The cnm locus, a canine homologue of human autosomal forms of centronuclear myopathy, maps to chromosome�2

Abstract

Myotubular/centronuclear myopathies are a nosological group of hereditary disorders characterised by severe architectural and metabolic remodelling of skeletal muscle fibres. In most myofibres, nuclei are found at an abnormal central position within a halo devoid of myofibrillar proteins. The X-linked form (myotubular myopathy) is the most prevalent and severe form in human, leading to death during early postnatal life. Maturation of fibres is not completed and fibres resemble myotubes. Linkage analysis in human has helped to identify MTM1 as the morbid gene. MTM1 encodes myotubularin, a dual protein phosphatase. In families in which myotubular myopathy segregates, detected mutations in MTM1 abolish the specific phosphatase activity targeting the second messenger phosphatidylinositol 3-phosphate. Autosomal forms (centronuclear) have a later onset and are often compatible with life. At birth, fibres are normally constituted but progressively follow remodelling with a secondary centralisation of nuclei. Their prevalence is low; hence, no linkage data can be performed and no molecular aetiology is known. In the Labrador Retriever, a spontaneous disorder strikingly mimics the clinical evolution of the human centronuclear myopathy. We have established a canine pedigree and show that the disorder segregates as an autosomal recessive trait in that pedigree. We have further mapped the dog locus to a region on chromosome 2 that is orthologous to human chromosome 10p. To date, no human MTM1 gene member has been mapped to this genetic region. This report thus describes the first spontaneous mammalian model of centronuclear myopathy and defines a new locus for this group of diseases.

Congenital myopathy is caused by mutation of HACD1

“…In contrast to dogs, the histology studies in our patients could not establish the centronuclear form of the myopathy. This may be attributed to the young age at which histological analyses were performed in our patients, and is in correlation with the age effect noted in dogs in which centrally located nuclei were observed in only 30% of myofibers at age 3, while at the age of 7 years, centralization was more obviously noted and detected in as much as 60% of fibers (10). Alternatively, the differences in myopathies in humans versus dogs could result from the difference in modifier genes contributing to the variable clinical stigmata.…”

“…The mutant dogs suffered from congenital myopathy with severe hypotonia. Histologic analysis of this dog model reveals CNM along with type 1 fiber atrophy and a type 2 fiber deficiency in skeletal muscle, which mimics human autosomal dominant and recessive forms of CNM (10). In contrast to dogs, the histology studies in our patients could not establish the centronuclear form of the myopathy.…”

“…Here, we present eight patients of one family with a loss-of-function mutation in HACD1 with gradual improvement with age: apnea and feeding problems that were detected at infancy had resolved thereafter; waddling gate and Gower sign detected up to age 14 years had resolved in adulthood and the older patient aged 35 years is not affected and functions normally in adulthood, although this patient had hypotonia when young. Interestingly, Labrador Retrievers with canine CNM resulting from a SINE mutation in HACD1 have progressively accentuated clinical features that generally stabilize (4,10). The mutant dogs suffered from congenital myopathy with severe hypotonia.…”

Congenital Myopathies: An Update

“…This study additionally uncovered triad abnormalities in biopsies from patients with MTM1 mutations. Subsequently, the observations of structural and functional abnormalities in the triad, including defective excitation-contraction coupling and altered calcium homeostasis, have been demonstrated and expanded upon in both murine and canine models of myotubular myopathy [64, 77, 78, 79••]. These studies have led to a conclusion that a major aspect of disease from MTM1 mutations is due to abnormalities in the excitation-contraction coupling machinery.…”

Centronuclear Myopathy in Labrador Retrievers: A Recent Founder Mutation in the PTPLA Gene Has Rapidly Disseminated Worldwide

“…Years ago, an autosomal recessive congenital canine CNM was described in Labradors from an experimental pedigree developed in France from two probands [10], [11]. By linkage analysis, the locus was mapped to canine chromosome 2, and an associated mutation was identified in a gene annotated as the protein tyrosine phosphatase-like A ( PTPLA ) gene.…”