TY - JOUR
T1 - 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
AU - Vahidnezhad, Hassan
AU - Youssefian, Leila
AU - Saeidian, Amir Hossein
AU - Touati, Andrew
AU - Pajouhanfar, Sara
AU - Baghdadi, Taghi
AU - Shadmehri, Azam Ahmadi
AU - Giunta, Cecilia
AU - Kraenzlin, Marius
AU - Syx, Delfien
AU - Malfait, Fransiska
AU - Has, Cristina
AU - Lwin, Su M.
AU - Karamzadeh, Razieh
AU - Liu, Lu
AU - Guy, Alyson
AU - Hamid, Mohammad
AU - Kariminejad, Ariana
AU - Zeinali, Sirous
AU - McGrath, John A.
AU - Uitto, Jouni
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.matbio.2018.11.006
DO - 10.1016/j.matbio.2018.11.006
M3 - Article
C2 - 30463024
AN - SCOPUS:85058421348
SN - 0945-053X
VL - 81
SP - 91
EP - 106
JO - Matrix Biology
JF - Matrix Biology
ER -