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FAM20A mutations can cause enamel-renal syndrome (ERS).

Wang SK, Aref P, Hu Y, Milkovich RN, Simmer JP, El-Khateeb M, Daggag H, Baqain ZH, Hu JC - PLoS Genet. (2013)

Bottom Line: Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

ABSTRACT
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 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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Family 1 from the Caribbean with FAM20A mutation c.992G>A; g.63853G>A; p.G331D.A: Pedigree. A dot marks person who donated samples for DNA sequencing. B: FAM20A exon 7 DNA sequencing chromatograms. The proband's parents (II:1 and II:2) were both heterozygous (R = A or G) at cDNA position 992 (arrowheads). The proband (III-1) had the c.992G>A transition mutation in both alleles of FAM20A. This mutation changed a conserved glycine with an aspartic acid (p.G331D). The proband's affected younger sister (III-4) and her infant niece (IV:1) were also homozygous for this mutation (not shown). II:1 and III:8 were heterozygous for a recognized polymorphism (rs2302234) in exon 7 (K = A or C) unrelated to the phenotype. C: Proband's panoramic radiograph. Note the many unerupted teeth. The mandibular and maxillary unerupted second molars show concave occlusal surfaces without enamel (arrowheads). D: Proband's oral photos. The maxillary central incisors are restored. The clinical crowns were short with hypoplastic enamel. There was a deep anterior overbite, a posterior cross-bite, and retained mandibular primary molars (letters K, L, S, T).
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pgen-1003302-g001: Family 1 from the Caribbean with FAM20A mutation c.992G>A; g.63853G>A; p.G331D.A: Pedigree. A dot marks person who donated samples for DNA sequencing. B: FAM20A exon 7 DNA sequencing chromatograms. The proband's parents (II:1 and II:2) were both heterozygous (R = A or G) at cDNA position 992 (arrowheads). The proband (III-1) had the c.992G>A transition mutation in both alleles of FAM20A. This mutation changed a conserved glycine with an aspartic acid (p.G331D). The proband's affected younger sister (III-4) and her infant niece (IV:1) were also homozygous for this mutation (not shown). II:1 and III:8 were heterozygous for a recognized polymorphism (rs2302234) in exon 7 (K = A or C) unrelated to the phenotype. C: Proband's panoramic radiograph. Note the many unerupted teeth. The mandibular and maxillary unerupted second molars show concave occlusal surfaces without enamel (arrowheads). D: Proband's oral photos. The maxillary central incisors are restored. The clinical crowns were short with hypoplastic enamel. There was a deep anterior overbite, a posterior cross-bite, and retained mandibular primary molars (letters K, L, S, T).

Mentions: The proband's parents were born in the Caribbean. Oral photos and a panoramic radiograph were obtained for the proband and DNA was collected from nine family members (Figure 1). The proband (III:1), his younger sister (III:4), and niece (IV:1) were affected. According to the proband, when his adult teeth finally came in they were the same size as his baby teeth and very short. As far as he remembers, his gums have always been large and bumpy. He reported that he was otherwise healthy with average height and weight. Intraoral photographs of the proband showed a mixed dentition, small dental crowns with generally thin enamel, and yellow discoloration. Over-retained primary molars in the mandibular arch and partially erupted maxillary premolars were observed. The proband had a deep anterior overbite, a posterior cross-bite, and a class III molar relationship. The vertical dimension appeared to be reduced. Radiographically, the proband had the full complement of permanent teeth, but eruption of the canines, mandibular premolars and molars was failed or delayed. No radiopaque enamel layer was apparent on any of the teeth. Even unerupted teeth with completed root formation lacked enamel. Pericoronal radiolucencies outlined by sclerotic borders were observed around unerupted teeth, symptomatic of a slow expansion of the dental follicle covering the crown. In some cases the dentin occlusal surface appeared concave and close to the pulp chamber, suggesting pre-eruptive crown resorption. Most teeth showed intrapulpal calcifications. The gingiva appeared to be hyperplastic.


FAM20A mutations can cause enamel-renal syndrome (ERS).

