title: Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability.
abstract: 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.
authors.affiliation: J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Bhalla
authors.forename: Yue
authors.initials: Y
authors.lastname: Luo
authors.forename: Tim
authors.initials: T
authors.lastname: Buchan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beachem
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Guzauskas
authors.forename: Sydney
authors.initials: S
authors.lastname: Ladd
authors.forename: Shelly J
authors.initials: SJ
authors.lastname: Bratcher
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Schroer
authors.forename: Janne
authors.initials: J
authors.lastname: Balsamo
authors.forename: Barbara R
authors.initials: BR
authors.lastname: DuPont
authors.forename: Jack
authors.initials: J
authors.lastname: Lilien
authors.forename: Anand K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002448:Cell Adhesion; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11; D002885:Chromosomes, Human, Pair 16; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D014178:Translocation, Genetic
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; C470936:KIRREL3 protein, human; D008565:Membrane Proteins; C070896:M-cadherin