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.