Degenerated Hair Follicle Cells and Partial Loss of Sebaceous and Eccrine Glands in a Familial Case of Axenfeld-Rieger Syndrome: An Emerging Role for the FOXC1/NFATC1 Genetic Axis

Publication date: Available online 10 November 2018

Source: Journal of Dermatological Science

Author(s): Hadla Hariri, Mazen Kurban, Christiane Al-Haddad, Akl C. Fahed, Sarin Poladian, Athar Kahlil, Oussama Abbas, Mariam Arabi, Fadi Bitar, Georges Nemer

Abstract

Background

Cutaneous malformations are at times associated with some forms of congenital heart defects. Many a times subtle cutaneous phenotypes maybe overlooked as their significance on the lives of individuals is minimal. Lebanon represents an area of high consanguinity, where the rates can go beyond 70% in some districts. For the past 6 years, we have been studying several genodermatoses in Lebanon including those with cardiac malformations.

Objectives

The main aim of this study is to document the genetic basis of a familial case of Axenfeld-Rieger Syndrome (ARS) with a mild cutaneous phenotype represented histologically with degeneration/ absence of hair follicles and incomplete formation of sebaceous and eccrine glands, in addition to the cardiac and ocular phenotypes.

Methods

Whole exome sequencing was performed on two identical-twins with ARS along with their affected father and non-affected mother. Sanger sequencing was used to confirm the mutation, and the effects of the mutations on protein function was assessed in vitro using transient transfections.

Results

A novel mutation inFOXC1 designated p.L240Rfs*75 was found in both twins and their father. The affected individuals share also a rare documented variant in NFATC1 designated p.V197 M. Both were absent from 200 Lebanese exomes. Our in vitro results suggested a gain of function activity of the FOXC1/NFATC1 complex, confirming its documented role in controlling murine hair follicle stem cells quiescence and regeneration.

Conclusion

This is the first documented human case with a mutation inFOXC1 regulating multi-organ developmental pathways that reflect a conserved mechanism in cell differentiation and proliferation.

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