Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability

Am J Hum Genet. 2008 Dec;83(6):703-13. doi: 10.1016/j.ajhg.2008.10.020. Epub 2008 Nov 13.


Cell-adhesion molecules play critical roles in brain development, as well as maintaining synaptic structure, function, and plasticity. Here we have found the disruption of two genes encoding putative cell-adhesion molecules, CDH15 (cadherin superfamily) and KIRREL3 (immunoglobulin superfamily), by a chromosomal translocation t(11;16) in a female patient with intellectual disability (ID). We screened coding regions of these two genes in a cohort of patients with ID and controls and identified four nonsynonymous CDH15 variants and three nonsynonymous KIRREL3 variants that appear rare and unique to ID. These variations altered highly conserved residues and were absent in more than 600 unrelated patients with ID and 800 control individuals. Furthermore, in vivo expression studies showed that three of the CDH15 variations adversely altered its ability to mediate cell-cell adhesion. We also show that in neuronal cells, human KIRREL3 colocalizes and interacts with the synaptic scaffolding protein, CASK, recently implicated in X-linked brain malformation and ID. Taken together, our data suggest that alterations in CDH15 and KIRREL3, either alone or in combination with other factors, could play a role in phenotypic expression of ID in some patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cadherins / chemistry
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Case-Control Studies
  • Cell Adhesion
  • Cell Adhesion Molecules, Neuronal / chemistry
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Chromosomes, Human, Pair 11
  • Chromosomes, Human, Pair 16
  • Cohort Studies
  • Female
  • Genetic Variation*
  • Humans
  • Intellectual Disability / genetics*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Middle Aged
  • Models, Biological
  • Protein Structure, Tertiary
  • Translocation, Genetic


  • Cadherins
  • Carrier Proteins
  • Cell Adhesion Molecules, Neuronal
  • KIRREL3 protein, human
  • Membrane Proteins
  • M-cadherin