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Biomedical subjects

U Seligsohn

Publications and source records attributed to U Seligsohn.

At least 19 recordsLinked to original sources
PubMed1998

A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.

The polymorphism G20210A in the 3' untranslated region of the prothrombin gene is associated with an increased level of factor II activity and confers a twofold to fivefold increase in the risk for venous thromboembolism. Among Caucasian populations, the prevalence of factor II G20210A heterozygotes is 1% to 6%, whereas in non-Caucasian populations it is very rare or absent. The aim of the present study was to discern whether factor II G20210A originated from a single or recurrent mutational events. Allele frequencies of four dimorphisms spanning 16 of 21 kb of the factor II gene were determined in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II G20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (P = .0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and only in 34% of 20210G normal alleles (P < .0001). These data strongly support a single origin for factor II G20210A that probably occurred after the divergence of Africans from non-Africans and of Caucasoid from Mongoloid subpopulations.

Africa, Northern↗
PubMed1998

Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII.

Combined deficiency of factors V and VIII is an autosomal recessive bleeding disorder resulting from alterations in an unknown gene on chromosome 18q, distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ER-Golgi intermediate compartment, was mapped to a YAC and BAC contig containing the critical region for the combined factors V and VIII deficiency gene. DNA sequence analysis identified two different mutations, accounting for all affected individuals in nine families studied. Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the two mutations demonstrate complete lack of expression of the mutated gene in these cells. These findings suggest that ERGIC-53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.

Amino Acid Sequence↗
PubMed1998

Association between hyperflexibility of the thumb and an unexplained bleeding tendency: is it a rule of thumb?

A bleeding tendency manifested by petechiae and ecchymoses is one of the most common causes for referral of patients to haematology clinics. Vessel wall pathology is not usually considered to be a cause for deranged haemostasis, although coexistence of increased capillary fragility and joint hypermobility have been reported. We determined the frequency of thumb hyperextensibility and scored the findings in a series of 44 patients referred because of ecchymoses and petechiae, as well as 261 control children and their mothers. All 44 patients had normal coagulation studies. Thumb flexibility score was +4 in 30 patients, +3 in eight patients, +2 in five patients and +1 in one of the index patients. In the control group, only one of 261 had a +4, and three had a +3 score, and two of 260 mothers had a +4 score. Ecchymoses were not observed in any of these subjects, nor in the +1 patients. Based on clinical presentation and normal coagulation studies, we suggest that our patients had an underlying subtype of Ehlers-Danlos syndrome. In view of the dramatically high occurrence of thumb hyperextensibility in patients with unexplained mild bleeding tendency, costly haemostatic and coagulation studies on such patients may not be necessary.

Child↗
PubMed1998

Prenatal diagnosis of Glanzmann thrombasthenia using the polymorphic markers BRCA1 and THRA1 on chromosome 17.

Glanzmann thrombasthenia is an autosomal recessive bleeding disorder caused by mutations in the genes encoding platelet GPIIb or GPIIIa. Both genes map to chromosome 17q21 and polymorphisms within this chromosomal region have been identified. In the current study, prenatal diagnosis was performed for a family that already had one affected child, patient 1, who had a compound heterozygous mutation in GPIIb. At the time of prenatal diagnosis, the maternal GPIIb mutation had been identified but the paternal GPIIb mutation was unknown. By sequence analysis, the fetus was identified as a carrier of the mother's mutation. To determine the probability of the fetus inheriting the father's mutation, haplotype analysis of DNA samples from the fetus, mother, father and affected child were performed using polymorphic markers on chromosome 17q12-q21. These markers included polymorphisms within the thyroid hormone receptor alpha1 gene (THRA1), the breast cancer gene (BRCA1), GPIIb, GPIIIa, and an anonymous marker D17S579. Heterozygosity within the THRA1, BRCA1 and GPIIIa polymorphic markers predicted that the fetus carried the father's normal allele. Based on genetic linkage studies, no recombination was identified with any of the informative markers, and from the map distance between GPIIb and BRCA1 the accuracy of diagnosis was predicted to be >98%. The father's mutation was subsequently identified and direct sequence analysis of fetal DNA confirmed that the fetus did not inherit the fathers' mutant allele.

BRCA1 Protein↗
PubMed1998

Glanzmann thrombasthenia in two Iraqi-Jewish siblings is caused by a novel splice junction mutation in the glycoprotein IIb.

