Two mutations in human BICC1 resulting in Wnt pathway hyperactivity associated with cystic renal dysplasia
✍ Scribed by Marine R.-C. Kraus; Séverine Clauin; Yvan Pfister; Massimo Di Maïo; Tim Ulinski; Daniel Constam; Christine Bellanné-Chantelot; Anne Grapin-Botton
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 224 KB
- Volume
- 33
- Category
- Article
- ISSN
- 1059-7794
No coin nor oath required. For personal study only.
✦ Synopsis
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 earlyonset 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.