Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 610467 (gene) , 619967 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: Centronuclear Myopathy (CNM)

Species-specific name: Type II fiber deficiency; Autosomal recessive muscular dystrophy; Hereditary myopathy of Labrador retrievers (HMLR)

Species-specific symbol: HMLR

History: The first clinical description of this disorder was by Kramer et al. (1976).

Inheritance: Tiret et al. (2003) showed that this disorder is autosomal recessive.

Mapping: Conducting a genome scan with 66 microsatellites on a four-generation pedigree that "comprised 40 dogs among which 20 were affected (12 females and 8 males)" Tiret et al. (2003) mapped this disorder to the centromeric region of chromosome CFA2. Subsequent fine mapping reduced this to an "18.1-cM interval between markers FH2087U and AHT132". Subsequent FISH-mapping "established orthology between the centromeric region of CFA2 and the GDI2-cREM human segment (HSA10p15/HSA10p12.1-p11.1)".

Molecular basis: Pelé et al. (2005) determined the molecular basis of this disorder by adopting a comparative positional cloning approach. Having mapped the canine disorder as described in the Mapping section above, they then studied the 208 human genes that are located in the orthologous region of chromosome HSA10p. Based on tissue expression and sequence motif, the most likely of these 208 genes was PTPLA (protein tyrosine phosphatase-like, member A). Sequencing of the canine PTPLA gene revealed the causative mutation as an insertion of a "tRNA-derived short interspersed repeat element (SINE)" in exon 2 ("PTPLA*g9459-9460ins236") which "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." PTPLA is known as HACD1 in NCBI Gene.

Clinical features: Centronuclear myopathy in Labradors presents with weakness, hypotonia, paresis and progressive skeletal muscle atrophy from at about 1 month of age (Walmsley et al., 2016). In rare cases, clinical signs may not become apparent until as late as 6 months of age. Affected dogs have abnormal deep tendon reflexes. Clinical signs become initially increasingly severe but may stabilise at approximately one year of age (Blot et al., 2002). There are a range of clinical presentations, ranging from mild disease with reduced exercise tolerance and gait abnormalities to more severe presentations involving obvious skeletal muscle atrophy and collapse. Dogs can have reduced muscle tone of the oesophagus leading to difficulties swallowing and a risk of sudden death, which can be reduced by gravity-assisted feeding (McKerrel & Braund, 1987). Clinical signs may be exacerbated by exposure to cold weather (McKerrel & Braund 1987). IT thanks DVM student Leo Rubinstein, who provided the basis of this contribution in May 2023.

Pathology: The skeletal muscle of affected dogs exhibits a number of characteristic changes including variation in fibre size, presence of angular fibres, altered oxidative staining, a predominance of type 1 myofibres, fibrosis and centralisation of nuclei (Walmsley et al., 2016). IT thanks DVM student Leo Rubinstein, who provided the basis of this contribution in May 2023.

Prevalence: Maurer et al. (2012) conducted a comprehensive world-wide survey by genotyping 7,426 Labradors from 18 countries for the PTPLA mutant reported by Pelé et al. (2005). All 80 affected dogs from 8 countries were homozygous for the same mutant allele, and none of the 1.172 heterozygous dogs from 13 countries was affected. The highest % of carriers were "found in the UK (19%), the USA (13%) and Canada (11,5%)". The UK estimate is similar to the UK estimate of 22%, reported by Owczarek-Lipska et al. (2011). Maurer et al. (2012) concluded that the mutant allele "resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires".

Breed: Labrador Retriever (Dog) (VBO_0200800).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: