Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogeneous diseases presenting with a wide clinical spectrum. Autosomal dominant LGMDs represent about 10-15%  and include  DNAJB6, transportin-3 defects.

TPNO3 encodes a nuclear membrane protein of the importin family which transports serine/arginine-rich proteins, such as splicing factors and HIV into the nucleus. LGMD D2 has dominant transmission, due to a nuclear dysfunction, which involves transportin-3 with dominant negative mechanism.

 The clinical spectrum of LGMD D2 was first identified in a large italo-spanish family, characterized by severe muscle weakness with onset in childhood in the pelvic girdle, while in adult cases both girdles are involved. The spectum now consists both of families and sporadic cases,there are  new familial cases identified with a frame-shift deletion and  isolated cases carrying missense mutation that present distinct clinical-genetic histopathologic and MRI features. Clinical and MRI features suggest that a spectrum of clinical phenotypes are present from a early childhood congenital myopathy to a late-onset pauci-symtomatic phenotype. 

The protein turnover is clearly linked to the activation of the autophagic machinery causing fiber atrophy.TNPO3 is involved in muscle differentiation we studied  C2C12 myoblasts: they normally express TNPO3, but its levels undergo quantitative variation in the nuclear and in the cytoplasmic compartments in myoblasts differentiating in myotubes. We found an involvement TNPO3 in the myogenic process and the analysis of TNPO3 and SRSF1 interaction during myogenesis, through structured illumination microscopy, showed that their dynamics follows the myogenesis.

The dysfunction of TNPO3 gene is related to the nuclear transport of SR proteins and suggests a novel nuclear disease mechanism,leading to muscular dystrophy. We present the study on cell model and their main possible applications to human disease. Perspectives for actual and possible therapeutic developments are considered.