title: Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia.
abstract: Bicaudal C homologue 1 (Bicc1) knockout in mice causes polycystic kidney disease and pancreas development defects, including a reduction in insulin-producing β-cells and ensuing diabetes. We therefore screened 137 patients with renal abnormalities or association of early-onset diabetes and renal disease for genetic alterations in BICC1. We identified two heterozygous mutations, one nonsense in the first K Homology (KH) domain and one missense in the sterile alpha motif (SAM) domain. In mice, Bicc1 blocks canonical Wnt signaling, mostly via its SAM domain. We show that the human BICC1, similar to its mouse counterpart, blocks canonical Wnt signaling. The nonsense mutation identified results in a complete loss of Wnt inhibitory activity. The point mutation in the SAM domain has a similar effect to a complete SAM domain deletion, resulting in a 22% loss of activity.
authors.affiliation: Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Station 19, Lausanne, Switzerland.
authors.forename: Marine R-C
authors.initials: MR
authors.lastname: Kraus
authors.forename: Séverine
authors.initials: S
authors.lastname: Clauin
authors.forename: Yvan
authors.initials: Y
authors.lastname: Pfister
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maïo
authors.forename: Tim
authors.initials: T
authors.lastname: Ulinski
authors.forename: Daniel
authors.initials: D
authors.lastname: Constam
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D018389:Codon, Nonsense; D005091:Exons; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020125:Mutation, Missense; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: C571508:Bicc1 protein, human; C540667:Bicc1 protein, mouse; D002352:Carrier Proteins; D018389:Codon, Nonsense; D016601:RNA-Binding Proteins