An A-->G transition in the acceptor splice site at the intron 19/exon 20 junction of the glycoprotein IIb gene was defined as a novel mutation causing Glanzmann thrombasthenia in two Iraqi-Jewish siblings. This mutant DNA was transcribed into four distinct species of mRNA, one of which resulted in a premature termination codon and the other three predicting deletions of 50, 61 or 72 amino acids, respectively.

Aged↗
PubMed1998

Analysis of genetic polymorphisms related to thrombosis and other risk factors in patients with retinal vein occlusion.

The purpose of this study was to investigate the role of genetic polymorphisms associated with venous and arterial thrombosis in patients with retinal vein occlusion (RVO). One-hundred and two consecutive patients with RVO were examined for factor V G1691A and factor II G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and apolipoprotein E4 by amplification of specific DNA fragments and restriction analysis. The risks exerted by these polymorphisms and by the conventional risk factors of RVO were evaluated by comparing their frequencies among patients and controls and by estimating the respective odds ratios. We found that the prevalences of the factor V G1691A, factor II G20210A, and apolipoprotein E4 polymorphisms were similar in the study and control groups. Logistic regression analysis involving the parameters for which significant differences were detected disclosed an odds ratio of 1.9 for MTHFR C677T homozygosity (95% confidence interval 0.95-3.81), an odds ratio of 2.12 for hypertension (95% confidence interval 1.16-3.73) and an odds ratio of 3.25 for a family history of stroke (95% confidence interval 1.07-9.51). Our data suggests that homozygosity for the MTHFR C677T polymorphism is a risk factor of RVO in addition to arterial hypertension and a family history of stroke.

Adult↗
PubMed1998

Mutations in the alphaIIb and beta3 genes that cause Glanzmann thrombasthenia can be distinguished by a simple procedure using transformed B-lymphocytes.

Glanzmann thrombasthenia (GT) is caused by a defect in either glycoprotein (GP)IIb (alphaIIb) or GPIIIa (beta3) genes and therefore screening of both genes is required for mutation identification. The beta subunit of the GPIIb/IIIa complex (beta3) forms a complex with another alpha subunit (alpha(v)) yielding the alpha(v)beta3 vitronectin receptor (VnR). GT patients with mutations in the GPIIIa gene that cause diminished synthesis of GPIIIa are deficient in both GPIIb/IIIa and VnR, whereas patients with mutations in the GPIIb gene are deficient in GPIIb/IIIa, yet express normal or increased VnR in their platelets. The presence or absence of VnR in platelet membranes of GT patients has therefore been used for distinguishing between mutations in the GPIIb gene and mutations in the GPIIIa gene. However, the method of assessing VnR in platelets is cumbersome and use of fresh platelets is indispensible. In the present work we devised a procedure for detection of the VnR in B-lymphocytes transformed by Epstein-Bar virus (EBV). The transformed lymphocytes transcribed GPIIIa mRNA but not GPIIb mRNA and expressed VnR on their surface. Using flow cytometry analysis or immuno-precipitation and western blotting VnR was found in B-lymphocytes of GT patients bearing a well characterized mutation in the GPIIb gene. In contrast, in B-lymphocytes of GT patients bearing 2 different mutations in the GPIIIa gene no VnR was detectable. Thus, for determining which gene is mutated in a GT patient, EBV-transformed B-lymphocytes are useful and can as well be used for analyses of GPIIIa mRNA and genomic DNA. Ten ml of blood are sufficient for the procedure.

B-Lymphocytes↗
PubMed1997

The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin.

Previous studies showed that factor XI (FXI) deficiency commonly observed in Ashkenazi Jews is caused by two similarly frequent mutations, type II (Glu117stop) and type III (Phe283Leu) with allele frequencies of 0.0217 and 0.0254, respectively. In Iraqi Jews, who represent the ancient gene pool of Jews, only the type II mutation was observed with an allele frequency of 0.0167. In this study we sought founder effects for each mutation by examination of four FXI gene polymorphisms enabling haplotype analysis in affected Jewish patients of Ashkenazi, Iraqi, and other origins and in Arab patients. Initial population surveys of 387 Middle Eastern Jews (excluding Iraqi Jews), 560 North African/Sephardic Jews, and 382 Arabs revealed allele frequencies for the type II mutation of 0.0026, 0.0027, and 0.0065, respectively. In contrast, the type III mutation was not detected in any of these populations. All 60 independent chromosomes bearing the type III mutation were solely observed in Ashkenazi Jewish patients and were characterized by a relatively rare haplotype. All 103 independent chromosomes bearing the type II mutation in patients of Ashkenazi, Iraqi, Yemenite, Syrian, and Moroccan Jewish origin and of Arab origin were characterized by another distinct haplotype that was rare among normal Ashkenazi Jewish, Iraqi Jewish, and Arab chromosomes. These findings constitute the first example of a mutation common to Ashkenazi Jews, non-Ashkenazi Jews, and Arabs and are consistent with the origin of type II mutation in a founder before the divergence of the major segments of Jews. Our findings also indicate that the type III mutation arose more recently in an Ashkenazi Jewish individual.

