A new mutation of the double-stranded RNA-specific adenosine deaminase gene in a family with dyschromatosis symmetrica hereditaria

BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules localized on the back of the extremities and caused by mutations in the double-stranded RNA-specific adenosine deaminase (DSRAD) gene. OBJECTIVE: To identify gene mutations of DSRAD in patients with DSH. METHODS: A Chinese pedigree of typical DSH was subjected to mutation detection in DSRAD. Direct sequencing of all PCR products of the whole coding regions of DSRAD was performed to identify the mutation. RESULTS: A missense mutation 2747G-->T in the DSRAD gene was found in the affected members but not in the healthy individuals in this family and in 50 unrelated controls. CONCLUSION: Our study found a novel missense mutation in exon 9 of the DSRAD gene. We add new variants to the knowledge of DSRAD mutations in DSH.     

遗传性对称性色素异常症一家系基因检测

目的 探讨遗传性对称性色素异常症(DSH)家系中双链RNA特异性腺苷脱氨酶(DSRAD)基因的突变.方法 收集患者临床资料,提取外周血DNA,PCR扩增DSRAD基因的全部外显子,并行DNA测序,以100例正常人作对照.结果 检测到家系中患者均存在DSRAD基因中第3076位碱基发生C→T的杂合突变,即c.3076C>T,对应1026位的精氨酸被色氨酸替代(p.R1026W),家系中未患病者及对照组正常人未发现相应突变.结论 发现p.R1026W错义突变是遗传性对称性色素异常症的致病基因的一个新突变,扩大DSH致病基因的突变谱.     

Identification of two novel mutations in Chinese patients with Dyschromatosis symmetrica hereditaria

Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the extremities. Pathogenic mutations in the DSRAD gene have recently been identified. In this study, we report and identify the mutations of the DSRAD gene in two Chinese pedigrees with DSH. Two novel mutations in the functional domains of the DSRAD gene were identified and verified in two pedigrees. The c.3244A>G (H1075R) mutation was found in all patients but not in the healthy individuals from family A and c.3335_3336delAT (Y1112fs→1112X) mutation was found in three patients but not in the healthy family members from family B. Our data suggests that these two novel mutations in the DSRAD gene could cause DSH and add new variants to the repertoire of DSRAD mutations in DSH. Ming Li and Chengrang Li contributed equally to this work.     

Two frameshift mutations in the RNA-specific adenosine deaminase gene associated with dyschromatosis symmetrica hereditaria

OBJECTIVE: To report and analyze the mutations of the double-stranded RNA-specific adenosine deaminase (DSRAD) gene in 2 Chinese pedigrees with dyschromatosis symmetrica hereditaria (DSH). DESIGN: Pedigree study. SETTING: Anhui province of China. PATIENTS: Two Chinese families, consisting of 19 individuals (family 1) and 5 individuals (family 2). INTERVENTIONS: We directly performed mutation detection of the DSRAD gene in 2 Chinese families with DSH by sequencing. The whole coding region of DSRAD was amplified by polymerase chain reaction, and products were analyzed by direct sequencing. MAIN OUTCOME MEASURES: Frameshift DSRAD gene mutations. RESULTS: The c.3513insC (Arg1171fs) mutation was found in all patients but not in the healthy individuals from family 1, and the c.3220_3224delGCATC (Gly1073fs) mutation was found in 2 patients but not in the healthy members of family 2. These 2 mutations were not found in 96 unrelated control individuals. CONCLUSION: Our data suggest that these 2 novel frameshift mutations in the DSRAD gene could cause DSH in the Chinese Han population and add new variants to the repertoire of DSRAD mutations in DSH.     

Two novel frameshift mutations of the DSRAD gene in Chinese pedigrees with dyschromatosis symmetrica hereditaria

Background Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant disorder characterized by a mixture of hyperpigmented and hypopigmented macules localized on the back of the extremities and caused by the mutations in the DSRAD gene. Methods Two Chinese pedigrees of typical DSH were subjected to mutation detection in DSRAD. Direct sequencing of all PCR products of the whole coding regions of DSRAD was performed to identify the mutation. Results The c.1615delG (p.V539fs) mutation was found in the affected members but not in the healthy individuals in family 1 and the c.ins1372‐9 CCACAGAT (p.D458fs) mutation was found in patients but not in the healthy members of family 2. Conclusion Our study found two novel frameshift mutations in the DSRAD gene. We add new variants to the knowledge of DSRAD mutations in DSH.     

Identification of a novel DSRAD gene mutation in a Chinese family with dyschromatosis symmetrica hereditaria

Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the limbs. Genetic studies have identified mutations in the DSRAD gene, encoding double-stranded RNA-specific adenosine deaminase, to be responsible for this disorder. In this study, we identified a novel mutation of DSRAD gene in a Chinese family with DSH. The mutation is a novel heterozygous nucleotide T→C transition at position 3617 in exon 15 of the DSRAD gene, which induces a M1206T change in the putative deaminase domain of DSRAD . Our study expands the database on the DSRAD gene mutations in DSH.     

