TIA1 is a gender-specific disease modifier of spinal muscular atrophy

Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant mortality. The allele C mouse model (C+/+) recapitulates various aspects of the mild SMA phenotype and offers an ideal system to monitor the role of disease-modifying factors over a longer period of time. We and others have reported that T-cell-restricted intracellular antigen 1 (TIA1), a RNA-binding protein, regulates SMN2 exon 7 splicing. In addition to its role in transcription and pre-mRNA splicing, TIA1 promotes stress granule formation, an essential cellular process in which SMN also plays an important role. To assess the impact of the loss of TIA1 on SMA severity, we generated C+/+/Tia1-/- mice. We show that Tia1-/- females but not males gain significant body weight during the early postnatal development. Our results reveal a surprisingly finding that the low level of SMN in C+/+/Tia1-/- mice has a counteracting effect on the female-specific body weight gain observed in Tia1-/- mice. We demonstrate that the loss on Tia1 coupled with low SMN has an age- and gender-specific effect on tail necrosis in C+/+/Tia1-/- mice. We observed gender-specific differences in the expression of a number of genes in brain of C+/+/Tia1-/- mice. Further, we show enhanced impairment of male reproductive organ development and exacerbated perturbations in expression of various genes in C+/+/Tia1-/- testes. This is the first report demonstrating the role of a protein factor in gender-specific disease modification of SMA, a major genetic disease affecting children and infants.