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Robert J. Desnick - One of the best experts on this subject based on the ideXlab platform.
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niemann pick disease a frequent missense mutation in the acid sphingomyelinase gene of ashkenazi jewish type a and b patients lysosomal hydrolase sphingomyelin lysosomal storage disease polymerase chain reaction Heterozygote Detection
2016Co-Authors: Orna Levran, Robert J. Desnick, Edward H SchuchmanAbstract:Although the A and B subtpes of Niemann- Pick disea (NPD) both result from the deficient activity of acid sphingomyelinase (ASM; sphingomyelin cholinephosphohydro- lase, EC 3.1.4.12) and the lysosomal accumulation of sphingo- myelin, they have remarkably disnct phenotypes. Type A dis- ease is a fatal neurodegenerative disorder of infancy, whereas type B disease has no neurologic manifestations and is characterized primarily by reticuloendothelial involvement and survival into adulthood. Both disorders are more frequent among individuals of Ashkenazi Jewish ancestry than in the general population. The recent isolation and characterization of cDNA and genomic sequences encoding ASM has facilitated investigation of the molecular lesions causing the NPD subtypes. Total RNA was reverse-transcribed, and the ASM cDNA from an Ashkenazi Jewish type A patient was specificaly amplified by the polymerase chain reaction (PCR). Molecular analysis of the PCR products revealed a G -* T transversion of nucleotide 1487, which occurred at a CpG dinucleotide and predicted an Arg -* Leu substitution in residue 496. Hybridization of PCR-amplified genomic DNA with allele-specific oligonucleotides indicated that the proband was homoalelic for the Arg -> Leu substitution and that both parents and several other relatives were heterozygous. This mutation was detected in 32% (10 of 31) of the Ashkenazi Jewish NPD type A alleles studied and occurred in only 5.6 % (2 of 36) of ASM alleles from non-Jewish type A patients. Of interest, the Arg -- Leu substitution occurred in one of the ASM alleles from the two Ashkenazi Jewish NPD type B patients studied and in none of the ASM alleles of 15 non-Jewish type B patients. In contrast, the mutation was not present in 180 ASM alleles from normal individuals of Ashkenazi Jewish descent. These findings identify a frequent missense mutation among NPD patients of Ashkenazi Jewish ancestry that results in neuronopathic type A disease when homoallelic and can result in the nonneuronopathic type B phenotype when heteroallelic. The identification of this ASM mutation in Ashkenazi Jewish patients should facilitate the pre-
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fabry disease twenty two novel mutations in the alpha galactosidase a gene and genotype phenotype correlations in severely and mildly affected hemizygotes and Heterozygotes
Journal of Investigative Medicine, 2000Co-Authors: Patricia Ashtonprolla, Kenneth H Astri, Junaid Shabbee, C M Eng, Robert J. DesnickAbstract:Background Fabry disease, an inborn error of glycosphingolipid catabolism, results from mutations in the X-chromosomal gene encoding the lysosomal exoglycosidase, alpha-galactosidase A (alpha-Gal A; EC 3.2.1.22). The nature of the molecular lesions in the alpha-Gal A gene in 36 unrelated families was determined in order to provide precise Heterozygote Detection, prenatal diagnosis, and to define genotype/phenotype correlations. Methods Genomic DNA was isolated from affected males and/or carrier females from 36 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and solid-phase or cycle sequencing. Markers closely linked to the alpha-Gal A gene were analyzed to determine if probands with the same mutations were related. Results Twenty-two novel mutations were identified including 10 missense (P40L, W95S, S148N, C172R, M187V, N224S, W226R, A230T, D266H, N320Y), three nonsense (Y134X, C142X, W204X in two families), three splice-site defects (IVS2(+1), IVS3(+1), IVS4(+1)) and six small deletions or insertions (26delA in two families, 672ins37, 774delAC, 833insA, 1139delC, 1188insT). Of the remaining 12 families (33.3%), each had a previously identified mutation, eight of which occurred at CpG dinucleotides including R112C (two families), R112H, R227Q, R227X (three families), and R301Q. Haplotype analysis of the mutant alleles that occurred in two or three presumably unrelated families revealed that the families with the rare novel alleles (W204X and 26delA) were probably related, whereas those with mutations involving CpG dinucleotides (R112C and R227X) were not, the latter being consistent with their origins as independent mutational events. Genotype/phenotype correlations revealed that certain mutations previously found in mild variant patients also were found in classic patients. In addition, the genotypes and spectrum of phenotypic severity were determined in five Heterozygotes with no family history. Conclusions These results illustrate the molecular heterogeneity of the lesions causing Fabry disease and emphasize the fact that CpG dinucleotides constitute important hot spots for mutation in the alpha-Gal A gene. These studies also permit precise Heterozygote Detection and prenatal diagnosis in these families, and delineate phenotype-genotype correlations in this disease.
