Genes and Related Proteins Involved in Amelogenesis Imperfecta

Stephanopoulos, Gregory; Garefalaki, M.-E.; Lyroudia, K.

doi:10.1177/154405910508401206

Cited by 124 publications

(120 citation statements)

References 127 publications

(184 reference statements)

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“…Mutations at both the AMELOGENIN (Xp22.3-p22.1) and ENAMELIN (4q21) loci contribute to a heterogenous group of human enamel disorders known as amelogenesis imperfecta (AI). Mutations at the AMELOGENIN locus are associated with X-linked AI, whereas those at the ENAMELIN locus underlie the genetic basis of autosomal dominant AI (36).…”

Section: Discussionmentioning

confidence: 99%

Ctip2/Bcl11b controls ameloblast formation during mammalian odontogenesis

Golonzhka

Metzger

Bornert

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor Ctip2/Bcl11b plays essential roles in developmental processes of the immune and central nervous systems and skin. Here we show that Ctip2 also plays a key role in tooth development. Ctip2 is highly expressed in the ectodermal components of the developing tooth, including inner and outer enamel epithelia, stellate reticulum, stratum intermedium, and the ameloblast cell lineage. In Ctip2 ؊/؊ mice, tooth morphogenesis appeared to proceed normally through the cap stage but developed multiple defects at the bell stage. Mutant incisors and molars were reduced in size and exhibited hypoplasticity of the stellate reticulum. An ameloblast-like cell population developed ectopically on the lingual aspect of mutant lower incisors, and the morphology, polarization, and adhesion properties of ameloblasts on the labial side of these teeth were severely disrupted. Perturbations of gene expression were also observed in the mandible of Ctip2 ؊/؊ mice: expression of the ameloblast markers amelogenin, ameloblastin, and enamelin was down-regulated, as was expression of Msx2 and epiprofin, transcription factors implicated in the tooth development and ameloblast differentiation. These results suggest that Ctip2 functions as a critical regulator of epithelial cell fate and differentiation during tooth morphogenesis.amelogenesis ͉ cellular differentiation ͉ enamel ͉ tooth development ͉ transcription factor

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Section: Discussionmentioning

confidence: 99%

Ctip2/Bcl11b controls ameloblast formation during mammalian odontogenesis

Golonzhka

Metzger

Bornert

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in several genes are associated with human AI (Hu et al, 2007;Stephanopoulos et al, 2005). In general, mutations that affect enamel matrix production (AMELX, AMBN, ENAM) tend to result in hypoplastic enamel while those that affect matrix removal (MMP20, KLK4) tend to result in hypomaturation of the enamel (Hu et al, 2007).…”

Section: (C-h) Amelogenin Endocytosis By Wt (Ceg) and Itgb6 2/2 Amementioning

confidence: 99%

Critical role for αvβ6 integrin in enamel biomineralization

Mohazab

Koivisto

Jiang

et al. 2012

Journal of Cell Science

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SummaryTooth enamel has the highest degree of biomineralization of all vertebrate hard tissues. During the secretory stage of enamel formation, ameloblasts deposit an extracellular matrix that is in direct contact with the ameloblast plasma membrane. Although it is known that integrins mediate cell-matrix adhesion and regulate cell signaling in most cell types, the receptors that regulate ameloblast adhesion and matrix production are not well characterized. We hypothesized that avb6 integrin is expressed in ameloblasts where it regulates biomineralization of enamel. Human and mouse ameloblasts were found to express both b6 integrin mRNA and protein. The maxillary incisors of Itgb6 2/2 mice lacked yellow pigment and their mandibular incisors appeared chalky and rounded. Molars of Itgb6 2/2 mice showed signs of reduced mineralization and severe attrition. The mineral-to-protein ratio in the incisors was significantly reduced in Itgb6 2/2 enamel, mimicking hypomineralized amelogenesis imperfecta. Interestingly, amelogenin-rich extracellular matrix abnormally accumulated between the ameloblast layer of Itgb6 2/2 mouse incisors and the forming enamel surface, and also between ameloblasts. This accumulation was related to increased synthesis of amelogenin, rather than to reduced removal of the matrix proteins. This was confirmed in cultured ameloblast-like cells, in which avb6 integrin was not an endocytosis receptor for amelogenins, although it participated in cell adhesion on this matrix indirectly via endogenously produced matrix proteins. In summary, integrin avb6 is expressed by ameloblasts and it plays a crucial role in regulating amelogenin deposition and/or turnover and subsequent enamel biomineralization.

