In affected members of a large Spanish family with autosomal dominant limb-girdle muscular dystrophy type 1F (LGMD1F; 608423) originally reported by Gamez et al. (2001), Melia et al. (2013) identified a heterozygous 1-bp deletion (c.2771A) in the TAG termination codon of the TNPO3 gene, resulting in extension of the reading frame by 15 codons downstream (Ter924CysextTer15). The mutation, which was identified by whole-genome sequencing, segregated with all 29 affected individuals in the family and was not present in 20 unaffected relatives. The mutation was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases, or in over 200 Spanish control alleles. Analysis of patient skeletal muscle cells showed that the mutant mRNA was expressed along with the wildtype protein. Immunostaining of patient muscle showed TNPO3 nuclear staining, but it was unevenly distributed and often limited to the periphery of nuclei compared to control muscle. Melia et al. (2013) postulated a dominant-negative toxic effect.
Independently and simultaneously, Torella et al. (2013) identified the same heterozygous frameshift mutation in affected members of the large Spanish family reported by Gamez et al. (2001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 137) database. Transfection of the mutation into HeLa cells showed that the mutant protein was localized around the periphery of the nucleus, whereas wildtype TNPO3 entered the nucleus.