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twenty novel mutations in the alpha galactosidase a gene causing fabry disease
Molecular Medicine, 1999Co-Authors: A. Kemal Topaloglu, Kenneth H Astri, Junaid Shabbee, C M Eng, Grace A Ashley, Ingzheng Tong, Robert J. DesnickAbstract:Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase α-galactosidase A (EC 3.2.1.22; α-Gal A). The nature of the molecular lesions in the α-Gal A gene in 30 unrelated families was determined to provide precise Heterozygote Detection, prenatal diagnosis, and define genotype-phenotype correlations. Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire α-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing. Twenty new mutations were identified, each in a single family: C142R, G183D, S235C, W236L, D244H, P259L, M267I, I289F, Q321E, C378Y, C52X, W277X, IVS4+4, IVS6+2, IVS6−1, 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously reported mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 families), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers closely flanking the α-Gal A gene indicated that the two patients with the N215S lesion were unrelated. The IVS4+4 mutation was a rare intronic splice site mutation that causes Fabry disease. These studies further define the heterogeneity of mutations in the α-Gal A gene causing Fabry disease, permit precise Heterozygote Detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease.
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fabry disease fourteen alpha galactosidase a mutations in unrelated families from the united kingdom and other european countries
European Journal of Human Genetics, 1996Co-Authors: Joanna P Davies, Jane A Hill, Kay Macdermo, Ya Wincheste, C M Eng, Sue Malcolm, Robert J. DesnickAbstract:The nature of the molecular lesions in the alpha-galactosidase A gene causing Fabry disease in 12 unrelated families from the United Kingdom and 4 from other European countries was determined in order to provide precise Heterozygote Detection and prenatal diagnosis for these families. The entire alpha-galactosidase A coding region and flanking intronic sequences were analyzed by amplification of genomic DNA and solid-phase direct sequencing or by SSCP analysis followed by solid-phase direct sequencing. Fourteen new mutations were identified including 10 missense mutations (M42V, R49S, C56Y, D92H, D93G, P205T, W236C, W287G, N298H, and W340R), 2 nonsense mutations (Q107X and Q119X) and 2 small deletions (257del18 and 1087del1). Together with the previously reported mutations, a total of 33 lesions in the alpha-galactosidase A gene have been identified in unrelated British families, further documenting the molecular genetic heterogeneity of this disease.
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congenital erythropoietic porphyria identification and expression of 10 mutations in the uroporphyrinogen iii synthase gene
Journal of Clinical Investigation, 1992Co-Authors: Cecilia A Warner, Robert J. DesnickAbstract:Congenital erythropoietic porphyria (CEP), an inborn error of heme biosynthesis, results from the deficient activity of uroporphyrinogen III synthase (URO-synthase). This autosomal recessive disorder is heterogeneous; patients with severe disease are often transfusion dependent, while milder patients primarily have cutaneous involvement. To investigate this phenotypic heterogeneity, exonic point mutations in the URO-synthase gene were identified in unrelated CEP patients. Four missense mutations were identified: (a) an A to G transition of nucleotide (nt) 184 that predicted a Thr to Ala substitution at residue 62 (designated T62A); (b) a C to T transition of nt 197 that encoded an Ala to Val replacement at residue 66 (A66V); (c) a T to C transition of nt 217 that predicted a Cys to Arg substitution at residue 73 (C73R); and (d) a C to T transition of nt 683 that resulted in a Thr to Met replacement at residue 228 (T228M). In addition, a G to A transition of nt 27 that did not change the encoded amino acid (A9A) was detected in an African patient. The T62A, C73R, and T228M alleles did not express detectable enzymatic activity, while the A66V allele expressed residual, but unstable activity. The C73R allele was present in eight of 21 unrelated CEP patients (21% of CEP alleles). In three patients, identification of both alleles permitted genotype-phenotype correlations; the A66V/C73R, T228M/C73R, and C73R/C73R genotypes had mild, moderately severe, and severe disease, respectively. These findings provide the first genotype-phenotype correlations and permit molecular Heterozygote Detection in this inherited porphyria.
C. Thomas Caskey - One of the best experts on this subject based on the ideXlab platform.
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Detection of Fabry's disease Heterozygotes by hair root analysis.
