title: FAM20A mutations associated with enamel renal syndrome.
abstract: We identified two families with an autosomal-recessive disorder manifested by severe enamel hypoplasia, delayed and failed tooth eruption, misshapen teeth, intrapulpal calcifications, and localized gingival hyperplasia. Genetic analyses identified novel FAM20A mutations associated with the disease phenotype in both families. The proband of Family 1 had an altered splice junction in Intron 1 (g.502011G>C; c.405-1G>C) and a missense mutation in Exon 8 (g.65094G>A; c.1207G>A; p.D403N). The missense mutation is notable because D(403) is strictly conserved among FAM20A homologues, and the corresponding defect in FAM20C caused osteosclerotic bone dysplasia and a loss of kinase activity. The proband at age 12 yrs tested negative for nephrocalcinosis. The proband and her affected father in Family 2 were homozygous for a single nucleotide deletion that altered a splice junction in Intron 10 (g.66622del; c.1361+4del). Minigene analyses demonstrated that this alteration precluded normal splicing. Immunohistochemistry (IHC) of mouse maxillary first molars localized FAM20A in secretory-stage ameloblasts, in odontoblasts, and in the eruption pathway. IHC of kidneys localized FAM20A in the renal tubules. We conclude that FAM20A is likely a secretory pathway kinase and that loss-of-function mutations cause pathology where its phosphorylations are necessary for normal development or homeostasis.
authors.affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, 1210 Eisenhower Place, Ann Arbor, MI 48108, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Wang
authors.forename: B M
authors.initials: BM
authors.lastname: Reid
authors.forename: S L
authors.initials: SL
authors.lastname: Dugan
authors.forename: J A
authors.initials: JA
authors.lastname: Roggenbuck
authors.forename: L
authors.initials: L
authors.lastname: Read
authors.forename: P
authors.initials: P
authors.lastname: Aref
authors.forename: A P H
authors.initials: AP
authors.lastname: Taheri
authors.forename: M Z
authors.initials: MZ
authors.lastname: Yeganeh
authors.forename: J P
authors.initials: JP
authors.lastname: Simmer
authors.forename: J C-C
authors.initials: JC
authors.lastname: Hu
mesh_terms: D000241:Adenosine; D000567:Amelogenesis Imperfecta / Q000235:genetics*; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003596:Cytosine; D003744:Dental Enamel Hypoplasia / Q000235:genetics; D003746:Dental Enamel Proteins / Q000235:genetics*; D003784:Dental Pulp Calcification / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D005885:Gingival Hyperplasia / Q000235:genetics; D006147:Guanine; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009397:Nephrocalcinosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014071:Tooth Abnormalities / Q000235:genetics; D014078:Tooth Eruption / Q000235:genetics
chemical_list: D003746:Dental Enamel Proteins; C571509:FAM20A protein, human; D006147:Guanine; D003596:Cytosine; D000241:Adenosine
keywords: amelogenesis imperfecta; delayed eruption; enamel; gingival hyperplasia; nephrocalcinosis; tooth