RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4.

Congenital anonychia is a rare autosomal-recessive disorder characterized by the absence of finger- and toenails. Recently, we and others identified the secreted Wnt signaling ligand R-spondin 4 (RSPO4) as the first gene known to be responsible for inherited anonychia. R-spondins are secreted proteins that activate the Wnt/beta-catenin signaling pathway. This puts anonychia on the growing list of congenital malformation syndromes caused by Wnt signaling pathway defects. Here, we expand the RSPO4 mutational spectrum by identification of the previously unknown mutations c.190C>T (p.Arg64Cys) in exon 2 and c.301C>T (p.Gln101X) in exon 3, thereby corroborating R-spondin 4 as the major protein in autosomal-recessive anonychia. Almost all RSPO4 mutations detected so far affect the highly conserved exons 2 and 3. Thus, we postulate that RSPO4 mutations preferentially cluster in the furin-like cysteine-rich domains of R-spondin 4, which is in line with experimental data proposing that for beta-catenin stabilization, a shortened protein comprising just these two regions is sufficient.