Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia

Abstract

Anonychia is an autosomal recessive disorder characterized by the congenital absence of finger- and toenails. In a large German nonconsanguineous family with four affected and five unaffected siblings with isolated total congenital anonychia, we performed genomewide mapping and showed linkage to 20p13. Analysis of the RSPO4 gene within this interval revealed a frameshift and a nonconservative missense mutation in exon 2 affecting the highly conserved first furin-like cysteine-rich domain. Both mutations were not present among controls and were shown to segregate with the disease phenotype. RSPO4 is a member of the recently described R-spondin family of secreted proteins that play a major role in activating the Wnt/ beta -catenin signaling pathway. Wnt signaling is evolutionarily conserved and plays a pivotal role in embryonic development, growth regulation of multiple tissues, and cancer development. Our findings add to the increasing body of evidence indicating that mesenchymal-epithelial interactions are crucial in nail development and put anonychia on the growing list of congenital malformation syndromes caused by Wnt-signaling-pathway defects. To the best of our knowledge, this is the first gene known to be responsible for an isolated, nonsyndromic nail disorder.

Figure  1.

Top left, Pedigree of the German nonconsanguineous family with isolated total congenital anonychia, with four affected and five unaffected siblings. Top right and middle right, Hands and feet of affected individual II-8, showing isolated total congenital anonychia. Middle left, Maternally transmitted guanine nucleotide insertion leading to a frameshift and premature truncation of the corresponding protein (c.92_93insG, p.Leu31fs). Bottom left, paternal nonconservative RSPO4 missense mutation c.218G→A leading to an amino acid exchange from cysteine to tyrosine at position 73 (p.Cys73Tyr). Bottom right, Multiple protein sequence alignment, generated with the program ClustalW with use of translation from genome assemblies and expressed sequences. Sequence comparison shows that the identified RSPO4 missense mutation c.218G→A (p.Cys73Tyr) affects an amino acid (displayed on a grayish background) that is highly conserved in evolution.

Figure  2.

X-ray of the right hand of affected individual II-8, showing no skeletal alteration or any degenerative or inflammable joint process.

Figure  3.

Genomewide linkage data generated using a panel of microsatellite markers with an average distance of 10 cM (Weber panel Version 10 [Research Genetics]), an ABI3100 sequence analyzer, and Genotyper software v3.7 (Applied Biosystems).