Abstract
Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Anheim M, Tranchant C, Koenig M : The autosomal recessive cerebellar ataxias. N Engl J Med 2012; 366: 636–646.
Sailer A, Houlden H : Recent advances in the genetics of cerebellar ataxias. Curr Neurol Neurosci Rep 2012; 12: 227–236.
Woods CG, Cox J, Springell K et al: Quantification of homozygosity in consanguineous individuals with autosomal recessive disease. Am J Hum Genet 2006; 78: 889–896.
Ikeda Y, Dick KA, Weatherspoon MR et al: Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 2006; 38: 184–190.
Cho E, Fogel BL : A family with spinocerebellar ataxia type 5 found to have a novel missense mutation within a SPTBN2 spectrin repeat. Cerebellum 2012; 12: 162–164.
Jacob FD, Ho ES, Martinez-Ojeda M, Darras BT, Khwaja OS : Case of infantile onset spinocerebellar ataxia type 5. J Child Neurol 2012, e-pub ahead of print 21 August 2012; doi:10.1177/0883073812454331.
Ahmed ZM, Morell RJ, Riazuddin S et al: Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hum Genet 2003; 72: 1315–1322.
Melchionda S, Ahituv N, Bisceglia L et al: MYO6, the human homologue of the gene responsible for deafness in Snell’s waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. Am J Hum Genet 2001; 69: 635–640.
Perkins EM, Clarkson YL, Sabatier N et al: Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 2010; 30: 4857–4867.
Forman OP, De Risio L, Stewart J, Mellersh CS, Beltran E : Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation. BMC Genet 2012; 13: 55.
Lise S, Clarkson Y, Perkins E et al: Recessive mutations in SPTBN2 implicate beta-III spectrin in both cognitive and motor development. PLoS Genet 2012; 8: e1003074.
Acknowledgements
We are indebted to the families that participated in this study. HJB was supported by the Deutsche Heredo-Ataxie-Gesellschaft e.V., http://www.ataxie.de. The research leading to these results received funding from the European Community's Seventh Framework Program FP7/2007-2013 under grant agreement 2012-305121 (project acronym NeurOmics) to RH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
HJB is employee of Bioscientia, which is part of a publicly traded diagnostic company. The remaining authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on European Journal of Human Genetics website
Rights and permissions
About this article
Cite this article
Elsayed, S., Heller, R., Thoenes, M. et al. Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations. Eur J Hum Genet 22, 286–288 (2014). https://doi.org/10.1038/ejhg.2013.150
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2013.150
Keywords
This article is cited by
-
The inherited cerebellar ataxias: an update
Journal of Neurology (2023)
-
A heterozygous GRID2 mutation in autosomal dominant cerebellar ataxia
Human Genome Variation (2022)
-
Spinocerebellar Ataxia Type 5 (SCA5) Mimicking Cerebral Palsy: a Very Early Onset Autosomal Dominant Hereditary Ataxia
The Cerebellum (2022)
-
Between SCA5 and SCAR14: delineation of the SPTBN2 p.R480W-associated phenotype
European Journal of Human Genetics (2018)
-
A Novel Homozygous Mutation in SPTBN2 Leads to Spinocerebellar Ataxia in a Consanguineous Family: Report of a New Infantile-Onset Case and Brief Review of the Literature
The Cerebellum (2018)
