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Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency
Journal article   Open access   Peer reviewed

Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency

Hassan Vahidnezhad, Leila Youssefian, Amir Hossein Saeidian, Andrew Touati, Sara Pajouhanfar, Taghi Baghdadi, Azam Ahmadi Shadmehri, Cecilia Giunta, Marius Kraenzlin, Delfien Syx, …
Matrix biology, v 81, pp 91-106
Aug 2019
DOI: https://doi.org/10.1016/j.matbio.2018.11.006
PMID: 30463024
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1016/j.matbio.2018.11.006View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

Epidermolysis bullosa Lysyl hydroxylase 3 PLOD3, type VII collagen, collagen glycosylation
Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in anchoring fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities, including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility. • Recessive dystrophic epidermolysis bullosa is caused by mutations in COL7A1. • We have evaluated a patient with multisystem disorder including blistering phenotype. • NGS identified mutations in PLOD3 encoding lysyl hydroxylase 3 (LH3). • The mutant LH3 was associated with reduced type VII collagen and anchoring fibrils. • PLOD3 is the second mutant gene associated with RDEB.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Cell Biology
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