Submission Details

The TNPO3 gene encodes transportin 3, a nuclear import receptor for serine/arginine-rich (SR) proteins, which are essential precursor-mRNA splicing factors. TNPO3 was first reported in relation to autosomal dominant limb-girdle muscular dystrophy (LGMD) in 2013 by two publications characterizing the same large family (Melia et al., Torella et al., PMID: 23543484, 23667635). TNPO3-related autosomal dominant LGMD is also known as LGMDD2 (MIM #608423). Muscle biopsy tissue typically shows centrally nucleated muscle fibers, rimmed vacuoles, and inclusion bodies (PMID: 11517331).

Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The genetic evidence for this curation includes 6 pts of variant-level evidence awarded to six probands heterozygous for four unique frameshift variants, all of which extend the protein by ~15-20 amino acids, including an identical 14 amino acids at the C-terminus (PMID: 23543484, 23667635, 31192305, 31071488, 31217819, 32403337; ClinVar SCV005419095.1; LOVD Individual #00436410, who could not be entered into the GCI). Other type of variants in TNPO3 should be interpreted with caution. Transportin-3 with the C-terminal extension displayed altered subcellular localization when expressed in HeLa cells, recapitulating the staining patterns observed in patient muscle tissue (PMID: 23543484). A seventh individual with a fifth frameshift variant resulting in the same extension has been reported without phenotype information (ClinVar SCV004491986.2). Variants in this gene segregated with the disease in three families, with the first large Italian-Spanish family yielding a maximum LOD score of 7.56 with 32 affected individuals, contributing 3 pts of segregation evidence.

This gene-disease relationship is also supported by experimental evidence (3 pts), including the protein's transporter function, altered expression in patient tissue, and Drosophila and cell culture models (PMID: 36789274, 32690349, 23543484, 11517331, 34547132). Although the mechanism of disease is not fully understood, TNPO3 variants have been posited to affect multiple systems, including nuclear transport and myofibrillar networks (PMID: 32690349). In summary, there is Definitive evidence supporting the relationship between TNPO3 and autosomal dominant limb girdle muscular dystrophy. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies GCEP on March 11, 2025 (SOP Version 11).

This gene-disease pair was originally evaluated by the Muscular Dystrophies and Myopathies GCEP in May 2023. It was re-evaluated in March 2025 and upgraded from Moderate to Definitive with the addition of new case and experimental data.