1. ¹Department of Human Genetics, RWTH Aachen University, Aachen, Germany
2. ²Department of Dermatology, University Hospital Maastricht, Maastricht, The Netherlands
3. ³Maastricht University Center for Molecular Dermatology (MUCMD), University Hospital Maastricht, Maastricht, The Netherlands
4. ⁴Department of Dermatology, GATA Military Medical School, Ankara, Turkey
5. ⁵Department of Dermatology, University of Athens, Athens, Greece

Correspondence: Dr Carsten Bergmann, Department of Human Genetics, RWTH Aachen University, Pauwelsstrae 30, Aachen D-52074, Germany. E-mail: cbergmann@ukaachen.de

Received 11 April 2007; Revised 21 May 2007; Accepted 13 June 2007; Published online 4 October 2007.

Abstract

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/-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 -catenin stabilization, a shortened protein comprising just these two regions is sufficient.