This report describes migraine, familial hemiplegic, 1 (FHM1); FHM1 exhibits autosomal dominant inheritance. The human gene implicated in this disease, CACNA1A, encodes a calcium voltage-gated channel alpha subunit. There is one high-scoring Drosophila ortholog, cac, for which classical loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\cac is orthologous to two additional human genes, CACNA1B and CACNA1E. CACNA1A is also implicated in spinocerebellar ataxia 6 (SCA6; MIM:183086; FBhh0000428) and congenital ataxia syndromes, CACNA1A-related (FBhh0000700).
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. Some longer isoforms encode only the α1A calcium channel subunit; others appear to encode a fusion protein. 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). Drosophila cac protein isoforms have very little overlap with the short α1ACT human isoform.
A number of CACNA1A variants implicated in FHM1 appear to be gain-of-function mutations. Mutations analogous to missense variants implicated in FHM1 were introduced into transgenic copies of the Drosophila cac gene and expressed pan-neuronally. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): S161L in the fly cac gene (corresponds to S218L in the human CACNA1A gene), designated cacSL.UAS.EGFP; R135Q in the fly cac gene (corresponds to R192Q in the human CACNA1A gene), designated cacRQ.UAS.EGFP. Observed phenotypes are mild for RQ-expressing animals; however, single mutant SL- and complex allele RQ,SL-expressing animals exhibit sharply decreased viability and neurophysiology defects, including neuronal hyperexcitability. The impact of pharmacological inhibitors of intracellular Ca2+ store release has been assessed.
[updated Jul. 2019 by FlyBase; FBrf0222196]
[MIGRAINE, FAMILIAL HEMIPLEGIC, 1; FHM1](https://omim.org/entry/141500)
[CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A](https://omim.org/entry/601011)
In migraine with aura, including familial hemiplegic migraine, the neurologic symptoms of aura are localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migraine headache. [Gene Reviews, Familial Hemiplegic Migraine; 2018.11.06]
Migraine is the most common type of chronic, episodic headache (MIM:157300). Familial hemiplegic migraine is a subtype of migraine with aura. [from MIM:141500; 2018.11.06]
FHM1 was first described in a family in which attacks of hemicranial pain and associated hemiparesis occurred in 4 generations. Vasoconstriction, followed by focal edema, was thought to be responsible for the neurologic manifestations. Subsequent authors have reported additional associated features: persistent cerebellar dysfunction; retinal degeneration, deafness, and nystagmus; coma, fever, and meningismus. [from MIM:141500; 2018.11.06]
Familial hemiplegic migraine-1 (FHM1) is caused by heterozygous mutation in the CACNA1A gene. [from MIM:141500; 2018.11.06]
CACNA1A encodes a calcium voltage-gated channel subunit; voltage-sensitive calcium channels mediate the entry of calcium ions into excitable cells. CACNA1A encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. [Gene Cards, CACNA1A; 2018.11.06]
In addition to full-length CACNA1A, use of an internal ribosomal entry site in the CACNA1A transcript generates the CACNA1A C-terminal polypeptide, or alpha-1ACT, which functions as a transcription factor that mediates cerebellar development (Du et al., 2013, pubmed:23827678). [from MIM:601011, 2018.01.12]
Many to one: 3 human to 1 Drosophila. The other human genes are CACNA1B and CACNA1E.
Moderate- to high-scoring ortholog of human CACNA1A, CACNA1B and CACNA1E (1 Drosophila to 3 human); Dmel\cac shares 43% identity and 53-55% similarity with the human genes.