Africa, Northern↗
PubMed1997

Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta3) is a second mutation in Iraqi Jews that stemmed from a distinct founder.

Glanzmann thrombasthenia (GT) is a rare bleeding disorder resulting from mutations in either glycoprotein (GP) IIb or GPIIIa genes. The disease is relatively frequent in highly inbred populations such as Iraqi Jews. The molecular basis of GT in 6 unrelated Iraqi-Jewish patients was previously identified as an 11-bp deletion in exon 12 of the GPIIIa gene. We now describe a second mutation found in 3 unrelated Iraqi-Jewish families that consists of an 11.2-kb deletion between an Alu repeat in intron 9 and exon 13 of the GPIIIa gene. The mutant DNA is transcribed into mRNA in which exons 10 through 13 are absent. Splicing of exon 9 directly to exon 14 leads to a shift in the reading frame resulting in a stop codon. The predicted protein is truncated in the middle of the third cysteine-rich domain before the transmembrane domain. Simple DNA-based methods were devised for identification of both mutations in Iraqi Jews for the purpose of carrier detection and prenatal diagnosis enabling prevention of GT. A survey of the general Iraqi-Jewish population for the first 11-bp deletion and the second 11.2-kb deletion disclosed that the allele frequency of the first mutation was 0.0043, whereas none of 700 individuals examined bore the second mutation (allele frequency <0.0007). Among 40 GT patients of Iraqi-Jewish origin 31 were homozygous for the first mutation, 4 were compound heterozygotes for the first and second mutations, and 2 were homozygous for the second mutation. Haplotype analyses using 4 polymorphic markers in the GPIIIa gene showed that each mutation originated in a distinct founder.

Adult↗
PubMed1997

Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping.

Combined Factors V and VIII deficiency is an autosomal recessive bleeding disorder identified in at least 58 families comprising a number of different ethnic groups. Affected patients present with a moderate bleeding tendency and have Factor V and Factor VIII levels in the range of 5-30% of normal. The highest frequency of the mutant gene is found in Jews of Sephardic and Middle Eastern origin living in Israel with an estimated disease frequency of 1:100,000. We sought to identify the gene responsible for combined Factors V and VIII deficiency using a positional cloning approach. Of 14 affected individuals from 8 unrelated Jewish families, 12 were the offspring of first-cousin marriages. After a genome-wide search using 241 highly polymorphic short tandem repeat (STR) markers, 13 of the 14 affected patients were homozygous for two closely linked 18q markers. Patients and all available family members were genotyped for 11 additional STRs spanning approximately 11 cM on the long arm of chromosome 18. Multipoint linkage analysis yielded a maximal log of the odds (LOD) score of 13.22. Haplotype analysis identified a number of recombinant individuals and established a minimum candidate interval of 2.5 cM for the gene responsible for combined Factors V and VIII deficiency. The product of this locus is likely to operate at a common step in the biosynthetic pathway for these two functionally and structurally homologous coagulation proteins. Identification of this gene should provide new insight into the biology of Factor V and Factor VIII production.

Chromosome Mapping↗
PubMed1997

A single genetic origin for a common Caucasian risk factor for venous thrombosis.

A common genetic risk factor for venous thrombosis among Caucasoid subpopulations is a polymorphism, nt G1691A, in blood coagulation factor V that replaces Arg506 with Gln and imparts resistance of factor Va to the anticoagulant, activated protein C. Haplotype analyses using six dimorphic sites in the factor V gene for 117 Caucasian subjects of Jewish, Arab, Austrian, and French origin who were homozygous for nt A1691 compared with 167 controls (nt G1691) support a single origin for this polymorphism. The nt G1691A mutation is estimated to have arisen circa 21,000 to 34,000 years ago, ie, after the evolutionary divergence of Africans from non-Africans and of Caucasoid from Mongoloid subpopulations.

Arginine↗
PubMed1997

Acquired von Willebrand disease in a patient with angiodysplasia resulting from immune-mediated clearance of von Willebrand factor.

