This report describes Parkinson disease 22 (PARK22, PD22), which is a subtype of Parkinson disease; PARK22 exhibits autosomal dominant inheritance. The human gene implicated in this disease is CHCHD2, which encodes a transcription factor that regulates transcription of COX4I2, a subunit of the terminal enzyme of the electron transport chain; CHCHD2 also appears to be a negative regulator of mitochondria-mediated apoptosis. In Drosophila, there is one high-scoring ortholog of CHCHD2, Dmel\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, CHCHD10.
Multiple UAS constructs of the human Hsap\CHCHD2 gene have been introduced into flies, including wild-type and variants associated with PARK22. Heterologous rescue (functional complementation) has been demonstrated using the wild-type human gene; rescue is not observed using the pathological variants. Variant(s) implicated in human disease tested (as transgenic human gene, CHCHD2): the T61I, R145Q, and P2L variant forms have been introduced into flies; P2L is described as a risk variant.
One variant has also been characterized as the analogous change in the fly gene. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): K164Q in the fly Chchd2 gene (corresponds to R145Q in the human CHCHD2 gene).
In Drosophila, loss of Dmel\Chchd2 function results in mitochondrial and neuronal phenotypes associated with PD pathology, including increased sensitivity to oxidative stress, progressive dopaminergic neuron loss and progressive locomotor dysfunction. Genetic interactions have been described for Dmel\Chchd2; see the Chchd2 gene report.
[updated Jul. 2020 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
[PARKINSON DISEASE 22, AUTOSOMAL DOMINANT; PARK22](https://omim.org/entry/616710)
[COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 2; CHCHD2](https://omim.org/entry/616244)
See general description of Parkinson disease.
Heterozygous mutation in the CHCHD2 gene may be a rare cause of autosomal dominant Parkinson disease (PARK22). [from MIM:616710; 2017.09.08]
The protein encoded by CHCHD2 (Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2) is a transcription factor that binds to the oxygen responsive element in the promoter of COX4I2, a subunit of the terminal enzyme of the electron transport chain. CHCHD2 has been shown that this protein is a negative regulator of mitochondria-mediated apoptosis. [Gene Cards, CHCHD2; 2017.09.11]
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.
