Five novel mutations in the ADAR1 gene associated with dyschromatosis symmetrica hereditaria

Abstract

BackgroundDyschromatosis symmetrica hereditaria (DSH) is an autosomal dominantly inherited skin disease associated with mutations of ADAR1, the gene that encodes a double-stranded RNA-specific adenosine deaminase. The purpose of this study was to investigate the potential mutations in ADAR1 in seven Chinese families with DSH.MethodsAll the coding exons including adjacent intronic as well as 5′ and 3′ untranslated region (UTR) of ADAR1 were screened by direct sequencing. Moreover, quantitative reverse-transcription polymerase chain (qRT-PCR) and Western blot were applied to determine the pathogenic effects associated with the mutations.ResultsMolecular genetic investigations detected five novel mutations (c.556C > T, c.3001C > T, c.1936_1937insTG, c.1065_1068delGACA and c.1601G > A resulting in p.Gln186X, p.Arg1001Cys, p.Phe646LeufsX16, p.Asp357ArgfsX47 and p.Gly471AspfsX30 protein changes, respectively) as well as two previously reported (c.2744C > T and c.3463C > T causing p.Ser915Phe and p.Arg1155Trp protein changes, respectively). Among them, we found that the substitution c.1601G > A at the last nucleotide of exon 2 compromised the recognition of the splice donor site of intron 2, inducing an aberrant transcript with 190-bp deletion in exon 2 and causing an approximately 50% reduction of ADAR1 mRNA level in affected individual. In addition, consistent with the predicted results, the expression patterns of other novel mutations were detected by Western blot.ConclusionWe identified five novel and two recurrent mutations of the ADAR1 gene in seven Chinese families with DSH and investigated potential effects of the novel mutations in this study. Our study expands the database on mutations of ADAR1 and for the first time, demonstrates the importance of exonic nucleotides at exon-intron junctions for ADAR1 splicing.

RNA rewriting, recoding, and rewiring in human disease

“…A majority of these mutations were located in the deaminase domain, suggesting that a mutant ADAR1 could form a dysfunctional homodimer complex and impair wild-type ADAR1 activity. In addition to the known mutations, a recent study established that haploinsufficiency of ADAR1 p150 was a specific determinant of DSH [77]. The authors identified a novel ADAR1 p150 mutant that generates a premature termination codon, resulting in elimination of the mutant transcript.…”

“…The authors identified a novel ADAR1 p150 mutant that generates a premature termination codon, resulting in elimination of the mutant transcript. This mutation did not have any effect on the expression of ADAR p110, thereby providing new insights into the role of ADAR1 p150 in DSH pathogenesis [77]. Another disease associated with genetic mutations in ADAR1 is Aicardi-Goutières syndrome (AGS), an autoimmune disorder that primarily targets the brain and skin.…”

Risk given byAGTpolymorphisms in inducing susceptibility to essential hypertension among isolated populations from a remote region of China: A case-control study among the isolated populations

“…In our study, no association was observed between these two polymorphisms (including A-20C and T174M) and EH among the both Hani and Yi populations. Previous researches have shown that the polymorphisms localized in the introns, 35,123 and exons, 124 close to the splice site would have effects on the process of mRNA splicing. In the bioinformatic analysis, it was observed that the c.620C>T (rs4762) led to the creation of new ESS (Motif 3, ESR, Motif 1, IIEs, Motif 2, Fas ) sites and the destruction of ESE (9G8, SC35, SF2/ASF(Ig), SF2/ ASF) sites, thereby weakening the splicing.…”

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases

“…In general, only nine mutations on the ADAR1 coding sequence have been identified in AGS patients, compared to the more than 130 amino acids that have been found to be mutated in DSH patients. In addition to Hayashi et al′s list of known mutations [39], novel mutations in ADAR1 that are associated with DSH have also been identified [40,41,42,43,44,45], including an in-frame insertion that leads to mis-splicing [43]. …”