An ADAMTSL2 Founder Mutation Causes Musladin-Lueke Syndrome, a Heritable Disorder of Beagle Dogs, Featuring Stiff Skin and Joint Contractures

Abstract

BackgroundMusladin-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.Methodology and Principal FindingsWe mapped the locus for MLS by genome-wide association to a 3.05 Mb haplotype on canine chromosome 9 (CFA9 (50.11–54.26; praw <10−7)), which was homozygous and identical-by-descent among all affected dogs, consistent with recessive inheritance of a founder mutation. Sequence analysis of a candidate gene at this locus, ADAMTSL2, which is responsible for the human TGFβ dysregulation syndrome, Geleophysic Dysplasia (GD), uncovered a mutation in exon 7 (c.660C>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.Conclusions/SignificanceThe 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.

ADAMTS proteins as modulators of microfibril formation and function

“…Canine ADAMTS10 and ADAMTS17 mutations cause open angle glaucoma and ectopia lentis in terriers [65,72,73]. One of the ADAMTSL2 point mutations found in human geleophysic dysplasia causes Musladin–Lueke syndrome (MLS) in beagles via a founder effect [74]. In affected beagles, joint contractures, small stature and stiff skin are prominent.…”

“…In skin biopsies from beagles with MLS, an extensive collagen network extending from the dermis to the subcutaneous tissue was demonstrated [74]. A skin biopsy from a WMS2 patient showed accumulation of abnormal fibrillin aggregates [17], and skin fibroblasts isolated from WMS1 patients showed thicker bundles of actin filaments than cells from unaffected individuals [63].…”

Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function

“…Recently MLS, a condition affecting beagle dogs was described; affected beagles are small, have thick hard skin, appear muscular and have severe distal extremity contractures [86]. The condition is caused by a founder mutation (Arg221Cys) that places a cysteine residue in the ADAMTSL2 spacer module, leads to formation of disulfide-bonded ADAMTSL2 dimers, and reduces secretion of the mutant protein [86].…”

“…The condition is caused by a founder mutation (Arg221Cys) that places a cysteine residue in the ADAMTSL2 spacer module, leads to formation of disulfide-bonded ADAMTSL2 dimers, and reduces secretion of the mutant protein [86]. Unlike GD, MLS is not a rapidly progressing disorder and appears to stabilize by about a year of age in affected dogs.…”

“…Intriguingly, an Arg221Cys mutation was recently described in a patient having recessive GD [59]. Skin histology from an affected dog showed a dense network of collagen spanning the dermis to the subcutaneous tissue [86], although it was not as dense as that reported in SSS [62]. …”