Clinical genetics, 2008Co-Authors: Arthur L Beaudet, C. Thomas CaskeyAbstract:The alpha-galactosidase/beta-hexosaminidase ratio was measured for individual hair roots as a method for Heterozygote Detection in Fabry's disease. Hair root analysis in control individuals revealed no striking sex difference in alpha-galactosidase/beta-hexosaminidase ratio when five males and five females were compared. The values for the ratio X 100, calculating both enzyme activities in nmol of product per min per microliter of hair extract, ranged from 0.8 to 9 for controls and from less than 0.1 to 0.4 for two hemizygous males. Hair root analysis in four Heterozygotes with clinical evidence of disease gave values for each individual in the control range, in the range for hemizygotes and in an intermediate range. The experience using hair root analysis for Heterozygote Detection in the X-linked Lesch-Nyhan syndrome suggests that this approch will be a sensitive Heterozygote Detection method which takes advantage of the occurrence of hairs with a deficient phenotype on the basis of Lyonization. We observed an affected male who was born to a female without clinical or biochemical evidence (examination included extensive hair root analysis) of Fabry's disease, thus documenting a likely instance of new mutation.
Arthur L Beaudet - One of the best experts on this subject based on the ideXlab platform.
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Detection of Fabry's disease Heterozygotes by hair root analysis.
Clinical genetics, 2008Co-Authors: Arthur L Beaudet, C. Thomas CaskeyAbstract:The alpha-galactosidase/beta-hexosaminidase ratio was measured for individual hair roots as a method for Heterozygote Detection in Fabry's disease. Hair root analysis in control individuals revealed no striking sex difference in alpha-galactosidase/beta-hexosaminidase ratio when five males and five females were compared. The values for the ratio X 100, calculating both enzyme activities in nmol of product per min per microliter of hair extract, ranged from 0.8 to 9 for controls and from less than 0.1 to 0.4 for two hemizygous males. Hair root analysis in four Heterozygotes with clinical evidence of disease gave values for each individual in the control range, in the range for hemizygotes and in an intermediate range. The experience using hair root analysis for Heterozygote Detection in the X-linked Lesch-Nyhan syndrome suggests that this approch will be a sensitive Heterozygote Detection method which takes advantage of the occurrence of hairs with a deficient phenotype on the basis of Lyonization. We observed an affected male who was born to a female without clinical or biochemical evidence (examination included extensive hair root analysis) of Fabry's disease, thus documenting a likely instance of new mutation.
K H Gustavson - One of the best experts on this subject based on the ideXlab platform.
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mutation analysis for prenatal diagnosis and Heterozygote Detection of gaucher disease type iii norrbottnian type
Prenatal Diagnosis, 1992Co-Authors: Niklas Dahl, Claes Wadelius, Goran Anneren, K H GustavsonAbstract:A single base substitution in exon 10 of the glucocerebrosidase gene was detected in families affected by Gaucher disease (GD) type III. This mutation, which results in the substitution of proline for leucine in position 444 of glucocerebrosidase, has been shown to result in type III GD in a Swedish population. Three fetuses at risk for GD type III were diagnosed as homozygous for the mutation and the pregnancies were terminated. In a fourth pregnancy, one parent was excluded as being a carrier and the risk of having a child affected by GD was ignored. Direct analysis of common mutations causal to GD is now available and improves prenatal diagnosis in families where the molecular defect has been characterized.
Bart Kempenaers - One of the best experts on this subject based on the ideXlab platform.
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characterization of the genome and transcriptome of the blue tit cyanistes caeruleus polymorphisms sex biased expression and selection signals
Molecular Ecology Resources, 2016Co-Authors: Jakob C Mueller, Heiner Kuhl, Bernd Timmermann, Bart KempenaersAbstract:Decoding genomic sequences and determining their variation within populations has potential to reveal adaptive processes and unravel the genetic basis of ecologically relevant trait variation within a species. The blue tit Cyanistes caeruleus – a long-time ecological model species – has been used to investigate fitness consequences of variation in mating and reproductive behaviour. However, very little is known about the underlying genetic changes due to natural and sexual selection in the genome of this songbird. As a step to bridge this gap, we assembled the first draft genome of a single blue tit, mapped the transcriptome of five females and five males to this reference, identified genomewide variants and performed sex-differential expression analysis in the gonads, brain and other tissues. In the gonads, we found a high number of sex-biased genes, and of those, a similar proportion were sex-limited (genes only expressed in one sex) in males and females. However, in the brain, the proportion of female-limited genes within the female-biased gene category (82%) was substantially higher than the proportion of male-limited genes within the male-biased category (6%). This suggests a predominant on-off switching mechanism for the female-limited genes. In addition, most male-biased genes were located on the Z-chromosome, indicating incomplete dosage compensation for the male-biased genes. We called more than 500 000 SNPs from the RNA-seq data. Heterozygote Detection in the single reference individual was highly congruent between DNA-seq and RNA-seq calling. Using information from these polymorphisms, we identified potential selection signals in the genome. We list candidate genes which can be used for further sequencing and detailed selection studies, including genes potentially related to meiotic drive evolution. A public genome browser of the blue tit with the described information is available at http://public-genomes-ngs.molgen.mpg.de.