An ADAMTSL2 founder mutation causes Musladin-Lueke Syndrome, a heritable disorder of beagle dogs, featuring stiff skin and joint contractures

• Published in: PloS one 2010-09, Vol.5 (9), p.e12817
• Main Authors: Bader, Hannah L, Ruhe, Alison L, Wang, Lauren W, Wong, Aaron K, Walsh, Kari F, Packer, Rebecca A, Mitelman, Jonathan, Robertson, Kathryn R, O'Brien, Dennis P, Broman, Karl W, Shelton, G Diane, Apte, Suneel S, Neff, Mark W
• Format: Article
• Language: English
• Subjects: Animals; Automation; Base Sequence; Biomedical engineering; Bone morphogenetic proteins; Cell Biology/Extra-Cellular Matrix; Cell Line; Chemical bonds; Chromosome 9; Chromosome Mapping; Deoxyribonucleic acid; Dimers; DNA; DNA polymerase; Dog Diseases - congenital; Dog Diseases - genetics; Dog Diseases - metabolism; Dog Diseases - physiopathology; Dogs; Dysplasia; Exons; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fibrillin; Fibroblasts; Fibrosis; Fines & penalties; Genetic aspects; Genetics; Genetics and Genomics/Disease Models; Genetics and Genomics/Gene Discovery; Genetics and Genomics/Gene Function; Genetics and Genomics/Genetics of Disease; Genomes; Genomics; Haplotypes; Heredity; Human behavior; Humans; Joint Diseases - genetics; Joint Diseases - metabolism; Joint Diseases - physiopathology; Joint Diseases - veterinary; Laboratories; Loci; Marfan syndrome; Mice; Microfibrils; Molecular Sequence Data; Mutation; Mutation, Missense; Myogenesis; Protein binding; Questioning; Skin; Skin Abnormalities - genetics; Skin Abnormalities - metabolism; Skin Abnormalities - physiopathology; Skin Abnormalities - veterinary; Transforming growth factors; Veterinary medicine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012817

Musladin-Lueke Syndrome (MLS) is a hereditary disorder affecting Beagle dogs that manifests with extensive fibrosis of the skin and joints. In this respect, it resembles human stiff skin syndrome and the Tight skin mouse, each of which is caused by gene defects affecting fibrillin-1, a major component of tissue microfibrils. The objective of this work was to determine the genetic basis of MLS and the molecular consequence of the identified mutation. We mapped the locus for MLS by genome-wide association to a 3.05 Mb haplotype on canine chromosome 9 (CFA9 (50.11-54.26; p(raw) T; p.R221C) perfectly associated with MLS (p-value=10(-12)). Murine ADAMTSL2 containing the p.R221C mutation formed anomalous disulfide-bonded dimers when transiently expressed in COS-1, HEK293F and CHO cells, and was present in the medium of these cells at lower levels than wild-type ADAMTSL2 expressed in parallel. The genetic basis of MLS is a founder mutation in ADAMTSL2, previously shown to interact with latent TGF-β binding protein, which binds fibrillin-1. The molecular effect of the founder mutation on ADAMTSL2 is formation of disulfide-bonded dimers. Although caused by a distinct mutation, and having a milder phenotype than human GD, MLS nevertheless offers a new animal model for study of GD, and for prospective insights on mechanisms and pathways of skin fibrosis and joint contractures.