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Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F.

Torella A, Fanin M, Mutarelli M, Peterle E, Del Vecchio Blanco F, Rispoli R, Savarese M, Garofalo A, Piluso G, Morandi L, Ricci G, Siciliano G, Angelini C, Nigro V - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: TIGEM (Telethon Institute of Genetics and Medicine), Napoli, Italy.

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.

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Related in: MedlinePlus

Western blot analysis of skeletal muscle tissue with antibodies to TNPO3.Equal amounts of muscle proteins from a LGMD1F patient and a control were run in each lane (10 µg) on a 9% SDS-polyacrylamide gel and then blotted onto nitrocellulose membrane. In this experiment, we used a monoclonal antibody that recognizes a recombinant fragment (Human) near the N terminus of TNPO3 at a 1∶100 dilution. A double band is visible in the patient only.
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pone-0063536-g003: Western blot analysis of skeletal muscle tissue with antibodies to TNPO3.Equal amounts of muscle proteins from a LGMD1F patient and a control were run in each lane (10 µg) on a 9% SDS-polyacrylamide gel and then blotted onto nitrocellulose membrane. In this experiment, we used a monoclonal antibody that recognizes a recombinant fragment (Human) near the N terminus of TNPO3 at a 1∶100 dilution. A double band is visible in the patient only.

Mentions: We then performed immunoblotting analyses of the skeletal muscle biopsy using the anti TNPO3 antibody. While mutant form A is virtually overlapping with wild-type form A, a mutant form B can be appreciated by western blot analysis of muscle samples as a higher molecular weight band (Figure 3).


Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F.

Torella A, Fanin M, Mutarelli M, Peterle E, Del Vecchio Blanco F, Rispoli R, Savarese M, Garofalo A, Piluso G, Morandi L, Ricci G, Siciliano G, Angelini C, Nigro V - PLoS ONE (2013)

Western blot analysis of skeletal muscle tissue with antibodies to TNPO3.Equal amounts of muscle proteins from a LGMD1F patient and a control were run in each lane (10 µg) on a 9% SDS-polyacrylamide gel and then blotted onto nitrocellulose membrane. In this experiment, we used a monoclonal antibody that recognizes a recombinant fragment (Human) near the N terminus of TNPO3 at a 1∶100 dilution. A double band is visible in the patient only.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646821&req=5

pone-0063536-g003: Western blot analysis of skeletal muscle tissue with antibodies to TNPO3.Equal amounts of muscle proteins from a LGMD1F patient and a control were run in each lane (10 µg) on a 9% SDS-polyacrylamide gel and then blotted onto nitrocellulose membrane. In this experiment, we used a monoclonal antibody that recognizes a recombinant fragment (Human) near the N terminus of TNPO3 at a 1∶100 dilution. A double band is visible in the patient only.
Mentions: We then performed immunoblotting analyses of the skeletal muscle biopsy using the anti TNPO3 antibody. While mutant form A is virtually overlapping with wild-type form A, a mutant form B can be appreciated by western blot analysis of muscle samples as a higher molecular weight band (Figure 3).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: TIGEM (Telethon Institute of Genetics and Medicine), Napoli, Italy.

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.

Show MeSH
Related in: MedlinePlus