Novel rare frameshift variation in aggressive periodontitis: Exomic and familial‐screening analysis

Abstract

Background Aggressive periodontitis (AgP), currently periodontitis grade C, presents early onset, rapid progression, and a poorly established genetic association. Thus, this study aimed to identify genetic variants associated with AgP via whole exome sequencing (WES) through a familial screening approach. Methods WES was performed in two nuclear families, including a proband and a parent affected by AgP and an unaffected parent and sibling. Common variants among affected individuals, excluding those common to healthy people, from each family, composed the data set associated with AgP. In silico analysis evaluated the impact of each variant on protein structure and protein‐protein interactions. Moreover, identified deleterious variants were validated in a populational analysis (n = 96). Results The missense single nucleotide variations (SNVs) rs142548867 in EEFSEC (c.668C>T), rs574301770 in ZNF136 (c.466C>G), and rs72821893 in KRT25 (c.800G>A) and the frameshift indels rs37146475 in GPRC6A (c.2323‐2324insT) and c.1366_1372insGGAGCAG in ELN were identified in AgP and have a predicted functional impact on proteins. In silico analysis indicated that the indel in GPRC6A generates a loss of the C‐terminal tail of the Gprca protein. Furthermore, this SNV was significantly associated with AgP in a population‐based investigation. Conclusion Novel frameshift variation in GPRC6A (c.2323‐2324insT) was identified as a potential genetic alteration associated with AgP occurrence.

The Impact of Diet, Nutrition and Nutraceuticals on Oral and Periodontal Health

“…Periodontitis develops severely in genetically predisposed individuals [ 26 , 27 ]. Genetic susceptibility is believed to be due to changes in the subject’s genes that lead to i) a lower efficiency of the immune system in controlling the growth of pathogenic bacteria; and/or ii) an imperfect regulation of the inflammatory response [ 28 , 29 , 30 , 31 , 32 ] which leads to an increase in the destructive side effects of inflammation [ 33 , 34 , 35 , 36 ]. As a matter of fact, Jekabsone et al [ 37 ] explored antibacterial, antinflammatory and cytoprotective capacity of Pelargonium sidoides DC root extract (PSRE) and proanthocyanidin fraction from PSRE (PACN) under conditions characteristic for periodontal disease.…”

Association of rs142548867 (EEFSEC) and periodontitis Grade C in a young Brazilian population

“…Structural and in silico analysis showed that this substitution was not predicted to promote conformational changes in the eEFSec protein structure. 15 Nevertheless, PolyPhen-2 prediction program pointed to a probability of 0.843 for this SNV to be a possible damaging substitution. PolyPhen-2 is a software that has been used to predict and estimate the probability of the missense mutation being damaging, based on functional annotation of variants, transcripts, and protein sequences, building conservation profiles.…”

“…This study was conducted based on previous results obtained by the research group, where the SNVs rs142548867 ( EEFSEC ), rs574301770 ( ZNF136 ), rs72821893 ( KRT25 ), and the indel rs371464745 ( GPR6CA ) were identified as closely related to PerioC development. 15 …”

“…The three variants are classified as missense – when the exchange of a nitrogenous base results in the substitution of the encoded amino acid, which can generate structural and, consequently, functional alterations in the protein. 15 …”

“…As the three variants found were classified as deleterious by the SIFT prediction algorithm – and the variations in the EEFSEC and ZNF136 genes were predicted as possibly harmful to protein synthesis by the Polyphen algorithm 15 – this study proposed to evaluate the allele and genotypic frequency of the SNVs rs142548867, rs574301770, and rs72821893 in a Brazilian population with PerioC and a control Brazilian population who were periodontally healthy (PH).…”