SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs.

Human centronuclear and myotubular myopathies belong to a genetically heterogeneous nosological group with clinical variability ranging from fatal disorder to mild weakness. The severe X-linked form is attributed to more than 200 different mutations in the myotubularin encoding gene (MTM1). In contrast, there are no reports regarding the molecular etiology or linkage studies on the autosomal forms of the disease. Labrador retrievers affected by spontaneous centronuclear myopathy (cnm) have clinical and histological features of the human disorder and represent the first model of recessive autosomal centronuclear myopathy. We previously mapped the cnm locus to the centromeric region of canine chromosome 2. No gene of the MTM1 family maps to the human homologous chromosomal region. Described herein is a disease-associated insertion within PTPLA exon 2, found in both alleles of all affected Labradors and in a single allele in obligate carriers. The inserted tRNA-derived short interspersed repeat element (SINE) has a striking effect on the maturation of PTPLA mRNA, whereby it can be spliced out, partially exonized or involved in multiple exon-skipping. As a result, the amount of wild-type transcripts falls to 1% in affected muscles. This example therefore recapitulates cumulative SINE-associated transcriptional defects that have been previously described as exclusive consequences of independent mutations. Although the function of PTPLA in metazoa remains unknown, the characterization of a hypomorphic mutation in Labradors with centronuclear myopathy provides new clues about the molecular complexity of skeletal myofiber homeostasis. These results also suggest that impaired PTPLA signaling might be implicated in human myopathies.