Rat anti-Mouse RSPO4 monoclonal antibody, clone 546304

R-spondin proteins are secreted agonists of canonical WNT/beta-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G> A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2). Cysteines in the FU-CRDs are strictly conserved, indicating their functional importance in WNT signaling through interaction with the leucine-rich repeat-containing G-protein-coupled receptors. This is the first RSPO1 missense mutation reported in association with human disease. (C) 2017 S. Karger AG, Basel

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.