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The Tsk2/+ mouse fibrotic phenotype is due to a gain-of-function mutation in the PIIINP segment of the Col3a1 gene. | LitMetric

AI Article Synopsis

  • Systemic sclerosis (SSc) is an autoimmune disorder that involves the excessive build-up of certain proteins in the skin and blood vessel changes, with unclear causes.
  • The study utilized the tight skin (Tsk)2/+ mouse model showing symptoms similar to SSc, and identified a specific mutation in the Col3a1 gene that likely drives these symptoms.
  • Unlike known mutations in humans linked to Ehlers-Danlos syndrome, this new mutation in Tsk2 is the first gain-of-function mutation observed in Col3a1, which contributes to skin fibrosis rather than a defect in collagen production.

Article Abstract

Systemic sclerosis (SSc) is a polygenic, autoimmune disorder of unknown etiology, characterized by the excessive accumulation of extracellular matrix (ECM) proteins, vascular alterations, and autoantibodies. The tight skin (Tsk)2/+ mouse model of SSc demonstrates signs similar to SSc including tight skin and excessive deposition of dermal ECM proteins. By linkage analysis, we mapped the Tsk2 gene mutation to <3 megabases on chromosome 1. We performed both RNA sequencing of skin transcripts and genome capture DNA sequencing of the region spanning this interval in Tsk2/+ and wild-type littermates. A missense point mutation in the procollagen III amino terminal propeptide segment (PIIINP) of collagen, type III, alpha 1 (Col3a1) was found to be the best candidate for Tsk2; hence, both in vivo and in vitro genetic complementation tests were used to prove that this Col3a1 mutation is the Tsk2 gene. All previously documented mutations in the human Col3a1 gene are associated with the Ehlers-Danlos syndrome, a connective tissue disorder that leads to a defect in type III collagen synthesis. To our knowledge, the Tsk2 point mutation is the first documented gain-of-function mutation associated with Col3a1, which leads instead to fibrosis. This discovery provides insight into the mechanism of skin fibrosis manifested by Tsk2/+ mice.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324084PMC
http://dx.doi.org/10.1038/jid.2014.455DOI Listing

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