Novel mutations of the RNA-specific adenosine deaminase gene (DSRAD) in Chinese families with dyschromatosis symmetrica hereditaria

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant skin disorder. It is also called "reticulate acropigmentation of Dohi" or "symmetric dyschromatosis of the extremities". The DSH locus has recently been mapped to chromosome 1q21 and pathogenic mutations were identified in the DSRAD gene encoding double-stranded RNA-specific adenosine deaminase in Japanese patients with DSH. We report here two novel point mutations, Q513X(1537C>T) and R916W(2746C>T) in the DSRAD gene identified in two Chinese families, respectively. These data suggest that mutations in DSRAD were also associated with DSH in Chinese. This is the first report on DSRAD as the causative gene of DSH in the Chinese population.     

遗传性对称性色素异常症家系的DSRAD基因突变

目的研究遗传性对称性色素异常症(DSH)家系中的DSRAD基因突变情况。方法收集了2个遗传性对称性色素异常症家系的外周血标本,用聚合酶链反应(PCR)扩增DSRAD基因的全部外显子并测序,检测2个家系中的患者及正常人和50例无关正常人的DSRAD基因。结果家系1中所有患者的DSRAD基因第2 565位至2 568位缺失GACT。家系2中所有患者的DSRAD基因第2 433位至2 434位均缺失AG。2家系中的正常人及50例无关正常人未发现突变。结论2个DSH家系患者均有DSRAD基因突变,可能由此引起编码蛋白的结构和功能改变,致皮肤色素异常。     

遗传性对称性色素异常症一家系DSRAD基因的突变

目的检测一个遗传性对称性色素异常症家系中的DSRAD基因突变情况。方法收集了一个遗传性对称性色素异常症家系的外周血标本,用聚合酶链反应(PCR)扩增DSRAD基因的全部15个外显子并测序,检测家系中的患者及正常人和100例无关正常人的DSRAD基因。结果家系中所有患者的DSRAD基因存在外显子3的杂合缺失突变:c.1615delG。家系中的正常人及100例无关正常人未发现此突变。结论发现DSH家系患者DSRAD基因的一个新的突变。     

遗传性对称性色素异常症DSRAD基因的一个新突变

目的检测遗传性对称性色素异常症(DSH)家系中的DSRAD基因突变情况,探讨DSH的基因型与表型的关系。方法收集2个DSH家系的临床资料,提取外周血DNA,应用PCR扩增DSRAD基因编码区的全部外显子及其侧翼序列并测序,分别检测2个家系中的患者及正常人,并选取50例无关正常人做对照。结果发现全部患者均存在DSRAD基因的杂合突变,家系1中所有患者的DSRAD基因第12内含子剪切位点突变c.3203-2AC(IVS12-2AC);家系2中所有患者的DSRAD基因缺失突变c.2433_2434delAG。但该两家系中的正常人及50例正常对照者未发现上述突变。结论此两个DSH家系中存在DSRAD基因的特异性突变,其可能使编码蛋白功能缺陷,导致皮肤色素异常。     

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

Dyschromatosis symmetrica hereditaria (DSH) is a pigmentary genodermatosis of autosomal dominant inheritance characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the dorsal aspects of the hands and feet. It is caused by mutations of the RNA-specific adenosine deaminase gene. We report the identification of a Chinese family with a three-generation pedigree of DSH, in whom a novel tyrosine substitution mutation in DSRAD was demonstrated: a heterozygous nucleotide A-->G transition at position 2879 in exon 10 of the DSRAD gene was detected.     

遗传性对称性色素异常症一家系致病基因的定位和突变研究

目的 探讨遗传性对称性色素异常症家系的致病基因。方法 明确先证者的临床诊断后,收集该家系成员的血样抽提基因组DNA,应用基因分型和连锁分析的方法进行基因定位,并对该定位区域内DSRAD基因直接测序,分析其突变位点。结果 基因分型和连锁分析将该家系的致病基因定位于1号染色体,和已知报道的区域一致。突变研究发现该家系所有患者的DSRAD基因2号外显子均携带CAA→TAA的突变,使得517位氨基酸由谷氨酰胺变成中止密码子。结论 该遗传性对称性色素异常症家系中的患者存在DSRAD基因的无义突变。     

遗传性对称性色素异常症两家系DSRAD基因突变分析

目的对2例遗传性对称性色素异常症(DSH)家系DSRAD基因中可能存在的突变进行鉴定。方法收集的两个遗传性对称性色素异常症家系和100份无亲缘关系正常人外周血标本,采用聚合酶链反应(PCR)方法扩增DSRAD基因的全部外显子并测序,结果和Genbank中相应序列进行比对。结果家系1中所有患者DSRAD基因检测到第9外显子存在一个旧的错义突变c.G2747A,导致p.R916Q;在家系2所有患者第12外显子发现一个新的错义突变c.C3124T,导致p.R1042C。两家系中正常人及无亲缘关系对照均未发现突变。结论两家系中均存在DSRAD基因的变异,导致编码蛋白的结构和功能发生改变。     

