Exome sequencing reveals independent SGCD deletions causing limb girdle muscular dystrophy in Boston terriers

Abstract

Background: Limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of inherited autosomal myopathies that preferentially affect voluntary muscles of the shoulders and hips. LGMD has been clinically described in several breeds of dogs, but the responsible mutations are unknown. The clinical presentation in dogs is characterized by marked muscle weakness and atrophy in the shoulder and hips during puppyhood. Methods: Following clinical evaluation, the identification of the dystrophic histological phenotype on muscle histology, and demonstration of the absence of sarcoglycan-sarcospan complex by immunostaining, whole exome sequencing was performed on five Boston terriers: one affected dog and its three family members and one unrelated affected dog. Results: Within sarcoglycan-δ (SGCD), a two base pair deletion segregating with LGMD in the family was discovered, and a deletion encompassing exons 7 and 8 was found in the unrelated dog. Both mutations are predicted to cause an absence of SGCD protein, confirmed by immunohistochemistry. The mutations are private to each family. Conclusions: Here, we describe the first cases of canine LGMD characterized at the molecular level with the classification of LGMD2F.

Sarcoglycan A Mutation in Miniature Dachshund Dogs Causes Limb Girdle Muscular Dystrophy 2D

“…This patchy staining can be secondary to the sarcoglycan deficiency. While the severity of clinical signs was milder than that described in a previous publication of δ-sarcoglycan deficiency in Boston terrier dogs (19), pathological changes in muscle biopsies and the persistently high CK activity were similar. Identification numbers on the far left refer to the dogs within the pedigrees of Figure 1.…”

“…Several well-described forms of muscular dystrophy are found in domestic dogs, with at least fifteen DMD mutations found in over 10 breeds (7 -18), as well as two sarcoglycan delta subunit (SGCD) mutations (19), reported to cause dystrophic clinical phenotypes similar to DMD, BMD and LGMD, respectively, as described in people. The DMD mutation responsible for X-linked muscular dystrophy in golden retriever dogs has been a model for testing new therapeutics for Duchenne type MD for many years (20,21).…”

A novel canine model for Duchenne muscular dystrophy (DMD): single nucleotide deletion in DMD gene exon 20

“…We have previously utilized WGS to identify a 7-base pair mutation in DMD exon 42 of a Cavalier King Charles spaniel (CKCS) dog [ 19 ], distinct from the splice site mutation reported earlier by Walmsley et al [ 8 ]. A recent study utilized whole exome sequencing to identify two distinct mutations in the sarcoglycan-δ (SGCD) gene of Boston terrier dogs with a condition akin to limb girdle muscular dystrophy of humans [ 26 ].…”

An exome sequencing based approach for genome-wide association studies in the dog

“…WES allows a direct assessment of the protein-coding regions inside the genome 26 . In the dog, as in other species, exome sequencing has been very successful in the identification of disease causing mutations for a range of dominant and recessive Mendelian disorders 27 – 31 . While WES is an efficient method to analyze directly the nucleotides of a patient’s DNA to discover the genetic cause of Mendelian phenotypes, we investigated the possibility to extend the paradigm of WES in the dog by evaluating the potential of WES to detect LD-based associations.…”