This report describes frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (FTDALS2), which is a subtype of amyotrophic lateral sclerosis. FTDALS2 exhibits autosomal dominant inheritance. The gene implicated in this disease is CHCHD10, which encodes a small mitochondrial protein that may be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure. The Drosophila gene most closely related to CHCHD10 is Chchd2, for which loss-of-function mutations, RNAi targeting constructs, alleles caused by insertional mutagenesis, and an amorphic allele created by targeted recombination have been generated. There are two additional moderate-scoring orthologs in flies, CG31007 and CG31008, and there is a second similar gene in human, CHCHD2.
A UAS construct of the wild-type human Hsap\CHCHD10 gene has been introduced into flies, but has not been characterized.
A variant implicated in FTDALS2 has been characterized in flies, using the fly gene with the analogous change. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): S81L in the fly Chchd2 gene (corresponds to S59L in the human CHCHD10 gene). A CHCHD10 variant implicated in a similar disease has also been characterized in this system; see ‘spinal muscular atrophy, Jokela type’ (FBhh0001228).
In Drosophila, loss of Dmel\Chchd2 function results in mitochondrial and neuronal phenotypes including increased sensitivity to oxidative stress, progressive dopaminergic neuron loss, progressive degeneration of photoreceptor cells, and progressive locomotor dysfunction. In fat body cells, loss of Chchd2 results in fragmented mitochondria. Genetic interactions have been described for Dmel\Chchd2; see the Chchd2 gene report.
[updated Jul. 2020 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 2; FTDALS2](https://omim.org/entry/615911)
[COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10](https://omim.org/entry/615903)
FTDALS2 is a late-onset neurodegenerative disorder comprising frontotemporal dementia, cerebellar ataxia, myopathy, and motor neuron disease consistent with amyotrophic lateral sclerosis. [from MIM:615911; 2020.07.25]
Frontotemporal dementia and/or amyotrophic lateral sclerosis-2 (FTDALS2) is caused by heterozygous mutation in the CHCHD10 gene. [from MIM:615911; 2020.07.25]
Overexpression of the S59L variant protein in HeLa cells led to fragmentation of the mitochondrial network as well as major ultrastructural abnormalities, similar to those observed in patient cells (Bannwarth et al., 2014; pubmed:24934289). [from MIM:615911; 2020.07.25]
CHCHD10 is a relatively small protein of the mitochondrial intermembrane space that is enriched at cristae junctions. It is predicted to be involved in oxidative phosphorylation or in maintenance of cristae morphology (Bannwarth et al., 2014; pubmed:24934289). [from MIM:615903; 2020.07.25]
High-scoring ortholog of human CHCHD2 and CHCH10 (3 Drosophila to 2 human). Dmel\Chchd2 shares 44-50% identity and 54-58% similarity with the human genes.
