesis of PD. The linkage analysis in Mendelian forms of PD especially in multiplex highly penetrant families is essential to elucidate biological mechanisms for PD susceptibility. Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. This review aims to give an overview of the existing evidence of multiples molecular pathways involving cytoplasmic organelles' function, neurodevelopmental mechanisms, synaptic vesicles endocytosis and trafficking, maintaining the integrity of the cytoskeleton and axonal transport in neurons. Understanding the molecular mechanisms following the identification of genes mutations and low-penetrance susceptibility alleles in familial and sporadic PD patients by genotyping technology and functional studies represent an essential step for the development of adequate biomarkers and potent therapies.

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Identification of TMEM230 mutations in familial Parkinson's disease

Cited by 165 publications

References 47 publications

Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population

Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

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