title: A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy.
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.
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Debbie
authors.initials: D
authors.lastname: Hicks
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.affiliation: Department of Neurology, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Muelas
authors.affiliation: Children's Hospital, Technical University Dresden, Dresden, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Köehler
authors.affiliation: Children's Hospital, Technical University Dresden, Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Hudson
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Muscle Immunoanalysis Unit, Newcastle upon Tyne Hospitals Trust, Newcastle, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Eagle
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Polvikoski
authors.affiliation: Northern Genetics Service, Institute of Human Genetics, Newcastle upon Tyne, UK.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Bailey
authors.affiliation: Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: James
authors.initials: J
authors.lastname: Miller
authors.affiliation: Neurosciences Clinical Academic Unit, Royal London Hospital, London, UK.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Radunovic
authors.affiliation: Hurstwood Park Neurological Centre, Haywards Heath, West Sussex, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hughes
authors.affiliation: Ninewells Hospital & Medical School, Ninewells, Dundee, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Roberts
authors.affiliation: Friedrich Baur Institute, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.affiliation: Friedrich Baur Institute, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Laval
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
mesh_terms: D000328:Adult; D000483:Alleles; D000075368:Anoctamins; D018118:Chloride Channels / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D018703:Founder Effect; D005820:Genetic Testing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D012737:Sex Factors
chemical_list: C547813:ANO5 protein, human; D000075368:Anoctamins; D018118:Chloride Channels