This report describes spinocerebellar ataxia 31 (SCA31), a subtype of spinocerebellar ataxia; SCA31 exhibits autosomal dominant inheritance. SCA31 is caused by a 2.5- to 3.8-kb insertion containing pentanucleotide repeats, predominantly (TGGAA)n [(UGGAA)n], within an intron of the BEAN1 gene. The fly model of SCA31 makes use of synthetic constructs consisting of variable numbers of TGGAA repeats; expression is controlled by the UAS/GAL4 system. This allows assessment of the effects of the pentanucleotide repeats independent of location within a specific gene; see the report for synthetic gene Zzzz\UGGAA. See also the human disease model report 'RNA repeat diseases' (FBhh0000059).
Using assays in the adult eye, expression of UGGAA repeats in the developing eye induced phenotypes indicative of toxicity, with severity of the phenotypes dependent on repeat length and gene dosage. For constructs causing the more severe phenotypes, accumulation of (UGGAA)n as RNA foci in eye imaginal discs was observed. In addition, translation of the repeat was demonstrated: translation of the UGGAA repeat in all frames results in the production of an identical polypeptide, poly-WNGME; an antibody directed against a WNGME tetramer showed presence of the repeat-associated polypeptide in the imaginal discs. [Note that the UGGAAUGGAA repeat sequence includes potential AUG start codons, so this case may not involve repeat-associated non-ATG translation (RAN).]
This system has been used to test the efficacy of naphthyridine carbamate dimer (NCD) against SCA31. When NCD was fed to larvae expressing UGGAA repeats in the developing eye, the degeneration phenotypes in the adult eye were suppressed.
[updated Jan. 2021 by FlyBase; FBrf0222196]
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias,' (SCAs) even though 'spinocerebellar' is a hybrid term, referring to both clinical signs and neuroanatomical regions (Margolis, 2003, pubmed:14628900). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord, and the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From MIM:164400, 2015.10.27]
The autosomal dominant cerebellar degenerative disorders are generally referred to as 'spinocerebellar ataxias' (SCAs). Neuropathologists have defined SCAs as cerebellar ataxias with variable involvement of the brainstem and spinal cord; the clinical features of the disorders are caused by degeneration of the cerebellum and its afferent and efferent connections, which involve the brainstem and spinal cord (Schols et al., 2004 pubmed:15099544; Taroni and DiDonato, 2004, pubmed:15263894). [From MIM:164400, 2015.10.27]
[SPINOCEREBELLAR ATAXIA 31; SCA31](https://omim.org/entry/117210)
[BRAIN-EXPRESSED, ASSOCIATED WITH NEDD4, 1; BEAN1](https://omim.org/entry/612051)
See general description of spinocerebellar ataxia. The average age at onset is in the 50's. Affected individuals have gait ataxia, cerebellar dysarthria, limb ataxia, decreased muscle tone, and horizontal gaze nystagmus. SCA31 is a common type of autosomal-dominant cerebellar ataxia in Japan. [from MIM:617018; 2017.09.25]
Spinocerebellar ataxia-31 (SCA31) is caused by a 2.5- to 3.8-kb insertion containing pentanucleotide repeats including (TGGAA)n within an intron of the BEAN gene; it is inherited as an autosomal dominant. It has been observed that the length of the SCA31 insertion is inversely correlated with the age at disease onset. [from MIM:617018; 2017.09.25]
Neuropathologic examination of 1 patient showed moderate cerebellar atrophy with Purkinje cell degeneration. [from MIM:617018; 2017.09.25]
In SCA31, disease-causing microsatellites consist of pentanucleotide repeat complexes, including (TGGAA)n, (TAGAA)n, (TAAAATAGAA)n, and (TAAAA)n, located in an intron shared by two different genes: brain expressed associated with NEDD4-1 (BEAN1) and thymidine kinase 2 (TK2). RNA foci containing UGGAA repeats were observed in Purkinje cell nuclei of SCA31 patients, but not in control individuals, therefore, (TGGAA)n is considered the critical motif of SCA31 pathogenesis, supporting a gain-of-toxic-function hypothesis of pathogenesis. [FBrf0235231 and references cited therein.]
The protein encoded by BEAN1 is one of several that interact with NEDD4, a member of a family of ubiquitin-protein ligases. [Gene Cards, BEAN1; 2017.09.27]
No gene orthologous to BEAN1 has been identified in Drosophila.
