title: Non-syndromic tooth agenesis associated with a nonsense mutation in ectodysplasin-A (EDA).
abstract: Mutations in the ectodysplasin-A (EDA) gene have been generally associated with X-linked hypohidrotic ectodermal dysplasia (XLHED). Recently, missense mutations in EDA have been reported to cause familial non-syndromic tooth agenesis. In this study, we report a novel EDA mutation in an Estonian family segregating non-syndromic tooth agenesis with variable expressivity. Affected individuals had no associated defects in other ectodermal organs. Using whole-exome sequencing, we identified a heterozygous nonsense mutation c.874G>T (p.Glu292X) in the TNF homology domain of EDA in all affected female patients. This protein-altering variant arose de novo, and the potentially causative allele was transmitted to affected offspring from the affected mother. We suggest that the dental phenotype variability described in heterozygous female carriers of EDA mutation may occur because of the differential pattern of X-chromosome inactivation, which retains reduced levels of EDA-receptor signaling in tissues involved in tooth morphogenesis. This results in selective tooth agenesis rather than XLHED phenotype. The present study broadens the mutation spectrum for this locus and demonstrates that EDA mutations may result in non-syndromic tooth agenesis in heterozygous females.
authors.affiliation: Institute of Molecular and Cell Biology, University of Tartu, Estonia. tiitn@ebc.ee
authors.forename: T
authors.initials: T
authors.lastname: Nikopensius
authors.forename: T
authors.initials: T
authors.lastname: Annilo
authors.forename: T
authors.initials: T
authors.lastname: Jagomägi
authors.forename: C
authors.initials: C
authors.lastname: Gilissen
authors.forename: M
authors.initials: M
authors.lastname: Kals
authors.forename: K
authors.initials: K
authors.lastname: Krjutškov
authors.forename: R
authors.initials: R
authors.lastname: Mägi
authors.forename: M
authors.initials: M
authors.lastname: Eelmets
authors.forename: U
authors.initials: U
authors.lastname: Gerst-Talas
authors.forename: M
authors.initials: M
authors.lastname: Remm
authors.forename: M
authors.initials: M
authors.lastname: Saag
authors.forename: A
authors.initials: A
authors.lastname: Hoischen
authors.forename: A
authors.initials: A
authors.lastname: Metspalu
mesh_terms: D000483:Alleles; D000848:Anodontia / Q000235:genetics*; D002874:Chromosome Mapping; D018389:Codon, Nonsense / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D053331:Ectodysplasins / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D006147:Guanine; D006579:Heterozygote; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008297:Male; D009805:Odontogenesis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053338:Receptors, Ectodysplasin / Q000235:genetics; D017421:Sequence Analysis; D020539:Sequence Analysis, Protein; D015398:Signal Transduction / Q000235:genetics; D040681:Structural Homology, Protein; D013941:Thymine; D048069:Tumor Necrosis Factors / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; C506018:EDA protein, human; D053331:Ectodysplasins; D053338:Receptors, Ectodysplasin; D048069:Tumor Necrosis Factors; D005973:Glutamine; D006147:Guanine; D013941:Thymine
keywords:    EDA gene; X-chromosome inactivation; exome sequencing; hypodontia/oligodontia; mutation