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. Epub 2010 Apr 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Kidney / metabolism
  • Kidney Diseases / genetics*
  • Kidney Diseases / metabolism
  • LDL-Receptor Related Proteins / genetics*
  • LDL-Receptor Related Proteins / metabolism
  • Limb Deformities, Congenital / genetics*
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Mutation
  • Oncogenes
  • Receptors, LDL / antagonists & inhibitors
  • Signal Transduction / physiology*
  • Syndactyly / genetics
  • Syndactyly / metabolism
  • Syndrome
  • beta Catenin / metabolism*


  • LDL-Receptor Related Proteins
  • LRP10 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Receptors, LDL
  • beta Catenin