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Eur J Med Genet. 2014 Apr;57(5):207-11. doi: 10.1016/j.ejmg.2014.01.005. Epub 2014 Jan 29.

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

Author information

1
Department of Neurology, Philipps University of Marburg, Germany.
2
Institute of Human Genetics, University of Lübeck, Germany.
3
Institut für Integrative und Experimentelle Genomik, University of Lübeck, Germany.
4
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
5
Center for Human Genetics, Dresden, Germany.
6
Institute of Human Genetics, Helmholtz-Zentrum München, Neuherberg, Germany.
7
Institute of Human Genetics, Helmholtz-Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, München, Germany.
8
Department of Neurology, Hans-Susemihl Hospital, Emden, Germany.
9
Institute of Human Genetics, University of Lübeck, Germany. Electronic address: Christine.Zuehlke@uksh.de.

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.

KEYWORDS:

CACNA1A; EA2; FHM1; Ion channel gene defects; Molecule dynamic simulation; SCA6; Spinocerebellar ataxia

PMID:
24486772
DOI:
10.1016/j.ejmg.2014.01.005
[Indexed for MEDLINE]
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