• autosomal recessive spinocerebellar ataxia 24

This report describes spinocerebellar ataxia autosomal recessive 24 (SCAR24), which is a subtype of spinocerebellar ataxia, autosomal recessive. The human gene implicated in this disease is UBA5 (ubiquitin-like modifier activating enzyme 5), which activates a key ubiquitin-like post-translational modifier protein. There is a single orthologous gene in Drosophila, Dmel\Uba5, or which loss-of-function mutations and RNAi-targeting constructs have been generated. The human UBA5 gene is also implicated in a form of epilepsy (EIEE44, MIM:617132).

Several genes (UFM1, UBA5, and UFC1) that have roles in a common ubiquitination-like post-translational-modification process have been tentatively implicated in development of autosomal recessive spinocerebellar ataxia (see also FBhh0000614 and FBhh0000615). In flies, RNAi-effected knockdown of any of the three orthologous genes results in similar phenotypes.

Multiple UAS constructs of the human Hsap\UBA5 gene have been introduced into flies, including wild-type and variants associated with SCAR24. Partial heterologous rescue (functional complementation) is observed when the wild-type human gene is used, but not when either disease-associated variant is used.

Variant(s) implicated in human disease tested (as transgenic human gene, UBA5): the R246* and K310E (K254E) variant forms have been introduced into flies; both of these variants are implicated in SCAR24.

Flies that are null for Dmel\Uba5 die during the embryonic stage. Ubiquitous knockdown of Dmel\Uba5 effected by RNAi results in adults with visible phenotypes, locomotor defects, and shortened lifespan. Neuron-specific knockdown results in neuroanatomical defects in larval neuromuscular junctions. Physical interactions of Dmel\Uba5 have been described; see below and in the Uba5 gene report.

[updated Sep. 2017 by FlyBase; FBrf0222196]