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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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Related in: MedlinePlus

Backscatter Scanning Electron Micrographs (bSEMs) of molar (#18) roots.A: The bSEM of molar after it was cut sagitally (mesial-distally). B: Higher magnification of smaller box in A showing the layered build-up resembling cellular cementum. Arrowheads mark the dentin-cementum border. C–D: Higher magnifications of the larger box in A showing the thick layers of “cellular cementum” covering the roots. In panel D a dark line is placed at the dentin surface. E: Higher magnification of the larger box in panel C showing the thick layers of “cellular cementum” covering the roots and how the lamellar pattern suggests that deposition of these layers was punctuated by periods of resorption that sometimes penetrated into the dentin. F–G: Higher magnification of the smaller box in panel C also showing how deposition of the layers of acellular cementum was punctuated by resorption that sometimes penetrated into the dentin.
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pgen-1003302-g010: Backscatter Scanning Electron Micrographs (bSEMs) of molar (#18) roots.A: The bSEM of molar after it was cut sagitally (mesial-distally). B: Higher magnification of smaller box in A showing the layered build-up resembling cellular cementum. Arrowheads mark the dentin-cementum border. C–D: Higher magnifications of the larger box in A showing the thick layers of “cellular cementum” covering the roots. In panel D a dark line is placed at the dentin surface. E: Higher magnification of the larger box in panel C showing the thick layers of “cellular cementum” covering the roots and how the lamellar pattern suggests that deposition of these layers was punctuated by periods of resorption that sometimes penetrated into the dentin. F–G: Higher magnification of the smaller box in panel C also showing how deposition of the layers of acellular cementum was punctuated by resorption that sometimes penetrated into the dentin.

Mentions: Backscatter SEMs of tooth #18 revealed that there was no enamel on the occlusal surface of the crown, although a thin, crusty material more highly mineralized than dentin covered part of the lateral coronal surfaces (Figure 9). Remarkably, only a small remnant of dentin, with apparent resorption lacunae at its edges, was evident in the mesial half of this FAM20A−/− molar crown. In its place was a laminated, bone-like material with osteocyte lacunae. Based upon the patterns of the growth lines, this lamellar bone had undergone repeated cycles of resorption and deposition. The calcifications in the pulp were unevenly mineralized. The most highly mineralized pulp material was comprised of incompletely coalesced spherical structures (calcospherites). Thus there appeared to be at least two types of pathological mineralization within the crown: lamellar-like bone and calcospherites that apparently formed by a different mechanism. Backscatter SEMs of the root region revealed thin roots, with normal-looking root dentin covered by a thick layer of laminated, cementum-like mineralized tissue similar to the lamellar mineralized tissue that had replaced dentin in the crown but with fewer osteocyte lacunae (Figure 10). The dentin was often separated from this thick cementum-like layer by a hypermineralized line that might represent the original cementum. This line was sometimes interupted at places where the root surface had been resorbed locally and replaced.


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)

Backscatter Scanning Electron Micrographs (bSEMs) of molar (#18) roots.A: The bSEM of molar after it was cut sagitally (mesial-distally). B: Higher magnification of smaller box in A showing the layered build-up resembling cellular cementum. Arrowheads mark the dentin-cementum border. C–D: Higher magnifications of the larger box in A showing the thick layers of “cellular cementum” covering the roots. In panel D a dark line is placed at the dentin surface. E: Higher magnification of the larger box in panel C showing the thick layers of “cellular cementum” covering the roots and how the lamellar pattern suggests that deposition of these layers was punctuated by periods of resorption that sometimes penetrated into the dentin. F–G: Higher magnification of the smaller box in panel C also showing how deposition of the layers of acellular cementum was punctuated by resorption that sometimes penetrated into the dentin.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003302-g010: Backscatter Scanning Electron Micrographs (bSEMs) of molar (#18) roots.A: The bSEM of molar after it was cut sagitally (mesial-distally). B: Higher magnification of smaller box in A showing the layered build-up resembling cellular cementum. Arrowheads mark the dentin-cementum border. C–D: Higher magnifications of the larger box in A showing the thick layers of “cellular cementum” covering the roots. In panel D a dark line is placed at the dentin surface. E: Higher magnification of the larger box in panel C showing the thick layers of “cellular cementum” covering the roots and how the lamellar pattern suggests that deposition of these layers was punctuated by periods of resorption that sometimes penetrated into the dentin. F–G: Higher magnification of the smaller box in panel C also showing how deposition of the layers of acellular cementum was punctuated by resorption that sometimes penetrated into the dentin.
Mentions: Backscatter SEMs of tooth #18 revealed that there was no enamel on the occlusal surface of the crown, although a thin, crusty material more highly mineralized than dentin covered part of the lateral coronal surfaces (Figure 9). Remarkably, only a small remnant of dentin, with apparent resorption lacunae at its edges, was evident in the mesial half of this FAM20A−/− molar crown. In its place was a laminated, bone-like material with osteocyte lacunae. Based upon the patterns of the growth lines, this lamellar bone had undergone repeated cycles of resorption and deposition. The calcifications in the pulp were unevenly mineralized. The most highly mineralized pulp material was comprised of incompletely coalesced spherical structures (calcospherites). Thus there appeared to be at least two types of pathological mineralization within the crown: lamellar-like bone and calcospherites that apparently formed by a different mechanism. Backscatter SEMs of the root region revealed thin roots, with normal-looking root dentin covered by a thick layer of laminated, cementum-like mineralized tissue similar to the lamellar mineralized tissue that had replaced dentin in the crown but with fewer osteocyte lacunae (Figure 10). The dentin was often separated from this thick cementum-like layer by a hypermineralized line that might represent the original cementum. This line was sometimes interupted at places where the root surface had been resorbed locally and replaced.

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