title: Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies.
abstract: The recently described human anion channel Anoctamin (ANO) protein family comprises at least ten members, many of which have been shown to correspond to calcium-activated chloride channels. To date, the only reported human mutations in this family of genes are dominant mutations in ANO5 (TMEM16E, GDD1) in the rare skeletal disorder gnathodiaphyseal dysplasia. We have identified recessive mutations in ANO5 that result in a proximal limb-girdle muscular dystrophy (LGMD2L) in three French Canadian families and in a distal non-dysferlin Miyoshi myopathy (MMD3) in Dutch and Finnish families. These mutations consist of a splice site, one base pair duplication shared by French Canadian and Dutch cases, and two missense mutations. The splice site and the duplication mutations introduce premature-termination codons and consequently trigger nonsense-mediated mRNA decay, suggesting an underlining loss-of-function mechanism. The LGMD2L phenotype is characterized by proximal weakness, with prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The MMD3 phenotype is associated with distal weakness, of calf muscles in particular. With the use of electron microscopy, multifocal sarcolemmal lesions were observed in both phenotypes. The phenotypic heterogeneity associated with ANO5 mutations is reminiscent of that observed with Dysferlin (DYSF) mutations that can cause both LGMD2B and Miyoshi myopathy (MMD1). In one MMD3-affected individual, defective membrane repair was documented on fibroblasts by membrane-resealing ability assays, as observed in dysferlinopathies. Though the function of the ANO5 protein is still unknown, its putative calcium-activated chloride channel function may lead to important insights into the role of deficient skeletal muscle membrane repair in muscular dystrophies.
authors.affiliation: Laboratoire de Neurogénétique de la Motricité, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bolduc
authors.forename: Gareth
authors.initials: G
authors.lastname: Marlow
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Khalil
authors.initials: K
authors.lastname: Saleki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Johan
authors.initials: J
authors.lastname: Kroon
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
authors.forename: Yves
authors.initials: Y
authors.lastname: Robitaille
authors.forename: Lucie
authors.initials: L
authors.lastname: Parent
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Kuniko
authors.initials: K
authors.lastname: Mizuta
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kamata
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.forename: Wim H J P
authors.initials: WH
authors.lastname: Linssen
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Mahjneh
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.forename: Rumaisa
authors.initials: R
authors.lastname: Bashir
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000328:Adult; D000368:Aged; D000075368:Anoctamins; D001483:Base Sequence; D002170:Canada; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D003513:Cycloheximide / Q000494:pharmacology; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D005190:Family; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics; D009132:Muscles / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: C547813:ANO5 protein, human; D000075368:Anoctamins; D018118:Chloride Channels; D018389:Codon, Nonsense; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D003513:Cycloheximide