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Journal article
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
Matrix biology, v 81, pp 91-106
Aug 2019
PMID: 30463024
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Abstract
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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Details
- Title
- 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
- Creators
- Hassan Vahidnezhad - Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, IranLeila Youssefian - Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USAAmir Hossein Saeidian - Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USAAndrew Touati - Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USASara Pajouhanfar - Thomas Jefferson UniversityTaghi Baghdadi - Imam Khomeini HospitalAzam Ahmadi Shadmehri - Islamic Azad University, Science and Research BranchCecilia Giunta - University Children's Hospital ZurichMarius Kraenzlin - University Hospital of BaselDelfien Syx - Ghent University HospitalFransiska Malfait - Ghent University HospitalCristina Has - University of FreiburgSu M. Lwin - King's College LondonRazieh Karamzadeh - Royan InstituteLu Liu - St Thomas' HospitalAlyson Guy - St Thomas' HospitalMohammad Hamid - Pasteur Institute of IranAriana Kariminejad - Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, IranSirous Zeinali - Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, IranJohn A. McGrath - St John's Institute of Dermatology, King's College London, Guy's Campus, LondonJouni Uitto - Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
- Publication Details
- Matrix biology, v 81, pp 91-106
- Publisher
- Elsevier
- Number of pages
- 16
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:000474501700006
- Scopus ID
- 2-s2.0-85058421348
- Other Identifier
- 991021860788504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology