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Eur J Hum Genet. 2014 Apr;22(4):505-10. doi: 10.1038/ejhg.2013.173. Epub 2013 Aug 28.

A novel locus for episodic ataxia:UBR4 the likely candidate.

Author information

1
Temple Street Children's University Hospital, Temple Street, Dublin, Ireland.
2
University College Dublin, Belfield, Dublin, Ireland.
3
The Adelaide and Meath Hospital, incorporating the National Children's Hospital (AMNCH), Tallaght, Dublin, Ireland.
4
Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
5
1] Temple Street Children's University Hospital, Temple Street, Dublin, Ireland [2] Our Lady's Children's Hospital, Crumlin, Dublin, Ireland [3] National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
6
1] University College Dublin, Belfield, Dublin, Ireland [2] The Academic Centre on Rare Diseases, University College Dublin, Belfield, Dublin, Ireland.

Abstract

Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca(2+) protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca(2+) control within neuronal cells highlights its potential for a role in this form of EA.

PMID:
23982692
PMCID:
PMC3953901
DOI:
10.1038/ejhg.2013.173
[Indexed for MEDLINE]
Free PMC Article
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