Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing.
Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness, which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM-associated haplotype followed by whole exome sequencing. Within the conserved haplotype, we identified a single heterozygous mutation c.1150G>A (p.E384K) in T-cell intracellular antigen-1 (TIA1) in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing, and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7, and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1,050 years, which coincides with the epoch of early seafaring across the Baltic Sea.
Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Joakim
J
Klar
Maria
M
Sobol
Atle
A
Melberg
Katrin
K
Mäbert
Adam
A
Ameur
Anna C V
AC
Johansson
Lars
L
Feuk
Miriam
M
Entesarian
Hanna
H
Orlén
Olivera
O
Casar-Borota
Niklas
N
Dahl
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D049310:Distal Myopathies / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005091:Exons; D018703:Founder Effect; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D039102:Poly(A)-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D016415:Sequence Alignment; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D000074019:T-Cell Intracellular Antigen-1
D039102:Poly(A)-Binding Proteins; D055540:Survival of Motor Neuron 2 Protein; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human