This report describes dentatorubral-pallidoluysian atrophy (DRPLA); DRPLA is inherited as an autosomal dominant. The human gene implicated in this disease is ATN1, which encodes atrophin 1 and functions as a transcription corepressor. DRPLA is one of a number cerebellar ataxias caused by expansion of CAG repeats within the coding region of the causative gene, resulting in an expanded run of glutamine (Q) residues in the encoded protein. There is one identified fly ortholog of ATN1, Gug, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. Dmel\Gug is orthologous to a second human gene, RERE.
Multiple UAS constructs of the human Hsap\ATN1 gene have been introduced into flies, including wild-type ATN1, C-terminal deletion constructs, and constructs with expanded (CAG)n repeats. Expression in the adult eye results in progressive eye depigmentation and retinal collapse; conditional expression in adult stages in neural and glial cells results in reduced viability and neural defects.
Variant(s) implicated in human disease tested (as transgenic human gene, ATN1): Q484_Q502 (CAG)n EXPANSION; most experiments have used a truncated protein with the polyQ expansion.
Loss-of-function alleles of Dmel\Gug are lethal, usually during the embryonic stage; somatic clones exhibit cell polarity defects. Physical and genetic interactions have been described for Dmel\Gug; see below and in the gene report for Gug.
Extensive studies have also been done with polyglutamine-only models in flies; see the disease report for polyglutamine diseases, polyQ models (FBhh0000001).
[updated Sep. 2018 by FlyBase; FBrf0222196]
[DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA](https://omim.org/entry/125370)
[ATROPHIN 1; ATN1](https://omim.org/entry/607462)
Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, choreoathetosis, and dementia or character changes in adults and ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children. The age of onset is from one to 62 years with a mean age of onset of 30 years. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia. Cardinal features in children are progressive intellectual deterioration, behavioral changes, myoclonus, and epilepsy. [from GeneReviews, DRPLA, pubmed:20301664 2016.03.10]
Small, round ubiquitin-immunoreactive intranuclear inclusions have been observed in both neurons and glial cells in various brain regions taken from DRPLA patients. Electron microscopy showed that such inclusions are composed of granular and filamentous structures. The findings strongly suggested that, in DRPLA, the occurrence of neuronal and glial inclusions is directly related to the causative expanded CAG repeat, that neurons are affected much more widely than previously recognized, and that glial cells are also involved in the disease process (Hayashi, et al, 1998, pubmed:9845282). Some patients with DRPLA have white matter lesions characterized neuropathologically by diffuse myelin pallor. The number of lesions correlates with increasing age, being milder in degree in juveniles and more severe in older adults. Immunoreactivity for polyglutamine in some glial nuclei was increased with larger expansions of (CAG)n repeats, indicating that oligodendrocytes are a target for the polyglutamine pathogenesis in DRPLA and may lead to white matter degeneration (Yamada, et al., 2002, pubmed:2402270). [from OMIM:125370, 2016.03.09]
The protein encoded by ATN1 acts a transcriptional corepressor. [from Gene Cards, ATN1; 2017.03.01]
Ortholog of human RERE and ATN1 (1 Drosophila to 2 human).
Dmel\Gug shares 24% identity and 31% similarity with human RERE, and 23% identity and 31% similarity with human ATN1.