Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.
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ABSTRACT:
SUBMITTER: Jaureguiberry G
PROVIDER: S-EPMC3782194 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.
Jaureguiberry Graciana G De la Dure-Molla Muriel M Parry David D Quentric Mickael M Himmerkus Nina N Koike Toshiyasu T Poulter James J Klootwijk Enriko E Robinette Steven L SL Howie Alexander J AJ Patel Vaksha V Figueres Marie-Lucile ML Stanescu Horia C HC Issler Naomi N Nicholson Jeremy K JK Bockenhauer Detlef D Laing Christopher C Walsh Stephen B SB McCredie David A DA Povey Sue S Asselin Audrey A Picard Arnaud A Coulomb Aurore A Medlar Alan J AJ Bailleul-Forestier Isabelle I Verloes Alain A Le Caignec Cedric C Roussey Gwenaelle G Guiol Julien J Isidor Bertrand B Logan Clare C Shore Roger R Johnson Colin C Inglehearn Christopher C Al-Bahlani Suhaila S Schmittbuhl Matthieu M Clauss François F Huckert Mathilde M Laugel Virginie V Ginglinger Emmanuelle E Pajarola Sandra S Spartà Giuseppina G Bartholdi Deborah D Rauch Anita A Addor Marie-Claude MC Yamaguti Paulo M PM Safatle Heloisa P HP Acevedo Ana Carolina AC Martelli-Júnior Hercílio H dos Santos Netos Pedro E PE Coletta Ricardo D RD Gruessel Sandra S Sandmann Carolin C Ruehmann Denise D Langman Craig B CB Scheinman Steven J SJ Ozdemir-Ozenen Didem D Hart Thomas C TC Hart P Suzanne PS Neugebauer Ute U Schlatter Eberhard E Houillier Pascal P Gahl William A WA Vikkula Miikka M Bloch-Zupan Agnès A Bleich Markus M Kitagawa Hiroshi H Unwin Robert J RJ Mighell Alan A Berdal Ariane A Kleta Robert R
Nephron. Physiology 20120101 1-2
<h4>Background/aims</h4>Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.<h4>Methods</h4>We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, ...[more]
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Project description:Amelogenesis imperfecta (AI) is a genetically and clinically heterogeneous group of inherited dental enamel defects. Commonly described as an isolated trait, it may be observed concomitantly with other orodental and/or systemic features such as nephrocalcinosis in Enamel Renal Syndrome (ERS, MIM#204690), or gingival hyperplasia in Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome (AIGFS, MIM#614253). Patients affected by ERS/AIGFS present a distinctive orodental phenotype consisting of generalized hypoplastic AI affecting both the primary and permanent dentition, delayed tooth eruption, pulp stones, hyperplastic dental follicles, and gingival hyperplasia with variable severity and calcified nodules. Renal exam reveals a nephrocalcinosis which is asymptomatic in children affected by ERS. FAM20A recessive mutations are responsible for both syndromes. We suggest that AIGFS and ERS are in fact descriptions of the same syndrome, but that the kidney phenotype has not always been investigated fully in AIGFS. The aim of this review is to highlight the distinctive and specific orodental features of patients with recessive mutations in FAM20A. We propose ERS to be the preferred term for all the phenotypes arising from recessive FAM20A mutations. A differential diagnosis has to be made with other forms of AI, isolated or syndromic, where only a subset of the clinical signs may be shared. When ERS is suspected, the patient should be assessed by a dentist, nephrologist and clinical geneticist. Confirmed cases require long-term follow-up. Management of the orodental aspects can be extremely challenging and requires the input of multi-disciplinary specialized dental team, especially when there are multiple unerupted teeth.
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Project description: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.
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Project description:Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis. Recently, mutations in FAM20A were reported to cause amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS), which closely resembles ERS except for the renal calcifications. We characterized three families with AIGFS and identified, in each case, recessive FAM20A mutations: family 1 (c.992G>A; g.63853G>A; p.Gly331Asp), family 2 (c.720-2A>G; g.62232A>G; p.Gln241_Arg271del), and family 3 (c.406C>T; g.50213C>T; p.Arg136* and c.1432C>T; g.68284C>T; p.Arg478*). Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to ERS. By characterizing teeth extracted from the family 3 proband, we demonstrated that FAM20A(-/-) molars lacked true enamel, showed extensive crown and root resorption, hypercementosis, and partial replacement of resorbed mineral with bone or coalesced mineral spheres. Supported by the observation of severe ectopic calcifications in the kidneys of Fam20a null mice, we conclude that FAM20A, which has a kinase homology domain and localizes to the Golgi, is a putative Golgi kinase that plays a significant role in the regulation of biomineralization processes, and that mutations in FAM20A cause both AIGFS and ERS.
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