title: 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.
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/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.
authors.affiliation: Department of Human Genetics, RWTH Aachen University, Aachen, Germany.
authors.forename: Nadina Ortiz
authors.initials: NO
authors.lastname: Brüchle
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
authors.forename: Valeska
authors.initials: V
authors.lastname: Frank
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Ahmet
authors.initials: A
authors.lastname: Akar
authors.forename: Erol
authors.initials: E
authors.lastname: Koc
authors.forename: Dimitris
authors.initials: D
authors.lastname: Rigopoulos
authors.forename: Maurice
authors.initials: M
authors.lastname: van Steensel
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002675:Child, Preschool; D003545:Cysteine / Q000737:chemistry; D005260:Female; D045683:Furin / Q000737:chemistry; D008040:Genetic Linkage; D006801:Humans; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009264:Nails, Malformed / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D019699:Thrombospondins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D000098907:R-Spondins
chemical_list: D003545:Cysteine; D045683:Furin; D008024:Ligands; D019699:Thrombospondins; D051153:Wnt Proteins; D051176:beta Catenin; C516169:RSPO4 protein, human; D000098907:R-Spondins