A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression

• Published in: European journal of medical genetics Vol. 57; no. 5; pp. 207 - 211
• Main Authors: Bürk, Katrin, Kaiser, Frank J, Tennstedt, Stephanie, Schöls, Ludger, Kreuz, Friedmar R, Wieland, Thomas, Strom, Tim M, Büttner, Thomas, Hollstein, Ronja, Braunholz, Diana, Plaschke, Jens, Gillessen-Kaesbach, Gabriele, Zühlke, Christine
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.04.2014
• Subjects: Adult; Aged; Aged, 80 and over; CACNA1A; Calcium Channels - genetics; Cerebellum - abnormalities; Cerebellum - pathology; Disease Progression; DNA Mutational Analysis; EA2; Female; FHM1; Genetic Association Studies; Humans; Ion channel gene defects; Male; Medical Education; Middle Aged; Models, Molecular; Molecule dynamic simulation; Mutation, Missense; Protein Structure, Tertiary; SCA6; Spinocerebellar ataxia; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - pathology; Molecule dynamic simulation; SCA6; Spinocerebellar ataxia; FHM1; EA2; CACNA1A; Ion channel gene defects
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2014.01.005

Abstract Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico , protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function. The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.