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FAM20A Mutations Can Cause Enamel-Renal Syndrome (ERS)

Wang, Shih-Kai; Aref, Parissa; Hu, Yuanyuan; Milkovich, Rachel N.; Simmer, James P.; El-Khateeb, Mohammad; Daggag, Hinda; Baqain, Zaid H.; Hu, Jan C-C.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN
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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...

Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations

Jaureguiberry, Graciana; De la Dure-Molla, Muriel; Parry, David; Quentric, Mickael; Himmerkus, Nina; Koike, Toshiyasu; Poulter, James; Klootwijk, Enriko; Robinette, Steven L.; Howie, Alexander J.; Patel, Vaksha; Figueres, Marie-Lucile; Stanescu, Horia C.;
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
EN
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162.35309%

FAM20A Mutations Associated with Enamel Renal Syndrome

Wang, S.K.; Reid, B.M.; Dugan, S.L.; Roggenbuck, J.A.; Read, L.; Aref, P.; Taheri, A.P.H.; Yeganeh, M.Z.; Simmer, J.P.; Hu, J.C.-C.
Fonte: SAGE Publications Publicador: SAGE Publications
Tipo: Artigo de Revista Científica
Publicado em /01/2014 EN
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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 D403 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.

Pathognomonic oral profile of Enamel Renal Syndrome (ERS) caused by recessive FAM20A mutations

de la Dure-Molla, Muriel; Quentric, Mickael; Yamaguti, Paulo Marcio; Acevedo, Ana-Carolina; Mighell, Alan J; Vikkula, Miikka; Huckert, Mathilde; Berdal, Ariane; Bloch-Zupan, Agnes
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 14/06/2014 EN
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305.52062%
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...

Further evidence for causal FAM20A mutations and first case of amelogenesis imperfecta and gingival hyperplasia syndrome in Morocco: a case report

Cherkaoui Jaouad, Imane; El Alloussi, Mustapha; Chafai El alaoui, Siham; Laarabi, Fatima Zahra; Lyahyai, Jaber; Sefiani, Abdelaziz
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 30/01/2015 EN
Relevância na Pesquisa
162.35309%

Pregnane X Receptor Knockout Mice Display Aging-Dependent Wearing of Articular Cartilage

Azuma, Kotaro; Casey, Stephanie C.; Urano, Tomohiko; Horie-Inoue, Kuniko; Ouchi, Yasuyoshi; Blumberg, Bruce; Inoue, Satoshi
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 06/03/2015 EN
Relevância na Pesquisa
185.7355%
Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

A secretory kinase complex regulates extracellular protein phosphorylation

Cui, Jixin; Xiao, Junyu; Tagliabracci, Vincent S; Wen, Jianzhong; Rahdar, Meghdad; Dixon, Jack E
Fonte: eLife Sciences Publications, Ltd Publicador: eLife Sciences Publications, Ltd
Tipo: Artigo de Revista Científica
Publicado em 19/03/2015 EN
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Although numerous extracellular phosphoproteins have been identified, the protein kinases within the secretory pathway have only recently been discovered, and their regulation is virtually unexplored. Fam20C is the physiological Golgi casein kinase, which phosphorylates many secreted proteins and is critical for proper biomineralization. Fam20A, a Fam20C paralog, is essential for enamel formation, but the biochemical function of Fam20A is unknown. Here we show that Fam20A potentiates Fam20C kinase activity and promotes the phosphorylation of enamel matrix proteins in vitro and in cells. Mechanistically, Fam20A is a pseudokinase that forms a functional complex with Fam20C, and this complex enhances extracellular protein phosphorylation within the secretory pathway. Our findings shed light on the molecular mechanism by which Fam20C and Fam20A collaborate to control enamel formation, and provide the first insight into the regulation of secretory pathway phosphorylation.

Caracteriza??o fenot?pica da s?ndrome da amelog?nese imperfeita e nefrocalcinose; Phenotypic characterization of the amelogenesis imperfecta and nephrocalcinosis syndrome

Dourado, Mauricio da Rocha
Fonte: UFVJM Publicador: UFVJM
Tipo: Dissertação de Mestrado
POR
Relevância na Pesquisa
297.98344%
ABSTRACT Amelogenesis imperfecta (AI) is a complex group of conditions that cause inherited defects of dental enamel in quantity or quality. Nephrocalcinosis (NC) is the deposition of calcium salts at the renal parenchyma, which may in the long term and in the absence of proper treatment, lead to chronic renal failure and other kidney disorders. These two conditions simultaneously represent the amelogenesis imperfecta and nephrocalcinosis syndrome (AINCS), or enamel renal syndrome, an autosomal recessive disorder caused by mutations in FAM20A gene, with few cases reported in the literature. The purpose of this study was to investigate the characteristics of the syndrome in patients from four Brazilian families. Patients underwent clinical examination, radiographic, renal and haematological investigation and biochemical markers examinations, being identified nine patients with this syndrome. Clinical examination revealed small and yellowish teeth, occlusal/incisal wear, retention of deciduous dentition and gingival hyperplasia. The radiographs showed pericoronal radiolucencies involving impacted permanent teeth, absence of contrast between enamel and dentin and intrapulpal calcifications. Biochemical tests showed low levels of 25-OH vitamin D and high levels of alkaline phosphatase and parathyroid hormone in four patients. Ultrasonography revealed bilateral nephrocalcinosis...

Whole-Exome Sequencing Identifies FAM20A Mutations as a Cause of Amelogenesis Imperfecta and Gingival Hyperplasia Syndrome

O'Sullivan, James; Bitu, Carolina C.; Daly, Sarah B.; Urquhart, Jill E.; Barron, Martin J.; Bhaskar, Sanjeev S.; Martelli-Júnior, Hercilio; dos Santos Neto, Pedro Eleuterio; Mansilla, Maria A.; Murray, Jeffrey C.; Coletta, Ricardo D.; Black, G
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 13/05/2011 EN
Relevância na Pesquisa
305.52062%
Amelogenesis imperfecta (AI) describes a clinically and genetically heterogeneous group of disorders of biomineralization resulting from failure of normal enamel formation. AI is found as an isolated entity or as part of a syndrome, and an autosomal-recessive syndrome associating AI and gingival hyperplasia was recently reported. Using whole-exome sequencing, we identified a homozygous nonsense mutation in exon 2 of FAM20A that was not present in the Single Nucleotide Polymorphism database (dbSNP), the 1000 Genomes database, or the Centre d'Etude du Polymorphisme Humain (CEPH) Diversity Panel. Expression analyses indicated that Fam20a is expressed in ameloblasts and gingivae, providing biological plausibility for mutations in FAM20A underlying the pathogenesis of this syndrome.