Public Release:  New genetic disorder of balance and cognition discovered

PLOS

The family of disorders known as ataxia can impair speech, balance and coordination, and have varying levels of severity. Scientists from the Universities of Oxford and Edinburgh have identified a new member of this group of conditions which is connected to 'Lincoln ataxia', so called because it was first found in the relatives of US President Abraham Lincoln. The results are published in the journal PLOS Genetics.

Lincoln ataxia affects the cerebellum, a crucial part of the brain controlling movement and balance. It is caused by an alteration in the gene for 'beta-III spectrin', a protein found in the cerebellum. Each person has two copies of a gene, and in Lincoln ataxia there is an alteration in only one of the two copies. Unexpectedly, the British scientists have found cases of alterations in both copies of the gene, causing a novel disorder called 'SPARCA1' which is associated with a severe childhood ataxia and cognitive impairment.

This is the first report of any spectrin-related disorder where both copies of the gene are faulty and has given important insights into both Lincoln ataxia and SPARCA1.

The work was done using whole genome sequencing, a relatively new technology which allows all of a person's genetics information to be analysed. In addition to sequencing work, the scientists characterized the condition using mice lacking beta-III spectrin. This analysis, combined with previous work, links the protein defect to changes in nerve-cell shape in the brain areas associated with cognition and coordinated movements. The work shows that loss of normal beta-III spectrin function underlies both SPARCA 1 and Lincoln ataxia, but a greater loss of beta-III spectrin is required before cognition problems arise.

The combination of methods used in this study highlight a broad role for spectrin in normal brain function beyond the cerebellum. There are many brain spectrins and the team are now searching for other abnormalities of spectrin function, as they believe these are part of an expanding group of conditions known as "neuronal spectrinopathies".

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CONTACT:
Dr Andrea H Németh
andrea.nemeth@eye.ox.ac.uk

FINANCIAL DISCLOSURE: This work was funded by AtaxiaUK (A Kwasniewska, AH Németh); the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health's NIHR Biomedical Research Centres funding scheme (S Lamble, A Kwasniewska, E Sadighi Akha, JC Taylor, SJL Knight, AH Németh) and the Oxford Radcliffe Hospital Flexibility and Sustainability Funding (AH Németh); The Wellcome Trust [076113] (P Donnelly), [085475] (P Donnelly), [093077] (M Jackson, Y Clarkson, E Perkins, D Suminaite, J Hope), [075491/Z/04] (J Ragoussis), [090532/Z/09/Z] (L Gregory, A Green, C Allan, S Lamble, D Buck, G Lunter); Medical Research Council (Hub grant G0900747 91070) (L Gregory, A Green, C Allan, S Lamble, D Buck); the Dementia and Neurodegenerative Diseases Network (AH Németh); and CNPq-Brazil (R Parolin Schnekenberg). The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

COMPETING INTERESTS: The authors have declared that no competing interests exist.

CITATION: Lise S, Clarkson Y, Perkins E, Kwasniewska A, Sadighi Akha E, et al. (2012) Recessive Mutations in SPTBN2 Implicate b-III Spectrin in Both Cognitive and Motor Development. PLoS Genet 8(12): e1003074. doi:10.1371/journal.pgen.1003074

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