Dyschromatosis symmetrica hereditaria with long hair on the forearms, hypo/hyperpigmented hair, and dental anomalies: Report of a novel <i>ADAR1</i> mutation

Kantaputra, Piranit Nik; Chinadet, Wannapa; Ohazama, Atsushi; Kono, Michihiro

doi:10.1002/ajmg.a.35488

Cited by 14 publications

(13 citation statements)

References 32 publications

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“…More recently, hair anomalies have also been described in patients with DHS. 57 Consistently, a conditional mouse model that lacks ADAR expression in the epidermis shows fur loss and skin pathology. In particular, epidermal necrosis and abnormal hair follicles were evident in these animals.…”

Section: Discussionmentioning

confidence: 88%

Diverse selective regimes shape genetic diversity atADARgenes and at their coding targets

et al. 2015

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A-to-I RNA editing operated by ADAR enzymes is extremely common in mammals. Several editing events in coding regions have pivotal physiological roles and affect protein sequence (recoding events) or function. We analyzed the evolutionary history of the 3 ADAR family genes and of their coding targets. Evolutionary analysis indicated that ADAR evolved adaptively in primates, with the strongest selection in the unique N-terminal domain of the interferoninducible isoform. Positively selected residues in the human lineage were also detected in the ADAR deaminase domain and in the RNA binding domains of ADARB1 and ADARB2. During the recent history of human populations distinct variants in the 3 genes increased in frequency as a result of local selective pressures. Most selected variants are located within regulatory regions and some are in linkage disequilibrium with eQTLs in monocytes. Finally, analysis of conservation scores of coding editing sites indicated that editing events are counter-selected within regions that are poorly tolerant to change. Nevertheless, a minority of recoding events occurs at highly conserved positions and possibly represents the functional fraction. These events are enriched in pathways related to HIV-1 infection and to epidermis/hair development. Thus, both ADAR genes and their targets evolved under variable selective regimes, including purifying and positive selection. Pressures related to immune response likely represented major drivers of evolution for ADAR genes. As for their coding targets, we suggest that most editing events are slightly deleterious, although a minority may be beneficial and contribute to antiviral response and skin homeostasis.

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Section: Discussionmentioning

confidence: 88%

Diverse selective regimes shape genetic diversity atADARgenes and at their coding targets

et al. 2015

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“…Till now, about 145 ADAR1 mutations have been reported in DSH patients, which consist of 80 missense and nonsense mutations, 11 splicing mutations, 37 small deletions, 14 small insertions, 2 small indels and 1 gross insertion [15-29]. So far, most known missense mutations (49 in 57, 86%) are located within the ADEAMc domain encompassing amino acids 839–1222 [3].…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Wang

et al. 2014

BMC Med Genet

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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.

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“…The deaminase domain, located in the codon from 886 to 1221 bp, represents approximately 27% of the length of the ADAR1 protein, (XuFeng et al, 2009). To date, over 130 unique ADAR1 gene mutations have been detected, with more than 60% of those located within the ADEAMc domain (Bilen et al, 2012;Kantaputra et al, 2012;Kawaguchi et al, 2012;Lai et al, 2012;Luo et al, 2012;Mizrahi et al, 2012;Mohana et al, 2012;Shi et al, 2012), suggesting that the domain is a hot spot for mutations. The ADEAMc domain catalyzes the deamination of adenosine to inosine in double-stranded RNA substrates to subsequently create alterative splicing sites or codon alterations, and thus ultimately leads to functional changes in proteins (Wagner et al, 1989;Rueter et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

A novel insertion mutation in the ADAR1 gene of a Chinese family with dyschromatosis symmetrica hereditaria

Zhu¹,

Zhu²,

Zhou³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis, characterized by a mixture of hyperpigmented and hypopigmented macules that are mainly present on the dorsal portions of the extremities. The DSH locus was mapped to chromosome 1q11-q12 and, subsequently, pathogenic mutations in the double-stranded RNA-specific adenosine deaminase (ADAR1) gene were identified. We performed a mutational analysis of the ADAR1 gene in a Chinese family that included three individuals affected with typical DSH phenotypes. Mutations within the entire coding region and the exon-intron boundaries of ADAR1 were detected and confirmed by polymerase chain reaction and direct sequencing, respectively. An insertion mutation within exon 12, c.3035_3036insC (p.P1012fsX1017), was identified in all family members affected by DSH, but not in the healthy members or 100 unrelated controls. This finding improves our understanding of the role of ADAR1 in DSH.

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Dyschromatosis symmetrica hereditaria with long hair on the forearms, hypo/hyperpigmented hair, and dental anomalies: Report of a novel ADAR1 mutation

Cited by 14 publications

References 32 publications

Diverse selective regimes shape genetic diversity atADARgenes and at their coding targets

Diverse selective regimes shape genetic diversity atADARgenes and at their coding targets

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

A novel insertion mutation in the ADAR1 gene of a Chinese family with dyschromatosis symmetrica hereditaria

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