Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia

Area of Science:

• Genetics
• Developmental Biology
• Cell Biology

Background:

• Cleft lip, with or without cleft palate (CL/P), is a frequent congenital birth defect affecting 0.4–2.0 per 1,000 live births.
• While most CL/P cases are non-syndromic, some are linked to single-gene mutations impacting orofacial development.
• CL/P is also associated with ectodermal dysplasia (ED) syndromes, highlighting genetic factors in craniofacial development.

Purpose of the Study:

• To identify the genetic cause of an autosomal recessive cleft lip/palate-ectodermal dysplasia syndrome (CLPED1).
• To elucidate the role of the identified gene in orofacial development and its potential link to viral interactions.

Main Methods:

• Positional cloning was employed to identify the causative gene for CLPED1.
• The study involved genetic analysis and characterization of the identified gene and its protein product.

Main Results:

• The gene responsible for CLPED1 was identified as PVRL1, which encodes nectin-1.
• Nectin-1 is an immunoglobulin (Ig)-related transmembrane cell-cell adhesion molecule and a key component of the NAP cell adhesion system.
• Nectin-1 also functions as the primary cell surface receptor for alpha-herpesviruses (HveC).

Conclusions:

• The identification of PVRL1 as the gene for CLPED1 provides critical insight into the genetic basis of syndromic CL/P.
• Nectin-1's dual role in cell adhesion and viral receptor function suggests a potential evolutionary advantage for heterozygotes, possibly conferring resistance to alpha-herpesvirus infections.
• The high prevalence of CLPED1 on Margarita Island may be attributed to this heterozygote advantage against viral pathogens.