Abstract
The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.
Highlights
T-cell intracellular antigen-I (TIA1, chr.2) is a broadly expressed RNA-binding protein required for the formation of cytoplasmic stress granules, which play a crucial role in preventing misfolded protein accumulation [1]
We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in SQSTM1 (p.Pro392Leu) and a variant in TIA1 (p.Asn357Ser)
There are two further cases of myopathy with rimmed vacuoles (MRVs) having the same TIA1 variant but a different SQSTM1 mutation (c.1165+1G>A) [8], one of whom was previously reported as having a SQSTM1-MRV [6]
Summary
T-cell intracellular antigen-I (TIA1, chr.2) is a broadly expressed RNA-binding protein required for the formation of cytoplasmic stress granules, which play a crucial role in preventing misfolded protein accumulation [1]. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV [5,6,7]. A single SQSTM1 mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient [6]. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, p.Asn357Ser) by Evila et al [8]. Evila et al.’s study reported an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient’s phenotype was not illustrated [8]. The authors raised the possibility of a digenic myopathy [8], which up to date has not been proven
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
