FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia.

Background: Isolated nail dysplasia is rare and has been reported in only a small number of families.

Objectives: To describe and characterize two Pakistani families with an autosomal-recessive inherited nail dysplasia.

Methods: Genome-wide linkage analysis; mutation screening of candidate genes by Sanger sequencing; cloning of FZD6 and protein analyses; immunohistochemistry.

Results: We mapped this genodermatosis to chromosome 8q22.3, and identified a homozygous nonsense mutation c.1750G>T (p.E584X) in the frizzled 6 (FZD6) gene in all affected individuals. Immunohistochemical analyses in nail sections from healthy individuals revealed strong expression of FZD6 in the ventral nail matrix and a less pronounced expression of FZD6 in the nail bed.

Conclusions: FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/β-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic nail disorders anonychia and nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated nail dysplasia. The present results emphasize the important role of the Wnt pathways in nail development and increase understanding of Wnt-mediated developmental events in general.