• autosomal dominant cerebellar ataxia

Known mutations in the human gene CACNA1A (calcium voltage-gated channel subunit alpha-1A) cause a range of neurological disorders with some overlapping symptoms and with highly variable severity; all exhibit autosomal dominant inheritance (MIM:601011). This report describes characterization of missense variants of CACNA1A that cause severe congenital disease, with severe early onset developmental delay, congenital ataxia, and other neurological abnormalities.

CACNA1A is bicistronic: it encodes the voltage-gated calcium channel subunit, plus a putative transcription factor, α1ACT. α1ACT initiates from an alternative downstream translation start site in the CACNA1A gene. There is one high-scoring fly ortholog of CACNA1A, cac, for which classical amorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Drosophila cac protein isoforms have very little overlap with the short α1ACT human isoform. Dmel\cac is also orthologous to two additional human genes, CACNA1B and CACNA1E.

Expansion of the (CAG)n repeat within the region that encodes α1ACT is associated with several of diseases associated with CACNA1A, most frequently with spinocerebellar ataxia 6 (SCA6; MIM:183086). UAS constructs of the α1ACT isoform of the human Hsap\CACNA1A gene have been introduced into flies, including the wild-type isoform, and a construct with expanded (CAG)n repeats; see the Human Disease Model Report for spinocerebellar ataxia 6 (FBhh0000428). Loss-of-function mutations of CACNA1A are frequently associated with episodic ataxia type 2 (EA2; MIM:108500), which is characterized by spells of incoordination and imbalance, often with slowly progressive ataxia, and with age of onset in childhood or early adulthood. Familial hemiplegic migraine 1 (FHM1; MIM:141500) is most frequently associated with missense mutations thought to be gain-of-function alleles; FHM1 may also be associated with slowly progressive ataxia.

In Drosophila, animals homozygous for amorphic mutations of Dmel\cac die in the embryonic stage. Animals carrying less severe mutations exhibit neuroanatomy, neurophysiology, and behavioral defects. Physical and genetic interactions of cac have been described; see below and in the cac gene report.

A large transgenic construct able to support production of all cac isoforms has been introduced into flies; missense variants analogous to R1673P and R1664Q in the human gene were introduced by targeted recombination. The wild-type construct and each of the missense constructs were tested for capacity to rescue the lethal cac phenotype; they were additionally characterized using phenotypes in the fly visual system. It was originally assumed that both R1673P and R1664Q are severe loss-of-function alleles, however, R1673P was found to exhibit dominant gain-of-function phenotypes. This is a critical distinction, since the efficacy of different medication regimens has been observed to differ for known loss-of-function vs. gain-of-function pathogenic variants of CACNA1A.

Variant(s) implicated in human disease tested [as analogous mutation in fly gene; amino acid coordinates for cac-PE (UniProtKB P91645)]: R1205P in the fly cac gene [corresponds to R1673P (R1672P) in the human CACNA1A protein]; R1196Q in the fly cac gene [corresponds to R1664Q (R1669Q) in the human CACNA1A protein]. By genomic location: R1205P requires X:11954217 , G>C (equivalent change in the cac transgene); R1664Q requires X:11954244 , G>A (equivalent change in the cac transgene); these changes are within an exon present in all Dmel\cac isoforms.

[updated Jan. 2018 by FlyBase; FBrf0222196]