title: 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.
authors.affiliation: Department of Human Genetics, Aachen University, Aachen, Germany. cbergmann@ukaachen.de
authors.forename: C
authors.initials: C
authors.lastname: Bergmann
authors.forename: J
authors.initials: J
authors.lastname: Senderek
authors.forename: D
authors.initials: D
authors.lastname: Anhuf
authors.forename: C T
authors.initials: CT
authors.lastname: Thiel
authors.forename: A B
authors.initials: AB
authors.lastname: Ekici
authors.forename: P
authors.initials: P
authors.lastname: Poblete-Gutierrez
authors.forename: M
authors.initials: M
authors.lastname: van Steensel
authors.forename: D
authors.initials: D
authors.lastname: Seelow
authors.forename: G
authors.initials: G
authors.lastname: Nürnberg
authors.forename: H H
authors.initials: HH
authors.lastname: Schild
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.forename: A
authors.initials: A
authors.lastname: Reis
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.forename: K
authors.initials: K
authors.lastname: Zerres
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002890:Chromosomes, Human, Pair 20; D008040:Genetic Linkage; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009264:Nails, Malformed / Q000000981:diagnostic imaging / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D011859:Radiography; D015398:Signal Transduction; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D000098907:R-Spondins
chemical_list: D019699:Thrombospondins; D051153:Wnt Proteins; C516169:RSPO4 protein, human; D000098907:R-Spondins