title: Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.
abstract: Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.
authors.affiliation: Division of Neuromuscular Medicine, The Ken and Ruth Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, s-ajroud@northwestern.edu.
authors.forename: Senda
authors.initials: S
authors.lastname: Ajroud-Driss
authors.forename: Faisal
authors.initials: F
authors.lastname: Fecto
authors.forename: Kaouther
authors.initials: K
authors.lastname: Ajroud
authors.forename: Irfan
authors.initials: I
authors.lastname: Lalani
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Calvo
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Mootha
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Nailah
authors.initials: N
authors.lastname: Siddique
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Tahmoush
authors.forename: Terry D
authors.initials: TD
authors.lastname: Heiman-Patterson
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
mesh_terms: D002892:Chromosomes, Human, Pair 22; D005190:Family; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D011647:Puerto Rico
chemical_list: C554426:CHCHD10 protein, human; D024101:Mitochondrial Proteins