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 the nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of a 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 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; 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 1481 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 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.

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

“…Several studies have characterized the effects of CHCHD10 by analyzing these mutations in skin fibroblasts from patients (14,9,20) or by overexpression of these mutations in WT cells (8,37). Here we show that CHCHD10 plays a key role in the regulation of electron transport chain function in the mitochondria as well as a novel role in the nucleus as a transcriptional repressor at the ORE. We selected two CHCHD10 mutations -P80L and G66V -for detailed study.…”

“…Little is known, however, about the physiological role of CHCHD10 (7). Most studies have focused on characterizing CHCHD10's effects in mitochondria by testing the effects of pathogenic mutations in a cell culture system (8,9,14). These studies have suggested that CHCHD10 affects stability of mitochondrial cristae (9, 14), COX activity (7), formation of mitochondrial networks (8), stability of mitochondrial DNA, and apoptosis (14).…”

“…CHCHD10, although highly expressed in heart and skeletal muscle (7), was discovered to be mutated in a proportion of individuals suffering from several neurodegenerative diseases (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The clinical effects of these mutations have been well described (18).…”

Mutation analysis ofCHCHD10in different neurodegenerative diseases

“…Mutations in CHCHD10 may disrupt the morphology of mitochondrial cristae, affect the stability of mitochondrial DNA, induce mitochondrial fragmentation, and reduce mitochondrial complex-IV activities Ajroud-Driss et al, 2015). Two novel variants identified in the current study, p.A35D and p.P23T, affect amino acids in the non-structured N-terminal region of CHCHD10 protein.…”

“…Affected family members were presented with a complex phenotype that included symptoms of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), cerebellar ataxia, Parkinson's disease and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range, including ALS/FTLD (p.S59L and p.P34S) Chaussenot et al, 2014), ALS (p.R15L and p.G66V) (Johnson et al, 2014;Muller et al, 2014), myopathy (p.R15S and p.G58R) (Ajroud-Driss et al, 2015) and lateonset spinal motor neuronopathy (p.G66V) (Penttila et al, 2015). All of them affect exon 2 (a mutational hotspot of CHCHD10).…”