Mutations in PVRL4, encoding cell adhesion molecule nectin-4, cause ectodermal dysplasia-syndactyly syndrome
Francesco Brancati1, Paola Fortugno, Irene Bottillo
1Department of Biomedical Sciences, Gabriele d'Annunzio University, Chieti, Italy. f.brancati@css-mendel.it
American Journal of Human Genetics
|August 10, 2010
Summary
Mutations in the PVRL4 gene cause ectodermal dysplasia-syndactyly syndrome (EDSS), a disorder affecting hair, teeth, and skin. This research identifies PVRL4 as a key gene in nectinopathies, impacting cell adhesion and development.
Area of Science:
- Genetics
- Cell Biology
- Developmental Biology
Background:
- Ectodermal dysplasias (EDs) encompass over 200 genetic disorders.
- Ectodermal dysplasia-syndactyly syndrome (EDSS) is characterized by hair and tooth abnormalities, alopecia, and cutaneous syndactyly.
Purpose of the Study:
- To identify the genetic cause of EDSS.
- To investigate the role of PVRL4 in EDSS pathogenesis and its function in cell adhesion.
Main Methods:
- Homozygosity mapping in a consanguineous family.
- Candidate gene analysis and mutation detection (sequencing).
- In vitro studies using patient-derived keratinocytes and murine embryo analysis.
Main Results:
- Mapped the EDSS locus to 1q23 and identified mutations in the PVRL4 gene.
- PVRL4 mutations led to amino acid changes, exon skipping, and impaired nectin-4 function.
- Demonstrated high nectin-4 expression in affected tissues and disrupted cell adhesion complexes in patient cells.
Conclusions:
- PVRL4 mutations are causative for EDSS, establishing it as a nectinopathy.
- Nectin-4 plays a crucial role in hair follicle and digit development via adherens junction formation.
- Understanding nectinopathies expands knowledge of cell adhesion disorders.
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