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Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide.

ABSTRACT: Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA(cnm) mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA(cnm) carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA(cnm) allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM.

SUBMITTER: Maurer M

PROVIDER: S-EPMC3465307 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide.

Maurer Marie M Mary Jérôme J Guillaud Laurent L Fender Marilyn M Pelé Manuel M Bilzer Thomas T Olby Natasha N Penderis Jacques J Shelton G Diane GD Panthier Jean-Jacques JJ Thibaud Jean-Laurent JL Barthélémy Inès I Aubin-Houzelstein Geneviève G Blot Stéphane S Hitte Christophe C Tiret Laurent L

PloS one 20121005 10

Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previ ...[more]

PMID: 23071563

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Project description:Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.

Project description:PurposeTo study retinal appearance and morphology in Labrador retrievers (LRs) heterozygous and homozygous for an ABCA4 loss-of-function mutation.MethodsOphthalmic examination, including ophthalmoscopy and simple testing of vision, was performed in five ABCA4wt/wt, four ABCA4wt/InsC, and six ABCA4InsC/InsC LRs. Retinas were also examined with confocal scanning laser ophthalmoscopy (cSLO) and optical coherence tomography (OCT). Infrared and fundus autofluorescence (FAF) images were studied, and outer nuclear layer (ONL) and neuroretinal thickness were measured in the central and peripheral area centralis.ResultsClinical signs in young ABCA4InsC/InsC LRs were subtle, whereas ophthalmoscopic findings and signs of visual impairment were obvious in old ABCA4InsC/InsC LRs. Retinal appearance and vision testing was unremarkable in heterozygous LRs regardless of age. The cSLO/OCT showed abnormal morphology including ONL thinning, abnormal outer retinal layer segmentation, and focal loss of retinal pigment epithelium in the fovea equivalent in juvenile ABCA4InsC/InsC LRs. The abnormal appearance extended into the area centralis and visual streak in middle-aged ABCA4InsC/InsC and then spread more peripherally. A mild phenotype was seen on cSLO/OCT and FAF in middle-aged to old ABCA4wt/InsC LRs.ConclusionsAbnormal appearance and morphology in the fovea equivalent are present in juvenile ABCA4InsC/InsC. In the older affected LRs, the visual streak and then the peripheral retina also develop an abnormal appearance. Vision deteriorates slowly, but some vision is retained throughout life. Older heterozygotes may show a mild retinal phenotype but no obvious visual impairment. The ABCA4InsC/InsC LR is a potential model for ABCA4-mediated retinopathies/juvenile-onset Stargardt disease in a species with human-sized eyes.Translational relevanceThe ABCA4InsC mutation causes juvenile-onset abnormal appearance of the fovea equivalent in affected dogs that slowly spreads in the retina, while only a mild phenotype is seen in older carriers. This is the first non-primate, large-animal model for ABCA4-related/STGD1 retinopathies in a species with a fovea equivalent.

Dataset Information

Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide.

Publications

Centronuclear myopathy in Labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide.

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