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 pathologica...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.QG00X) 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.展开更多
Aim:Thiamine-responsive megaloblastic anaemia syndrome(TRMA)is the association of diabetes mellitus,anaemia and deafness,due to mutations in SLC19A2,encoding a thiamine transporter protein.This is a unique monogenic f...Aim:Thiamine-responsive megaloblastic anaemia syndrome(TRMA)is the association of diabetes mellitus,anaemia and deafness,due to mutations in SLC19A2,encoding a thiamine transporter protein.This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data.We aimed to study genotype-phenotype relationships and long-term follow-up in our cohort.Methods:We have studied 13 patients from seven families and have follow-up data for a median of 9 y(2-30 y).Results:All patients originated from Kashmir or Punjab,and presented with non-immune,insulin deficient diabetes mellitus,sensorineural deafness and a variable anaemia in the first 5 y of life,the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow.The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25 mg/d,but during puberty thiamine supplements became ineffective,and almost all patients require insulin therapy and regular blood transfusions in adulthood.All patients are homozygous for mutations in the SLC19A2 gene.We have identified a novel missense mutation(T158R)that was excluded in 100 control alleles.Conclusion:Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements;however,most patients become fully insulin dependent after puberty.A mutation screening strategy is feasible and likely to identify mutations in almost all cases.展开更多
基金supported by Projects in the National Science and Technology Pillar Program in the Eleventh Five-year Plan Period(2006BAI05A07)National High-Tech Research and Development Program of China(863 Program)(2006AA02A408)+5 种基金Major State Basic Research Development Program of China(973 Program)(2006cb500700)National Key Technologies Research and Development Program of China(2004BA720A03)National Natural Science Foundation of China(30400262,30470619,30710303061,30871354,30971585)New Century Excellent Talents in University of Department of EducationKey Project of Natural Science Foundation of Hunan Province(08JJ3048)Graduate Degree Thesis Innovation Foundation of Central South University(2008yb030)
文摘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.QG00X) 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.
文摘Aim:Thiamine-responsive megaloblastic anaemia syndrome(TRMA)is the association of diabetes mellitus,anaemia and deafness,due to mutations in SLC19A2,encoding a thiamine transporter protein.This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data.We aimed to study genotype-phenotype relationships and long-term follow-up in our cohort.Methods:We have studied 13 patients from seven families and have follow-up data for a median of 9 y(2-30 y).Results:All patients originated from Kashmir or Punjab,and presented with non-immune,insulin deficient diabetes mellitus,sensorineural deafness and a variable anaemia in the first 5 y of life,the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow.The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25 mg/d,but during puberty thiamine supplements became ineffective,and almost all patients require insulin therapy and regular blood transfusions in adulthood.All patients are homozygous for mutations in the SLC19A2 gene.We have identified a novel missense mutation(T158R)that was excluded in 100 control alleles.Conclusion:Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements;however,most patients become fully insulin dependent after puberty.A mutation screening strategy is feasible and likely to identify mutations in almost all cases.
