title: Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.
abstract: Tooth development is controlled by the same processes that regulate formation of other ectodermal structures. Mutations in the genes underlying these processes may cause ectodermal dysplasia, including severe absence of primary or permanent teeth. Four consanguineous Palestinian families presented with oligodontia and hair and skin features of ectodermal dysplasia. Appearance of ectodermal dysplasia was consistent with autosomal recessive inheritance. Exome sequencing followed by genotyping of 56 informative relatives in the 4 families suggests that the phenotype is due to homozygosity for KREMEN1 p.F209S (c.626 T>C) on chromosome 22 at g.29,521,399 (hg19). The variant occurs in the highly conserved extracellular WSC domain of KREMEN1, which is known to be a high affinity receptor of Dickkopf-1, a component of the Dickkopf-Kremen-LRP6 complex, and a potent regulator of Wnt signaling. The Wnt signaling pathway is critical to development of ectodermal structures. Mutations in WNT10A, LRP6, EDA, and other genes in this pathway lead to tooth agenesis with or without other ectodermal anomalies. Our results implicate KREMEN1 for the first time in a human disorder and provide additional details on the role of the Wnt signaling in ectodermal and dental development.
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Yasmin A
authors.initials: YA
authors.lastname: Issa
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Lara
authors.initials: L
authors.lastname: Kamal
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Amal Abu
authors.initials: AA
authors.lastname: Rayyan
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Dima
authors.initials: D
authors.lastname: Dweik
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
mesh_terms: D000293:Adolescent; D000848:Anodontia / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D060449:Wnt Signaling Pathway
chemical_list: C486075:KREMEN1 protein, human; D008565:Membrane Proteins