title: A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree.
abstract: Charcot-Marie-Tooth (CMT) disease represents a clinically and genetically heterogeneous group of inherited neuropathies. Here, we report a five-generation family of eight affected individuals with CMT disease type 2, CMT2. Genome-wide linkage analysis showed that the disease phenotype is closely linked to chromosomal region 10p13-14, which spans 5.41 Mb between D10S585 and D10S1477. DNA-sequencing analysis revealed a nonsense mutation, c.1455T>G (p.Tyr485(∗)), in exon 8 of dehydrogenase E1 and transketolase domain-containing 1 (DHTKD1) in all eight affected individuals, but not in other unaffected individuals in this family or in 250 unrelated normal persons. DHTKD1 mRNA expression levels in peripheral blood of affected persons were observed to be half of those in unaffected individuals. In vitro studies have shown that, compared to wild-type mRNA and DHTKD1, mutant mRNA and truncated DHTKD1 are significantly decreased by rapid mRNA decay in transfected cells. Inhibition of nonsense-mediated mRNA decay by UPF1 silencing effectively rescued the decreased levels of mutant mRNA and protein. More importantly, DHTKD1 silencing was found to lead to impaired energy production, evidenced by decreased ATP, total NAD(+) and NADH, and NADH levels. In conclusion, our data demonstrate that the heterozygous nonsense mutation in DHTKD1 is one of CMT2-causative genetic alterations, implicating an important role for DHTKD1 in mitochondrial energy production and neurological development.
authors.affiliation: State Key Laboratory of Medical Genomics, Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wang-Yang
authors.initials: WY
authors.lastname: Xu
authors.forename: Ming-Min
authors.initials: MM
authors.lastname: Gu
authors.forename: Lian-Hua
authors.initials: LH
authors.lastname: Sun
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Guo
authors.forename: Hou-Bao
authors.initials: HB
authors.lastname: Zhu
authors.forename: Jian-Fang
authors.initials: JF
authors.lastname: Ma
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Yuan
authors.forename: Ying
authors.initials: Y
authors.lastname: Kuang
authors.forename: Bao-Jun
authors.initials: BJ
authors.lastname: Ji
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Hong-Xin
authors.initials: HX
authors.lastname: Zhang
authors.forename: Fu-Ting
authors.initials: FT
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Sheng-di
authors.initials: SD
authors.lastname: Chen
authors.forename: Zhu-Gang
authors.initials: ZG
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002681:China; D018389:Codon, Nonsense; D005091:Exons; D005260:Female; D023061:Gene Order; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex; D007658:Ketone Oxidoreductases / Q000235:genetics*; D008297:Male; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D059365:Nonsense Mediated mRNA Decay; D010375:Pedigree
chemical_list: D018389:Codon, Nonsense; D007658:Ketone Oxidoreductases; C578281:DHTKD1 protein, human; D007655:Ketoglutarate Dehydrogenase Complex