In 2 unrelated Japanese families (families A and C) segregating autosomal dominant Parkinson disease 22 (PARK22; 616710), Funayama et al. (2015) identified a C-to-T transition at nucleotide 182 of the CHCHD2 gene (c.182C-T, NM_016139.2), resulting in a threonine-to-isoleucine substitution at codon 61 (T61I). In the first family the mutation segregated with disease but was identified in 3 unaffected individuals aged 55 years, 56 years, and 35 years, respectively; mean age of onset in this family was 55.5 years (range, 48 to 61 years). In the second family only 2 members could be tested; both had the mutation. One of these had disease onset at 10 years of age, was 50 years old at the time of the report, and had upper limb essential tremor and gait disturbance as his only symptoms. This variant was not found among 559 unaffected Japanese controls or in the 1000 Genomes Project, Human Genetic Variation (HGVD), NHLBI ESP, or dbSNP (build 138) databases. Haplotype analysis estimated that the mutation arose independently in each family.
In response to the report of Funayama et al. (2015), Iqbal and Toft (2015) searched the ExAC database on March 20, 2015 to provide additional information about the reported CHCHD2 variants. The T61I variant was not present, providing strong genetic evidence of its pathogenicity.
Cornelissen et al. (2020) transfected FLAG-tagged wildtype and T61I mutant CHCHD2 into human fibroblasts. Both localized to the mitochondria, but the T61I mutant was found to precipitate in the mitochondrial intermembrane space due to decreased solubility. Functional studies showed that the T61I mutant resulted in decreased complex IV substrate-driven respiration, increased reactive oxygen species, and increased apoptosis. Because the T61I mutation significantly impaired the solubility of wildtype CHCHD2, possibly by resulting in insoluble wildtype/T61I dimers, a dominant-negative effect was established.
