P.154 A novel TIA1 frameshift variant in a dominant myopathy family

Abstract

The proband is a 58-year-old woman with a 6-7-year history of wasting of the thumb muscles. The clinical phenotype resembles Welander distal myopathy (WDM). The family history suggests autosomal dominant inheritance: the proband's father had abnormal gait in his 30s, developed weak hands in his 50s, and required AFOs by his 70s. Two paternal uncles and one paternal aunt were similarly affected and clinically examined more than 30 years ago. These relatives are now deceased, preventing genetic analysis. A biopsy from the upper limb extensor muscles of the affected uncle revealed fibers containing rimmed vacuoles, in line with a WDM-like phenotype. Clinical examination of the proband revealed mild symmetrical weakness of shoulder abduction, marked wasting of the thenar eminence and first dorsal interosseus muscles bilaterally, and asymmetric weakness of finger and thumb abduction and finger extension. Creatine kinase was within normal limits, and peripheral neurophysiological assessment showed myopathic changes in the intrinsic hand and peroneus tertius muscles. Whole body MRI revealed bilateral diffuse signal change on STIR sequences of the superficial thenar muscles and accompanied by bilateral fatty infiltration on T1 images. Sequencing of the proband revealed a heterozygous variant in <i>TIA1</i> (NM_022173.3: c.1144_1145delinsC; p.G382Rfs*7). The RNA-binding protein <i>TIA1</i> is a key component of stress granules and it is also involved in splicing regulation. The <i>TIA1</i> missense mutation p.E384K has previously been established as the cause of classical Welander distal myopathy, whereas the p.N357S variant drives a myopathic phenotype in patients with a <i>SQSTM1</i> mutation. The identified <i>TIA1</i> variant was hence a good candidate for causing the disease in our family. The deletion-insertion mutation causes a frameshift in the C-terminal prion-like domain of the TIA1 protein, replacing the last 5 amino acids with a novel 7-amino-acid tail. While mutant GFP-TIA1 did showed similar expression and solubility as the wild type protein, imaging studies suggest that the mutation may — similarly to other pathogenic <i>TIA1</i> variants — cause disease through altered stress granule dynamics. Our results strongly suggest that the <i>TIA1</i> c.1144_1145delinsC (p.G382Rfs*7) is the cause of Welander distal myopathy in this family.