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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 3 from Iran with FAM20A nonsense mutations in exon 2 (c.406C>T; g.50213C>T; p.R136*) and in exon 11 (c.1432C>T; g.68284C>T; p.R478*).A: Pedigree consistent with a recessive pattern of inheritance. B: Exon 2 (left) and exon 11 DNA sequencing chromatograms. The proband (III:16) is heterozygous for nonsense mutations in exon 2 (c.406C>T) and exon 11 (c.1432C>T). The unaffected brother (III:17) is only heterozygous for the c.406C>T mutation in exon 2. C: Panoramic radiograph of proband. Note the lack of enamel, pericoronal radiolucencies over the unerupted mandibular third molars (arrowheads), and apparent crown resorption of the left mandibular second molar (#18).
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pgen-1003302-g003: Family 3 from Iran with FAM20A nonsense mutations in exon 2 (c.406C>T; g.50213C>T; p.R136*) and in exon 11 (c.1432C>T; g.68284C>T; p.R478*).A: Pedigree consistent with a recessive pattern of inheritance. B: Exon 2 (left) and exon 11 DNA sequencing chromatograms. The proband (III:16) is heterozygous for nonsense mutations in exon 2 (c.406C>T) and exon 11 (c.1432C>T). The unaffected brother (III:17) is only heterozygous for the c.406C>T mutation in exon 2. C: Panoramic radiograph of proband. Note the lack of enamel, pericoronal radiolucencies over the unerupted mandibular third molars (arrowheads), and apparent crown resorption of the left mandibular second molar (#18).

Mentions: Family 3 was a large kindred from Iran with two affected cousins (Figure 3). All of the proband's teeth were extracted (and some saved) prior to recruitment. A pre-surgical panoramic radiograph showed no radiopaque enamel, delayed tooth eruption, intrapulpal calcifications, and pericoronal radiolucencies. DNA was obtained from the proband and her younger, unaffected brother. Only FAM20A was characterized by mutational analyses. The proband was a compound heterozygote for two C>T transitions that both resulted in premature translation termination (TGA) codons. The nonsense mutations were in exon 2 (c.406C>T; g.50213C>T; p.R136*) and in exon 11 (c.1432C>T; g.68284C>T; p.R478*). The unaffected younger brother was heterozygous for the nonsense mutation in exon 2, but his exon 11 sequence was normal on both alleles. The exon 2 nonsense mutation was previously reported to cause AIGFS when found on both FAM20A alleles [24].


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 3 from Iran with FAM20A nonsense mutations in exon 2 (c.406C>T; g.50213C>T; p.R136*) and in exon 11 (c.1432C>T; g.68284C>T; p.R478*).A: Pedigree consistent with a recessive pattern of inheritance. B: Exon 2 (left) and exon 11 DNA sequencing chromatograms. The proband (III:16) is heterozygous for nonsense mutations in exon 2 (c.406C>T) and exon 11 (c.1432C>T). The unaffected brother (III:17) is only heterozygous for the c.406C>T mutation in exon 2. C: Panoramic radiograph of proband. Note the lack of enamel, pericoronal radiolucencies over the unerupted mandibular third molars (arrowheads), and apparent crown resorption of the left mandibular second molar (#18).
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Related In: Results  -  Collection

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pgen-1003302-g003: Family 3 from Iran with FAM20A nonsense mutations in exon 2 (c.406C>T; g.50213C>T; p.R136*) and in exon 11 (c.1432C>T; g.68284C>T; p.R478*).A: Pedigree consistent with a recessive pattern of inheritance. B: Exon 2 (left) and exon 11 DNA sequencing chromatograms. The proband (III:16) is heterozygous for nonsense mutations in exon 2 (c.406C>T) and exon 11 (c.1432C>T). The unaffected brother (III:17) is only heterozygous for the c.406C>T mutation in exon 2. C: Panoramic radiograph of proband. Note the lack of enamel, pericoronal radiolucencies over the unerupted mandibular third molars (arrowheads), and apparent crown resorption of the left mandibular second molar (#18).
Mentions: Family 3 was a large kindred from Iran with two affected cousins (Figure 3). All of the proband's teeth were extracted (and some saved) prior to recruitment. A pre-surgical panoramic radiograph showed no radiopaque enamel, delayed tooth eruption, intrapulpal calcifications, and pericoronal radiolucencies. DNA was obtained from the proband and her younger, unaffected brother. Only FAM20A was characterized by mutational analyses. The proband was a compound heterozygote for two C>T transitions that both resulted in premature translation termination (TGA) codons. The nonsense mutations were in exon 2 (c.406C>T; g.50213C>T; p.R136*) and in exon 11 (c.1432C>T; g.68284C>T; p.R478*). The unaffected younger brother was heterozygous for the nonsense mutation in exon 2, but his exon 11 sequence was normal on both alleles. The exon 2 nonsense mutation was previously reported to cause AIGFS when found on both FAM20A alleles [24].

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