NEUROMUSCULAR CASE OF THE MONTH - AUGUST 2005

Genetic test now available for Centronuclear Myopathy in Labrador Retrievers (Formerly called Inherited Myopathy of Labrador Retrievers or type 2 Fiber Deficiency)
Contributed by Drs. Laurent Tiret and Stéphane Blot
Alfort School of Veterinary Medicine- France
http://www.labradorcnm.com

The genetic cause of Inherited Myopathy of Labrador Retrievers has been recently identified. This result has been obtained after a ten-year collaborative research program achieved by the Laboratory of Neurobiology and the Laboratory of Molecular and Cellular Genetics at the Alfort School of Veterinary Medicine, France.

A DNA mutation test is now available. A web site has been launched http://www.labradorcnm.com.

It provides owners, breeders, agents and veterinarians with information on the disease, a step by step procedure and on-line forms to have a dog tested. Individual results are strictly confidential (a PDF certificate is e-mailed to the owner). However, for owners wishing to have a positive result publicly available, the web site also offers a White-List with clean dogs. The list is continually updated with dogs that hopefully passed the test.

Centronuclear Myopathy (CNM) is a disabling disease affecting Labrador Retrievers that has been described for 30 years. The majority of identified cases are from America (US and Canada), and Europe(United Kingdom, France, Germany, and Switzerland); and some have been reported in Finland, Australia and other countries. The number of affected dogs varies in these countries and frequently depends upon which fashionable studs and dams have been extensively used for breeding. Recently the numbers of affected litters appear to be increasing. At birth, affected puppies are indistinguishable from their control littermates. At one month of age, the absence of tendon reflexes is noticed and used as an early and reliable diagnosis. The age of onset varies between 2 to 5 months, with an awkward gait and decreased exercise tolerance. Generalized muscle weakness is exacerbated with cold. Clinical signs generally stabilize at one year of age. In adults, the most striking clinical feature of disease progression is the atrophy of temporal, cervical and leg muscles, leading to a ventroflexion of the neck, abnormal postures and movements (see the movie on the web site). No significant premature death could be observed. Nevertheless, dogs may require medical care if they suffer from respiratory complications due to megaesophagus. The histological hallmark is the central location of nuclei in muscle fibers in biopsy sections.  In a normal muscle, most nuclei are located around the periphery of the muscle fibers with <1% having a central location. some rare nuclei can be observed at the center of cells (<1%). In affected muscles, a high percentage of fibers have centralized nuclei. The myopathy was thus called "centronuclear myopathy", abbreviated CNM. This myopathy affecting Labrador retriever dogs is the only known mammalian model for a similarly named human myopathy.

CNM is a recessive genetic disease. In 2003, molecular genetics analyses enabled us to demonstrate that the disease-associated region is located on the canine chromosome 2. Focusing on candidate genes in that region allowed us to find an insertion of a repetitive exogenous element of 236 base pairs in exon 2 of the PTPLA gene. The insertion was shown to segregate in accordance with transmission of the disease.

Legend to Figure: DNA test used to identify PTPLA alleles. After DNA is extracted from cheek or blood cells, it is amplified using specific primers flanking the exogenous insertion in exon 2 of the PTPLA gene. The products resulting from this amplification are migrated on a gel which allows discrimination of these products depending upon their size. Dogs that do not carry the mutation (cleared dogs) have two copies of a normal allele: a single small band appears on the gel. Affected dogs are dogs that have inherited two mutated alleles of the PTPLA gene and therefore, only an upper band including the 236 bp inserted element (also called the mutated allele) is visible on the gel. Carriers are dogs that have inherited a normal copy and a mutated allele: on the gel, the two bands are detected. The mutation leads to an abnormal expression pattern of the gene and only 1% of normal PTPLA transcripts are detected in muscles from affected dogs. The mutation is therefore nearly a null mutation in PTPLA gene.

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