Enamel–Renal–Gingival syndrome, hypodontia, and a novel <i>FAM20A</i> mutation

Kantaputra, Piranit Nik; Bongkochwilawan, Chotika; Kaewgahya, Massupa; Ohazama, Atsushi; Kayserili, Hülya; Erdem, Arzu Pınar; Aktören, Oya; Güven, Yeliz

doi:10.1002/ajmg.a.36579

Cited by 24 publications

(29 citation statements)

References 17 publications

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“…5,20 Noticeably, a two-nucleotide deletion in Exon 1, c.34_35del (p.Leu2Alafs*67), has been reported in 5 families of ERS, but not documented in gnomAD or ExAC database, which seems to be a mutation hotspot. 3,[21][22][23][24] However, those cases were all homozygotes for the mutation and mostly from Mediterranean region with probably similar genetic background, indicating a potential founder effect. Therefore, identity by descent (IBD) seems to underlie the genetic etiology of many ERS cases reported all over the world.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of gingival tissues of enamel‐renal syndrome

Wang

Lin

Zhong

et al. 2019

J of Periodontal Research

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Background and objective Biallelic loss‐of‐function mutations of human FAM20A have been known to cause enamel‐renal syndrome (ERS), featured by agenesis of dental enamel, nephrocalcinosis, and other orodental abnormalities, including gingival hyperplasia. However, while the histopathology of this gingival anomaly has been analyzed, its underlying molecular mechanism remains largely unknown. This study aimed to unravel the pathogenesis of gingival hyperplasia in ERS. Methods Whole‐exome sequencing was conducted for an ERS case. Transcriptome analyses, using RNA sequencing, of the patient's gingiva were performed to unravel dysregulated molecules and aberrant biological processes underlying the gingival pathology of ERS, which was further confirmed by histology and immunohistochemistry. Results Two novel frameshift FAM20A mutations in Exon 1 (g.5417delG; c.129delG; p.Cys44Alafs*101) and Exon 5 (g.62248_62249delAG; c.734_735delAG; p.Glu245Glyfs*11) were identified. Transcriptional profiling of patient's gingival tissue revealed a total of 1683 genes whose expression had increased (1129 genes) or decreased (554 genes) at least 2‐fold compared to control gingival tissues. There were 951 gene ontology (GO) terms of biological process being significantly over‐represented or under‐represented. While GOs involved in extracellular matrix organization, angiogenesis, biomineralization, and epithelial cell proliferation appeared to be activated in ERS gingiva, genes related to keratinocyte differentiation, epithelial development, and keratinization were of decreased expression. FAM20A immunohistochemistry revealed a strong reactivity at the suprabasal layers of epithelium in control gingiva but showed a significantly diminished and scattered signal in ERS tissues. For genes showing significant over‐expression in the transcriptome analyses, namely ALPL, SPARC, and ACTA2, an increased immunoreactivity was observed. Conclusion Our results unraveled a potential role for FAM20A in homeostasis of both gingival epithelium and connective tissues.

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Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of gingival tissues of enamel‐renal syndrome

Wang

Lin

Zhong

et al. 2019

J of Periodontal Research

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“…In connection with other syndromes the gene FAM20A seems to have an impact on AI and tooth eruption (Cho et al, 2012). It also influences AI of hypoplastic type with gingival fibromatosis and AI with nephrocalcinosis or enamelrenal syndrome, rare autosomal recessive disorders (Kantaputra et al, 2014;Wang et al, 2014).…”

Section: Genetics Of Aimentioning

confidence: 99%

A Randomized Controlled Trial of Crown Therapy in Young Individuals with Amelogenesis Imperfecta

et al. 2015

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Amelogenesis imperfecta (AI) is a rare, genetically determined defect in enamel mineralization. Existing treatment recommendations suggest resin-composite restorations until adulthood, although such restorations have a limited longevity. New crown materials allow for minimal preparation techniques. The aim of this study was to compare the quality and longevity of 2 crown types-Procera and IPS e.max Press-in adolescents and young adults with AI. A secondary aim was to document adverse events. We included 27 patients (11 to 22 y of age) with AI in need of crown therapy in a randomized controlled trial using a split-mouth technique. After placing 119 Procera crowns and 108 IPS e.max Press crowns following randomization, we recorded longevity, quality, adverse events, and tooth sensitivity. After 2 y, 97% of the crowns in both crown groups had excellent or acceptable quality. We found no significant differences in quality between Procera and IPS e.max Press crowns. Tooth sensitivity was significantly reduced after crown therapy (P < 0.001). Endodontic complications occurred in 3% of crowns. The results show that it is possible to perform crown therapy with excellent results and without severe complications in young patients with AI. The study is registered at http://www.controlled-trials.com (ISRCTN70438627).

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“…These AI patients with FAM20A mutations have several major dental abnormalities such as generalized hypoplastic enamel, intrapulpal calcification, delayed tooth eruption, and failure of tooth development as well as gingival hyperplasia23. More recently, a non-dental phenotype of nephrocalcinosis has also been reported in the AI patients with FAM20A mutation, further indicating the potential molecular function of FAM20A in biomineralization456789. FAM20B encodes a protein kinase that phosphorylates xylose residue in the tetrasaccharide glycosaminoglycan (GAG)-protein linkage region in the Golgi apparatus10, thereby regulating the subsequent GAG chain assembly11.…”

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confidence: 95%

FAM20A binds to and regulates FAM20C localization

Ohyama

Lin

Govitvattana

et al. 2016

Sci Rep

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Mutations in the Family with sequence similarity (FAM) 20 gene family are associated with mineralized tissue phenotypes in humans. Among these genes, FAM20A mutations are associated with Amelogenesis Imperfecta (AI) with gingival hyperplasia and nephrocalcinosis, while FAM20C mutations cause Raine syndrome, exhibiting bone and craniofacial/dental abnormalities. Although it has been demonstrated that Raine syndrome associated-FAM20C mutants prevented FAM20C kinase activity and secretion, overexpression of the catalytically inactive D478A FAM20C mutant was detected in both cell extracts and the media. This suggests that FAM20C secretion doesn’t require its kinase activity, and that another molecule(s) may control the secretion. In this study, we found that extracellular FAM20C localization was increased when wild-type (WT), but not AI-forms of FAM20A was co-transfected. On the other hand, extracellular FAM20C was absent in the conditioned media of mouse embryonic fibroblasts (MEFs) derived from Fam20a knock-out (KO) mouse, while it was detected in the media from WT MEFs. We also showed that cells with the conditioned media of Fam20a WT MEFs mineralized, but those with the conditioned media of KO MEFs failed to mineralize in vitro. Our data thus demonstrate that FAM20A controls FAM20C localization that may assist in the extracellular function of FAM20C in mineralized tissues.

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Enamel–Renal–Gingival syndrome, hypodontia, and a novel FAM20A mutation

Cited by 24 publications

References 17 publications

Transcriptome analysis of gingival tissues of enamel‐renal syndrome

Transcriptome analysis of gingival tissues of enamel‐renal syndrome

A Randomized Controlled Trial of Crown Therapy in Young Individuals with Amelogenesis Imperfecta

FAM20A binds to and regulates FAM20C localization

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