Wang SK, Aref P, Hu Y, Milkovich RN, Simmer JP, El-Khateeb M, Daggag H, Baqain ZH, Hu JC - PLoS Genet. (2013)

Family 1 from the Caribbean with FAM20A mutation c.992G>A; g.63853G>A; p.G331D.A: Pedigree. A dot marks person who donated samples for DNA sequencing. B: FAM20A exon 7 DNA sequencing chromatograms. The proband's parents (II:1 and II:2) were both heterozygous (R = A or G) at cDNA position 992 (arrowheads). The proband (III-1) had the c.992G>A transition mutation in both alleles of FAM20A. This mutation changed a conserved glycine with an aspartic acid (p.G331D). The proband's affected younger sister (III-4) and her infant niece (IV:1) were also homozygous for this mutation (not shown). II:1 and III:8 were heterozygous for a recognized polymorphism (rs2302234) in exon 7 (K = A or C) unrelated to the phenotype. C: Proband's panoramic radiograph. Note the many unerupted teeth. The mandibular and maxillary unerupted second molars show concave occlusal surfaces without enamel (arrowheads). D: Proband's oral photos. The maxillary central incisors are restored. The clinical crowns were short with hypoplastic enamel. There was a deep anterior overbite, a posterior cross-bite, and retained mandibular primary molars (letters K, L, S, T).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585120&req=5

pgen-1003302-g001: Family 1 from the Caribbean with FAM20A mutation c.992G>A; g.63853G>A; p.G331D.A: Pedigree. A dot marks person who donated samples for DNA sequencing. B: FAM20A exon 7 DNA sequencing chromatograms. The proband's parents (II:1 and II:2) were both heterozygous (R = A or G) at cDNA position 992 (arrowheads). The proband (III-1) had the c.992G>A transition mutation in both alleles of FAM20A. This mutation changed a conserved glycine with an aspartic acid (p.G331D). The proband's affected younger sister (III-4) and her infant niece (IV:1) were also homozygous for this mutation (not shown). II:1 and III:8 were heterozygous for a recognized polymorphism (rs2302234) in exon 7 (K = A or C) unrelated to the phenotype. C: Proband's panoramic radiograph. Note the many unerupted teeth. The mandibular and maxillary unerupted second molars show concave occlusal surfaces without enamel (arrowheads). D: Proband's oral photos. The maxillary central incisors are restored. The clinical crowns were short with hypoplastic enamel. There was a deep anterior overbite, a posterior cross-bite, and retained mandibular primary molars (letters K, L, S, T).
Mentions: The proband's parents were born in the Caribbean. Oral photos and a panoramic radiograph were obtained for the proband and DNA was collected from nine family members (Figure 1). The proband (III:1), his younger sister (III:4), and niece (IV:1) were affected. According to the proband, when his adult teeth finally came in they were the same size as his baby teeth and very short. As far as he remembers, his gums have always been large and bumpy. He reported that he was otherwise healthy with average height and weight. Intraoral photographs of the proband showed a mixed dentition, small dental crowns with generally thin enamel, and yellow discoloration. Over-retained primary molars in the mandibular arch and partially erupted maxillary premolars were observed. The proband had a deep anterior overbite, a posterior cross-bite, and a class III molar relationship. The vertical dimension appeared to be reduced. Radiographically, the proband had the full complement of permanent teeth, but eruption of the canines, mandibular premolars and molars was failed or delayed. No radiopaque enamel layer was apparent on any of the teeth. Even unerupted teeth with completed root formation lacked enamel. Pericoronal radiolucencies outlined by sclerotic borders were observed around unerupted teeth, symptomatic of a slow expansion of the dental follicle covering the crown. In some cases the dentin occlusal surface appeared concave and close to the pulp chamber, suggesting pre-eruptive crown resorption. Most teeth showed intrapulpal calcifications. The gingiva appeared to be hyperplastic.

Bottom Line: Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis.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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.

ABSTRACT
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 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.

Show MeSH
Related in: MedlinePlus