An ADAMTSL2 Founder Mutation Causes Musladin-Lueke Syndrome, a Heritable Disorder of Beagle Dogs, Featuring Stiff Skin and Joint Contractures
An ADAMTSL2 Founder Mutation Causes Musladin-Lueke Syndrome, a Heritable Disorder of Beagle Dogs, Featuring Stiff Skin and Joint Contractures
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DOI：
10.1371/journal.pone.0012817
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发表时间：
2010-09-17
期刊：
影响因子：
3.7
通讯作者：
Neff, Mark W.
中科院分区：
文献类型：
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作者：
Bader, Hannah L.;Ruhe, Alison L.;Neff, Mark W.
背景资料：Musladin-Lueke综合征（MLS）是一种影响比格犬的遗传性疾病，表现为皮肤和关节的广泛纤维化。在这方面，它类似于人类僵硬皮肤综合症和皮肤紧绷小鼠，两者都是由影响组织微纤维主要成分原纤蛋白-1的基因缺陷引起的。这项工作的目的是确定MLS的遗传基础和鉴定的突变的分子后果。方法和主要发现：我们通过全基因组关联将MLS的基因座定位到犬9号染色体上的3.05 Mb单倍型（CFA 9（50.11-54.26; p（raw）T; p.R221C），该单倍型与MLS完全相关（p值= 10（-12））。当在COS-1、HEK 293 F和CHO细胞中瞬时表达时，含有p.R221C突变的小鼠ADAMTSL 2形成异常的二硫键二聚体，并且在这些细胞的培养基中以低于平行表达的野生型ADAMTSL 2的水平存在。MLS的遗传基础是ADAMTSL 2中的创始者突变，先前显示与潜伏的TGF-β结合蛋白相互作用，该蛋白结合人胰岛素-1。创始人突变对ADAMTSL 2的分子效应是形成二硫键二聚体。虽然由不同的突变引起，并且具有比人类GD更温和的表型，但MLS仍然为GD的研究以及对皮肤纤维化和关节挛缩的机制和途径的前瞻性见解提供了新的动物模型。
Background: 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.Methodology and Principal Findings: 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.Conclusions/Significance: The genetic basis of MLS is a founder mutation in ADAMTSL2, previously shown to interact with latent TGF-beta 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.