title: Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene.
abstract: In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies.
authors.affiliation: Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, VHIR, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129 08035 Barcelona, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Melià
authors.forename: Akatsuki
authors.initials: A
authors.lastname: Kubota
authors.forename: Saida
authors.initials: S
authors.lastname: Ortolano
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Vílchez
authors.forename: Josep
authors.initials: J
authors.lastname: Gámez
authors.forename: Kurenai
authors.initials: K
authors.lastname: Tanji
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bonilla
authors.forename: Lluís
authors.initials: L
authors.lastname: Palenzuela
authors.forename: Israel
authors.initials: I
authors.lastname: Fernández-Cadenas
authors.forename: Anna
authors.initials: A
authors.lastname: Pristoupilová
authors.forename: Elena
authors.initials: E
authors.lastname: García-Arumí
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D028961:beta Karyopherins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C546476:TNPO3 protein, human; D028961:beta Karyopherins
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