TNPO3 – Limb-Girdle Muscular Dystrophy 1F

Transportin-3 (TNPO3) variants underlie autosomal dominant limb-girdle muscular dystrophy 1F (LGMD1F), characterized by proximal pelvic girdle weakness and slow progression. Four independent probands have been reported: a large Italian-Spanish kindred with a frameshift in TNPO3 and an isolated LGMD case with a missense change (PMID:23667635), and a Hungarian family with a novel frameshift observed in mother and son (PMID:31071488). Segregation of heterozygous TNPO3 variants in two families supports a dominant inheritance pattern.

The predominant inheritance mode is autosomal dominant. Segregation analysis identified two additional affected relatives carrying the same TNPO3 variant (PMID:31071488). Case reports and series encompass four probands with heterozygous TNPO3 variants.

The variant spectrum includes C-terminal truncating frameshifts—c.2767del (p.Arg923AspfsTer17) (PMID:31071488); c.2771del (p.Ter924CysextTer?) (PMID:23543484); and rare missense alleles such as c.2453G>A (p.Arg818Gln) (PMID:23667635). No recurrent or founder variants beyond these reports have been described.

Affected individuals present early proximal muscle weakness, slower motor milestones (first walking at 14–18 months; HP:0001270), and pelvic girdle muscle involvement (PMID:31071488). Prevalence is ultra-rare, with carrier frequency below detection in population databases.

Functional studies demonstrate that C-terminal–extended TNPO3 mislocalizes around nuclei, disrupts importin-β transport of serine/arginine-rich splicing factors, and induces nuclear envelope abnormalities in patient muscle (PMID:23543484; PMID:23667635). In Drosophila models, muscle-targeted expression of mutant TNPO3 recapitulates muscle degeneration and atrophy, reversible by autophagy inhibition (PMID:34547132). Patient-derived myoblasts corrected by CRISPR-Cas9 editing of the TNPO3 deletion show normalized TNPO3 expression, rescued autophagy, and restored transcriptomic profiles (PMID:36789274).

No conflicting evidence disputes the TNPO3–LGMD1F association. Overall, strong genetic segregation and concordant functional models support a pathogenic role of heterozygous TNPO3 truncations via a dominant-negative or toxic gain-of-function mechanism. Key take-home: Genetic testing for TNPO3 frameshift variants is recommended for diagnosis of LGMD1F and informs potential autophagy-modulating therapeutic strategies.

References

• PLoS one • 2013 • Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PMID:23667635
• Brain • 2013 • Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene. PMID:23543484
• European Journal of Medical Genetics • 2019 • A novel pathogenic variant in TNPO3 in a Hungarian family with limb-girdle muscular dystrophy 1F. PMID:31071488
• FASEB journal • 2021 • Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model. PMID:34547132
• Molecular Therapy Nucleic Acids • 2023 • CRISPR-Cas9 editing of a TNPO3 mutation in a muscle cell model of limb-girdle muscular dystrophy type D2. PMID:36789274

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