LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome

  • Am J Hum Genet. 2010 May 14;86(5):696-706. doi: 10.1016/j.ajhg.2010.03.004.
Yun Li  1 ,  Barbara Pawlik ,  Nursel Elcioglu ,  Mona Aglan ,  Hülya Kayserili ,  Gökhan Yigit ,  Ferda Percin ,  Frances Goodman ,  Gudrun Nürnberg ,  Asim Cenani ,  Jill Urquhart ,  Boi-Dinh Chung ,  Samira Ismail ,  Khalda Amr ,  Ayca D Aslanger ,  Christian Becker ,  Christian Netzer ,  Pete Scambler ,  Wafaa Eyaid ,  Hanan Hamamy ,  Jill Clayton-Smith ,  Raoul Hennekam ,  Peter Nürnberg ,  Joachim Herz ,  Samia A Temtamy ,  Bernd Wollnik
Affiliations
  • 1. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
PMID: 20381006 DOI: 10.1016/j.ajhg.2010.03.004
Abstract

Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is now shown to be commonly associated with kidney anomalies. We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By Sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. Our findings increase the spectrum of congenital anomalies associated with abnormal lipoprotein receptor-dependent signaling.