title: An intronic LINE-1 element insertion in the dystrophin gene aborts dystrophin expression and results in Duchenne-like muscular dystrophy in the corgi breed.
abstract: Duchenne muscular dystrophy (DMD) is a dystrophin-deficient lethal muscle disease. To date, the catastrophic muscle wasting phenotype has only been seen in dystrophin-deficient humans and dogs. Although Duchenne-like symptoms have been observed in more than a dozen dog breeds, the mutation is often not known and research colonies are rarely established. Here, we report an independent canine DMD model originally derived from the Pembroke Welsh corgi breed. The affected dogs presented clinical signs of muscular dystrophy. Immunostaining revealed the absence of dystrophin and upregulation of utrophin. Histopathologic examination showed variable fiber size, central nucleation, calcification, fibrosis, neutrophil and macrophage infiltration and cardiac focal vacuolar degeneration. Carrier dogs also displayed mild myopathy. The mutation was identified as a long interspersed repetitive element-1 (LINE-1) insertion in intron 13, which introduced a new exon containing an in-frame stop codon. Similar mutations have been seen in human patients. A colony was generated by crossing carrier females with normal males. Affected puppies had a normal birth weight but they experienced a striking growth delay in the first 5 days. In summary, the new corgi DMD model offers an excellent opportunity to study DMD pathogenesis and to develop novel therapies.
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA. smithbf@auburn.edu
authors: Bruce F
authors: BF
authors: Smith
authors: Yongping
authors: Y
authors: Yue
authors: Philip R
authors: PR
authors: Woods
authors: Joe N
authors: JN
authors: Kornegay
authors: Jin-Hong
authors: JH
authors: Shin
authors: Regina R
authors: RR
authors: Williams
authors: Dongsheng
authors: D
authors: Duan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003402:Creatine Kinase / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D016189:Dystrophin / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006652:Histological Techniques; D054643:INDEL Mutation / Q000235:genetics*; D007150:Immunohistochemistry; D007438:Introns / Q000235:genetics*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology; D049411:Utrophin / Q000378:metabolism
chemical_list: D017931:DNA Primers; D016189:Dystrophin; D049411:Utrophin; D003402:Creatine Kinase