LImb-girdle muscular dystrophy 1F/D2 is a rare neuromuscular disorder with  autosomal dominant or sporadic inheritance.So far three families and few sporadic patients have been described.

Clinical investigation reveals a high variability, spanning from a severe chilhood form  to a slow adult-onset phenotype.The genetic defect has been identified in causative mutations in TNPO3 gene,that codes for transportin-3 ,a dimeric protein that transports from cytoplasm to nucleus SR rich proteins involved in alternative splicing and RNA metabolism.

We analized  muscle biopsies of a daughter/mother couple  by  histochemical techniques, we performed MURF1 immunoblotting ,  studied by immunohistochemistry the expression of transportin-3 and  cytoskeletal proteins myotilin and desmin  ,evaluated fiber atrophy and hypertrophy factors.The patients were followed clinically and by muscle MRI imaging.

Myo-MIRNAs(Mir1,MiR 206,Mir133a,Mirr133b )were obtained from serum and analised as possible biomarkers .

There was a generalised fiber atriophy that increased in two subsequent biopsies of the daughter.In both patients there was accumulation of cytoskeleton (desmin,myotilin ) causing large protein aggregates.Immunoblotting revealed increase of MURF-1 a marker of ubiquitin -proteasome degradation pathway, leading to muscle atrophy.

MURF-1 showed an increased level in  the daughter that had a severe course and correlated with clinical worsening both in  functional performances and  neuroimaging.

Transportin-3 protein was present in perinuclear and cytoplasmic level suggesting a block of import/export of proteins.

Among myo-microRNAs there was progressive and selective increased expression of MicroRNA 206, which is related to muscle remodeling.

The variability of clinical phenotype together with histopathological and molecular findings suggest that several molecular pathways are involved, such as protein shuttling from cytoplasm to nucleus,blocked autophagy with protein aggregates formation.

We also found that Mir-206 represents a biomarker of disease progression.