A new family with transportinopathy: increased clinical heterogeneity

Abstract

We describe a family with a novel TNPO3 mutation of limb–girdle muscular dystrophy D2 (or LGMD 1F), a rare muscle disorder with autosomal dominant inheritance, first identified in an Italo-Spanish family where the causative defect has been found to be due to TNPO3 gene mutation, encoding transportin-3 protein (TNPO3). We present the clinical, histopathological and muscle magnetic resonance imaging (MRI) features in two patients, mother and son Hungarian origin, affected by LGMD D2 and correlate their clinical, MRI and histopathological data found in this condition. The affected son presented early pelvic girdle muscle weakness and thin muscles similar to a congenital myopathy; the mother was less compromised and had an LGMD phenotype. Muscle MRI showed a very pronounced lower limb muscle atrophy in both patients. The most relevant change obtained in the child muscle biopsy was a generalized type 1 fibre atrophy. The two patients presented the same mutation, but a different phenotype has been observed in mother and son.

Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model

“…4,6 First identified in an Italo-Spanish family, it is caused by deletion of an adenine in the stop codon of the TNPO3 gene which extends the C-terminal of the protein by 15 amino acids. 9,10 Although two new families and a sporadic case of LGMDD2 with different TNPO3 mutations have recently been identified, 14 of the 15 amino acids initially described in the disease are conserved, [10][11][12][13][14] thus strongly supporting the pathogenic role of this sequence. Given that our sTNPO-3mut flies include this pathogenic sequence, we believe that our fly model will have general application to understand LGMDD2 despite the different mutations that may originate the disease.…”

“…(A) Peptide sequence of wild type and different mutations in TNPO3 as described in Refs. [10][11][12][13][14] The wild-type sequence is indicated in black; purple sequence indicates the 14 amino acids conserved in all mutations and green marks new amino acids as a consequence of frameshift mutations. (B) Representative blots and quantification of TNPO3 and HA were performed using protein extracts from thoraces of control flies (MHC-Gal4>UAS-GFP), flies expressing wild-type TNPO3 (MHC-Gal4>UAS-TNPO3wt), and mutant TNPO3 flies (MHC-Gal4>UAS-TNPO3mut).…”

“…Nonetheless, these new mutations cause a similar extension in the C-terminal domain of TNPO3, with 14 identical amino acids (Figure 1A), so they are predicted to play the same pathogenic role as c.2771delA. 6,[10][11][12][13][14] Due to the dominant nature of LGMDD2 pathology, overexpression of the human TNPO3mut version of the protein was hypothesized to be sufficient to trigger similar muscular defects in the fly. To this end, two transgenic Drosophila were generated: one expressed a transgene with the c.2771delA mutant version of human TNPO3 (UAS-TNPO3mut), and another expressed the wild type version (UAS-TNPO3wt) as control of the former.…”

“…Importantly, all mutations give rise to a common 14-amino-acid C-terminal extension, which plays a pathogenic role regardless of the mutation type that generates it. 6,[9][10][11][12][13][14] TNPO3 is a Ran-GTP-dependent βimportin that binds to serine and arginine-rich proteins (SR proteins) through its C-terminal domain, transporting them from cytosol to the nucleus. SR proteins include essential splicing factors and proteins mainly involved in mRNA splicing and metabolism.…”

Dysphagia in adult myopathies

“…Since these patients were wheelchairbound swallowing difficulty seems to be associated with advanced disease [85] . In another subtype of dominant LGMD which is due to a mutation in the termination codon of transportin 3 (TNPO3) gene dysphagia is found in 30% of the cases [86] . Interestingly, dysphagia may be transient [87] .…”