Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta

Santos, Maria Cristina Leme Godoy dos; Hart, Patricia; Ramaswami, Mukundhan; Kanno, Cláudia Misue; Hart, Thomas C.; Line, Sérgio Roberto Peres

doi:10.1186/1746-160x-3-8

Cited by 20 publications

(11 citation statements)

References 40 publications

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“…2 To date, AI has been linked to mutations in six enamel proteins and proteinases (ENAM, AMBN, AMELX, MMP20, KLK4, and AMELOTIN), but many of the known AI kindreds do not have mutations in any of these genes. 16,77 Our findings in Fam20a -/-and Fam20c -/-mice strongly suggest that mutations in these genes might be responsible for some types of AI in humans. Figure 27.…”

Section: Discussionmentioning

confidence: 79%

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

et al. 2012

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The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b -/-embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a-/-mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c-/-mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c -/-mice.Keywords amelogenesis imperfecta, knockout, rickets, phosphatonin, ectopic mineralization, biomineralization, dentin, osteomalacia, osteosclerosisThe FAM20 family of secreted proteins in mammals consists of three members (FAM20A, FAM20B, and FAM20C) that were initially thought to have roles in regulating the differentiation and function of hematopoietic and other tissues. 65 Since then, there have been reports linking mutations in both FAM20A and FAM20C to developmental disorders involving bones and/or teeth, suggesting a role for FAM20 proteins in modulating biomineralization processes. In humans, a mutation in FAM20A was recently linked to the occurrence of amelogenesis imperfecta and gingival hyperplasia in a consanguineous family. 69 However, lesions were not reported in bones or teeth of transgenic mice with a partial deletion of Fam20a, and their stunted growth was attributed to malnutrition and an unspecified metabolic disorder. 4 To the best of our knowledge, there have been only two reports elucidating the function FAM20B, which was shown to be a kinase that phosphorylates glycosaminoglycans 50 and in vivo to be involved in cartilage matrix production and skeletal development in zebrafish. 2...

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Section: Discussionmentioning

confidence: 79%

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

et al. 2012

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“…If calcification or biomineralization process was disturbed, the formation of bone and tooth would also be disturbed and cause several diseases such as AI. To date, AI has been linked to mutations in six enamel proteins and proteinases (ENAM, AMBN, AMELX, MMP20, KLK4, and AMELOTIN), but many of the known AI kindreds do not have mutations in any of these genes [9,10]. In this study, we found typical AI and gum hypertrophy happened in Fam20a -/-mice.…”

Section: Discussionmentioning

confidence: 49%

Loss of FAM20A protein induces Amelogenesis Imperfecta in mice

2015

Integr Mol Med

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FAM20A is a member of family of related proteins that has been named family with sequence similarity 20 (FAM20) with three members (FAM20A, FAM20B and FAM20C) in mammals. Recently, some studies have reported that patients with Amelogenesis Imperfecta caused by FAM20A mutation displayed several dental phenotypes including hypoplastic enamel, failure of tooth development and gingival hyperplasia. We have reported a transgenic mouse line with a 58-kb fragment deletion that encompasses part of the Fam20a gene and its upstream region shows growth disorder. In the present study, we aimed to clarify how the loss of Fam20a protein influenced the development of dental tissues in the Fam20a -/-mouse. The light microscopic study (LM) of paraffin-embedded specimens demonstrated hypoplastic enamel and gingival hyperplasia in the Fam20a -/-mice. The LM of ground sections of the mandibles containing teeth showed that there was no enamel covering the coronal dentine. Immunohistochemical study of the mandibles (paraffin-embedded specimens) indicated that Fam20a protein expressed in osteoid tissue and tooth germ of Fam20a +/+ mice, but does not expressed in Fam20a -/-mice. In conclusion, this study revealed that the FAM20A protein is required for enamel formation.

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“…Subsequently, a large Brazilian family with hypomineralized AI was studied using broad genomic screening and showed linkage with chromosomal region 8q24.3 (Mendoza et al 2007). Another report analyzed the known candidate genes ENAM, AMBN, AMELX, MMP20, KLK4, and amelotin (AMNT) in two Brazilian families by PCR and sequencing and excluded the participation of these genes in the hypomineralized AI phenotype (Santos et al 2007). Surprisingly, at the beginning of 2008, two studies carried out by the same group of researchers reported 6 mutations in the FAM83H gene, found in region 8q24.3, which is responsible for hypocalcified ADAI (Lee et al 2008a).…”

Section: Phenotype-genotype Correlations In Autosomally Inherited Casesmentioning

confidence: 95%

“…Furthermore, it has been known for some time that the defects in causal genes explain less than half of all cases of AI (Hart et al 2003a;Kim et al 2006;Santos et al 2007). The recent discovery of the 8q24.3 chromosomal locus, and the participation of genes such as DLX3, FAM83H, and WDR72 in the etiology of AI, reveals that the selection of candidate genes is biased (Kim et al 2006Mendoza et al 2007).…”

Section: New Candidate Genesmentioning

confidence: 99%

Defining a New Candidate Gene for Amelogenesis Imperfecta: From Molecular Genetics to Biochemistry

et al. 2010

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Amelogenesis imperfecta is a group of genetic conditions that affect the structure and clinical appearance of tooth enamel. The types (hypoplastic, hypocalcified, and hypomature) are correlated with defects in different stages of the process of enamel synthesis. Autosomal dominant, recessive, and X-linked types have been previously described. These disorders are considered clinically and genetically heterogeneous in etiology, involving a variety of genes, such as AMELX, ENAM, DLX3, FAM83H, MMP-20, KLK4, and WDR72. The mutations identified within these causal genes explain less than half of all cases of amelogenesis imperfecta. Most of the candidate and causal genes currently identified encode proteins involved in enamel synthesis. We think it is necessary to refocus the search for candidate genes using biochemical processes. This review provides theoretical evidence that the human SLC4A4 gene (sodium bicarbonate cotransporter) may be a new candidate gene.

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Exclusion of known gene for enamel development in two Brazilian families with amelogenesis imperfecta

Cited by 20 publications

References 40 publications

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

Loss of FAM20A protein induces Amelogenesis Imperfecta in mice

Defining a New Candidate Gene for Amelogenesis Imperfecta: From Molecular Genetics to Biochemistry

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