title: Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F.
abstract: Limb-girdle muscular dystrophies (LGMD) are genetically and clinically heterogeneous conditions. We investigated a large family with autosomal dominant transmission pattern, previously classified as LGMD1F and mapped to chromosome 7q32. Affected members are characterized by muscle weakness affecting earlier the pelvic girdle and the ileopsoas muscles. We sequenced the whole exome of four family members and identified a shared heterozygous frame-shift variant in the Transportin 3 (TNPO3) gene, encoding a member of the importin-β super-family. The TNPO3 gene is mapped within the LGMD1F critical interval and its 923-amino acid human gene product is also expressed in skeletal muscle. In addition, we identified an isolated case of LGMD with a new missense mutation in the same gene. We localized the mutant TNPO3 around the nucleus, but not inside. The involvement of gene related to the nuclear transport suggests a novel disease mechanism leading to muscular dystrophy.
authors.affiliation: TIGEM (Telethon Institute of Genetics and Medicine), Napoli, Italy.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Torella
authors.forename: Marina
authors.initials: M
authors.lastname: Fanin
authors.forename: Margherita
authors.initials: M
authors.lastname: Mutarelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Peterle
authors.forename: Francesca
authors.initials: F
authors.lastname: Del Vecchio Blanco
authors.forename: Rossella
authors.initials: R
authors.lastname: Rispoli
authors.forename: Marco
authors.initials: M
authors.lastname: Savarese
authors.forename: Arcomaria
authors.initials: A
authors.lastname: Garofalo
authors.forename: Giulio
authors.initials: G
authors.lastname: Piluso
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D059472:Exome / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*; D028961:beta Karyopherins / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; C546476:TNPO3 protein, human; D028961:beta Karyopherins