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A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy

Lookup NU author(s): Dr Debbie Hicks, Dr Anna Sarkozy, Dr Nuria Muelas Gomez, Professor Gavin Hudson, Professor Patrick Chinnery, Dr Rita Barresi, Dr Michelle Eagle, Dr Tuomo Polvikoski, Dr James Miller, Dr Steven Laval, Professor Volker StraubORCiD, Professor Hanns Lochmuller, Emerita Professor Katherine Bushby

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Abstract

The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100 000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular dystrophy patients.


Publication metadata

Author(s): Hicks D, Sarkozy A, Muelas N, Koehler K, Huebner A, Hudson G, Chinnery PF, Barresi R, Eagle M, Polvikoski T, Bailey G, Miller J, Radunovic A, Hughes PJ, Roberts R, Krause S, Walter MC, Laval SH, Straub V, Lochmuller H, Bushby K

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2011

Volume: 134

Issue: 1

Pages: 171-182

Print publication date: 01/01/2011

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/brain/awq294

DOI: 10.1093/brain/awq294


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Funding

Funder referenceFunder name
National Commissioning Group (NCG)
036825MD-NET of TREAT-NMD
036825Newcastle University of TREAT-NMD
MD-NET 01GM0887German Ministry of Education and Research (BMBF, Bonn, Germany)

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