两个遗传性对称性色素异常症家系的DSRAD基因剪切突变

目的研究两个遗传性对称性色素异常症(DSH)家系中的DSRAD基因突变情况。方法收集了2个遗传性对称性色素异常症家系的外周血标本,用聚合酶链反应(PCR)扩增DSRAD基因的全部外显子并测序,检测2个家系中的患者及正常人和100例无关正常人的DSRAD基因。结果家系1中所有患者的DSRAD基因第6号内含子与第7号外显子交界处检测到一新的c.2271-3AG剪切突变。家系2中所有患者的DSRAD基因第12号外显子与第12号内含子交界处检测到一新的c.3202+5GA剪切突变。2家系中的正常人及100例无关正常人未发现突变。结论 2个DSH家系患者均有DSRAD基因剪切部位突变,可能由此引起非正常的基因剪切,导致编码蛋白的结构和功能改变,致皮肤色素异常。     

Mutational spectrum of the ADAR1 gene in dyschromatosis symmetrica hereditaria

Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the extremities and caused by the mutations of adenosine deaminase acting on RNA1 (ADAR1) gene. We screened 14 unrelated families or sporadic cases for mutation in the full coding sequence of this gene. Eight novel heterozygous mutations of ADAR1 and four known mutations were identified, including four missense mutations (p.R26K, p.Y1192D, p.R916Q, p.R1155W), six frameshift mutations (p.N205fsX217, p.V211fsX217, p.V404fsX417, p.I914fsX927, p.L1053fsX1076, p.L1070fs1092), and two nonsense mutations (p.R474X, p.R1096X). Interestingly, we failed to detect any mutations of ADAR1 in one family. Including our data, there are now 93 different mutations reported in 105 independent patients that we have tabulated. From the review of clinical features in these reports, we found that the same mutation could lead to different phenotypes even in the same family and did not establish a clear correlation between genotypes and phenotypes. Finally this study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ADAR1 gene.     

Mutation analysis of the ADAR1 gene in dyschromatosis symmetrica hereditaria and genetic differentiation from both dyschromatosis universalis hereditaria and acropigmentatio reticularis

Dyschromatosis symmetrica hereditaria (DSH) (also called "reticulate acropigmentation of Dohi") is a pigmentary genodermatosis of autosomal dominant inheritance. We have clarified for the first time four pathological mutations of the double-stranded RNA-specific adenosine deaminase gene (ADAR1 or DSRAD) in four DSH pedigrees. In this paper, we report 16 novel mutations containing six missense substitutions (p.V906F, p.K1003R, p.G1007R, p.C1036S, p.S1064F, p.R1078C), two splice site mutations (IVS2+2T>G, IVS8+2T>A), six frameshift mutations (p.H216fs, p.K433fs, p.G507fs, p.P727fs, p.V955fs, p.K1201fs), and two nonsense mutations (p.R426X, p.Q600X) found in Japanese patients with DSH. We did not establish any clear correlation between the clinical phenotypes and the genotypes of ADAR1 gene mutations in our examination of 16 cases plus four pedigrees. None of the different mutations identified in our studies of 20 cases suggested any founder effect. Furthermore, we did not identify any mutations in the ADAR1 gene of three patients with dyschromatosis universalis hereditaria or three patients with acropigmentatio reticularis, indicating that the two diseases are completely different from DSH, although they have sometimes been suggested to be phenotypical variations of DSH.     

遗传性对称性色素异常症三家系ADAR1基因突变检测

【摘要】 目的 探讨3个遗传性对称性色素异常症家系中ADAR1基因的突变情况。方法 收集血样,用PCR结合DNA直接测序的方法,检测3个家系中的患者、患者亲属及与家系无关的50例健康个体的ADAR1基因突变情况。 结果 所研究的3个家系中均存在ADAR1基因的异常。包括A及C家系中2个错义突变（c.1760A > G导致p.Y587C,c.3620G > T导致p.G1207V）,B家系中1个移码突变（c.2433-2434delAG）。3个家系中未患病个体和健康对照均未发现相应突变。 结论 3个ADAR1基因突变中,2个错义突变均为新突变,可能是导致遗传性对称性色素异常症发病的分子机制之一。     

Six novel mutations of the ADAR1 gene in Chinese patients with dyschromatosis symmetrica hereditaria

BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominantly inherited dermatosis and characterized by a mixture of hyperpigmented and hypopigmented macules on the back of hands and feet. The DSH locus was mapped to chromosome 1q21 and subsequently pathogenic mutations were identified in the adenosine deaminase acting on RNA1 (ADAR1) gene in 2003. OBJECTIVE: In this study, we performed a mutation analysis of the ADAR1 gene in eight Chinese families and one sporadic patient with typical DSH. METHODS: PCR and direct sequencing of the ADAR1 gene were performed to identify and confirm the mutations in the eight families and the sporadic patient. RESULTS: Six novel and one known mutations were identified, including four missense mutations (p.K1105N, p.G1047R, p.F1099L, p.G1068R), two frameshift mutations (p.Q779fs-792x, p.P441fs-463x) and one nonsense mutation (p.R1096x). CONCLUSION: Six novel mutations were found in five unrelated families and one sporadic case, which have further improved our understanding on the role of ADAR1 in DSH. Interestingly, we failed to detect any mutations of ADAR1 in two families.