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“…The substrates for Fam20A are unknown; however, mutations in FAM20A are known to cause amelogenesis imperfecta (AI) and enamel renal syndrome (ERS) in humans (26)(27)(28)(29). AI is a clinically and genetically heterogeneous group of disorders characterized by improper formation of enamel, a highly mineralized tissue comprising the outer surface of the vertebrate tooth (30). Patients with ERS have clinical features of AI along with renal calcifications (31).…”

mentioning

confidence: 99%

Crystal structure of the Golgi casein kinase

Xiao

Tagliabracci

Wen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The family with sequence similarity 20 (Fam20) kinases phosphorylate extracellular substrates and play important roles in biomineralization. Fam20C is the Golgi casein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs. Mutations in Fam20C cause Raine syndrome, an osteosclerotic bone dysplasia. Here we report the crystal structure of the Fam20C ortholog from Caenorhabditis elegans. The nucleotide-free and Mn/ ADP-bound structures unveil an atypical protein kinase-like fold and highlight residues critical for activity. The position of the regulatory αC helix and the lack of an activation loop indicate an architecture primed for efficient catalysis. Furthermore, several distinct elements, including the presence of disulfide bonds, suggest that the Fam20 family diverged early in the evolution of the protein kinase superfamily. Our results reinforce the structural diversity of protein kinases and have important implications for patients with disorders of biomineralization.P rotein phosphorylation is a fundamental mechanism that regulates numerous physiological processes (1, 2). Protein kinases have evolved to function as dynamic switches relaying signals in response to various stimuli by transferring a phosphate from ATP to target proteins (3-5). Most phosphoproteins are found within the cell, residing in the nuclei and cytosol; however, secreted proteins, including casein and other members of the secretory calciumbinding phosphoprotein family, are phosphorylated as well (6). We recently identified a family of kinases that reside in the secretory pathway and function to phosphorylate extracellular substrates (7,8). One member of this family, Fam20C (family with sequence similarity 20, member C), is the physiological casein kinase that phosphorylates multiple secreted proteins within a Ser-x-Glu/pSer motif (7, 9, 10). The importance of this discovery is underscored by the fact that some 75% of the phosphoproteins identified in human serum and cerebrospinal fluid contain phosphate within this motif (11-13). Furthermore, mutations in FAM20C cause Raine syndrome, a deadly osteosclerotic bone dysplasia characterized by generalized osteosclerosis, ectopic calcifications, and characteristic facial features (14-16). Most individuals with Raine syndrome die within a few weeks after birth; however, nonlethal cases with dental abnormalities and clinical features of hypophosphatemia have been reported (17,18). Loss of Fam20C in mice also results in severe bone and tooth anomalies, as well as hypophosphatemia (19)(20)(21).Two other closely related Fam20C paralogs, Fam20A and Fam20B, are present in humans (22). Fam20B is ubiquitously expressed and phosphorylates xylose within the tetrasaccharide linkage region of proteoglycans (23). This phosphorylation event may influence glycosaminoglycan biosynthesis (24). Genetic deletion of Fam20B in mice results in embryonic lethality at E13.5, and mutations in Danio rerio result in reduced cartilage matrix production and skeletal defects (19,25). The substra...

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Genes and Related Proteins Involved in Amelogenesis Imperfecta

Cited by 124 publications

References 127 publications

Ctip2/Bcl11b controls ameloblast formation during mammalian odontogenesis

Ctip2/Bcl11b controls ameloblast formation during mammalian odontogenesis

Critical role for αvβ6 integrin in enamel biomineralization

Crystal structure of the Golgi casein kinase

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