Periodontal disease and FAM20A mutations

Kantaputra, Piranit Nik; Bongkochwilawan, Chotika; Lubinsky, Mark; Pata, Supansa; Kaewgahya, Massupa; Tong, Huei Jinn; Cairns, James R. Ketudat; Güven, Yeliz; Chaisrisookumporn, Nipon

doi:10.1038/jhg.2017.26

Cited by 23 publications

(31 citation statements)

References 45 publications

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“…These mutations (variants) are considerably rare and mostly identified only in a specific population. For example, the p.Leu117Cysfs*22 (c.349_367del) mutation is found in 3 out of 13 260 chromosomes in EAS with a MAF of 0.0002262 and has been identified in two Thai families of ERS, suggesting inheritance from a common ancestor . 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 .…”

Section: Discussionmentioning

confidence: 94%

“…(c.349_367del) mutation is found in 3 out of 13 260 chromosomes in EAS with a MAF of 0.0002262 and has been identified in two Thai families of ERS, suggesting inheritance from a common ancestor. 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.…”

Section: Discussionmentioning

confidence: 99%

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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: 94%

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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“…Despite its possible critical role of Periostin reported in certain tissues including PDL, there has been so far no gene mutations found in humans. Among the FAM20 family, it has been reported that periodontitis may be a part of clinical phenotypic spectrum in FAM20A mutations 29 . Some reports showed the presence of periodontitis in non-lethal type of Raine syndrome, where FAM20C is mutated, but genotype-phenotype correlation was not established.…”

Section: Discussionmentioning

confidence: 99%

“…Among the FAM20 family, it has been reported that periodontitis may be a part of clinical phenotypic spectrum in FAM20A mutations 29 . Some reports showed the presence of periodontitis in non-lethal type of Raine syndrome, where FAM20C is mutated, but genotype–phenotype correlation was not established.…”

Section: Discussionmentioning

confidence: 99%

FAM20C directly binds to and phosphorylates Periostin

Lin

Ohyama

et al. 2020

Sci Rep

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It is widely accepted that FAM20C functions as a Golgi casein kinase and has large numbers of kinase substrates within the secretory pathway. It has been previously reported that FAM20C is required for maintenance of healthy periodontal tissues. However, there has been no report that any extracellular matrix molecules expressed in periodontal tissues are indeed substrates of FAM20C. In this study, we sought to identify the binding partner(s) of FAM20C. FAM20C wild-type (WT) and its kinase inactive form D478A proteins were generated. These proteins were electrophoresed and the Coomassie Brilliant Blue (CBB)-positive bands were analyzed to identify FAM20C-binding protein(s) by Mass Spectrometry (MS) analysis. Periostin was found by the analysis and the binding between FAM20C and Periostin was investigated in cell cultures and in vitro. We further determined the binding region(s) within Periostin responsible for FAM20C-binding. Immunolocalization of FAM20C and Periostin was examined using mouse periodontium tissues by immunohistochemical analysis. In vitro kinase assay was performed using Periostin and FAM20C proteins to see whether FAM20C phosphorylates Periostin in vitro. We identified Periostin as one of FAM20C-binding proteins by MS analysis. Periostin interacted with FAM20C in a kinase-activity independent manner and the binding was direct in vitro. We further identified the binding domain of FAM20C in Periostin, which was mapped within Fasciclin (Fas) I domain 1–4 of Periostin. Immunolocalization of FAM20C was observed in periodontal ligament (PDL) extracellular matrix where that of Periostin was also immunostained in murine periodontal tissues. FAM20C WT, but not D478A, phosphorylated Periostin in vitro. Consistent with the overlapped expression pattern of FAM20C and Periostin, our data demonstrate for the first time that Periostin is a direct FAM20C-binding partner and that FAM20C phosphorylates Periostin in vitro.

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“…Fam20B phosphorylates a xylose residue during the biosynthesis of proteoglycans and plays a key role in regulating glycan elongation (Koike et al, 2009; Wen et al, 2014). Mutations of Fam20A result in AI and ectopic calcification such as nephrocalcinosis, analogous to the defects caused by non-lethal Fam20C mutations (Volodarsky et al, 2015; Cherkaoui Jaouad et al, 2015, Wang et al, 2014, 2013; O'Sullivan et al, 2011; Kantaputra et al, 2014b, 2014a; Jaureguiberry et al, 2012; Cho et al, 2012; Cabral et al, 2013; Kantaputra et al, 2017). We have previously demonstrated that Fam20A lacks an essential residue for catalysis and is therefore the first pseudokinase identified in the secretory pathway (Cui et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding

Cui

Zhu

Zhang

et al. 2017

eLife

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Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI. Fam20A binds ATP in the absence of divalent cations, and strikingly, ATP is bound in an inverted orientation compared to other kinases. Fam20A forms a dimer in the crystal, and residues in the dimer interface are critical for Fam20C activation. Together, these results provide structural insights into the function of Fam20A and shed light on the mechanism by which Fam20A mutations cause disease.DOI: http://dx.doi.org/10.7554/eLife.23990.001

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Periodontal disease and FAM20A mutations

Cited by 23 publications

References 45 publications

Transcriptome analysis of gingival tissues of enamel‐renal syndrome

Transcriptome analysis of gingival tissues of enamel‐renal syndrome

FAM20C directly binds to and phosphorylates Periostin

Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding

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