A patient with a severe bleeding tendency due to acquired von Willebrand disease (VWD) is presented. Although no underlying disorder has emerged during 6 years of follow-up, an immune-mediated mechanism was responsible for acquired VWD in this patient as demonstrated by detection of von Willebrand factor (VWF)/anti-VWF complexes in the patient's plasma and their removal by protein A-sepharose beads and resumption of normal haemostasis with correction of VWF antigen, VWF activity and VWF multimeric pattern after treatment of the patient with high-dose gammaglobulin. Detection of anti-VWF antibodies in the patient's plasma had a significant impact on the choice of therapeutic intervention to control bleeding.

Angiodysplasia↗
PubMed1997

Bleeding predictors in factor-XI-deficient patients.

Bleeding in factor-XI-deficient patients is mainly injury-related. Parameters influencing bleeding particularly in patients with minor factor XI deficiency have not been defined. We utilized a logistic regression model to analyze parameters influencing bleeding tendency in subjects from 45 families with factor XI deficiency. Bleeding manifestations were documented in 58% of 26 homozygous or doubly heterozygous factor-XI-deficient patients, in 20% of 46 heterozygous factor-XI-deficient patients and in 9% of 47 family members with a normal factor XI genotype. Odds ratios for bleeding in homozygotes or double heterozygotes were 13 and in heterozygotes 2.6 with 95% confidence intervals of 3.8-45 and 0.8-9.0, respectively. Bleeding correlated negatively with factor XI level (r = -0.36, P = 0.0001) with major factor XI deficiency being a strong predictor of bleeding (P = 0.011). Minor factor XI deficiency and blood group O slightly contributed to bleeding. Although factor VIII and factor XI levels were correlated (r = 0.48, P = 0.0001), levels of factor VIII and von Willebrand factor were not predictors of bleeding. Bleeding was more common following operative procedure involving mucosal membranes (P < 0.01). The designed model enabled prediction of bleeding manifestations with an overall accuracy of 78% and 82% in heterozygotes.

Case-Control Studies↗
PubMed1997

Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families.

In this report we describe the molecular basis of FXIII a-subunit deficiency in three unrelated Palestinian Arab families. In three patients representing each family two substitutions were identified in exon 14 on both alleles: C to G change resulting in a Gln651Glu substitution (a previously described polymorphism) and a T to C transition causing Leu660Pro substitution. The latter is a new mutation which creates a restriction site for FnuDII enzyme. Restriction analysis performed in members of the three families clearly distinguished between severely affected patients, obligate carriers and unaffected subjects. A population survey failed to detect the mutation among 250 Jewish individuals but did detect two heterozygotes among 300 Arabs suggesting a 0.0033 frequency for the Pro660 allele in this population. In two out of the three families the Pro660 allele was linked to allele 5 of the 5' short tandem repeat polymorphism within the FXIII a-subunit gene suggesting that the mutation might have occurred at least twice. cDNA obtained from mRNA isolated from patients' platelets and monocytes appeared similar in size to that of normal control indicating that the Leu660Pro mutation does not affect mRNA synthesis. Computer modeling based on cristallographic studies of the a-subunit of factor XIII predicted that the mutant protein is expected to misfold into a structure which is either unstable or susceptible to degradation.

Arabs↗
PubMed1997

Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency.

Purpura fulminans is associated with homozygous protein C and homozygous protein S deficiency or may follow bacterial or viral infections. We present 2 children from 2 unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation. This report emphasizes the need for evaluation of hereditary defects in the inhibitory mechanisms of blood coagulation in patients with purpura fulminans at any age.

Child, Preschool↗
PubMed1996

Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis.

It is remarkable that certain patients with heterozygous protein C (PC) deficiency manifest venous thromboembolism (VTE), whereas others, particularly those belonging to families with homozygous PC deficiency, remain asymptomatic. The goals of the present study of a family, in which the proband had homozygous PC deficiency, were to identify members with and without VTE, to determine the mutation causing PC deficiency, and to search for the R506Q mutation of factor V (FV) causing activated PC resistance. Heterozygosity for a T298M mutation in exon 9 of the PC gene was found in the father of the homozygous proband who died of massive thrombosis. Based on analysis of a three-dimensional molecular model of PC, we speculate that this mutation causes type I deficiency due to disruption of packing of hydrophobic side chains and loss of an H-bond between Q184 and T298. Forty-six family members were examined for the T298M mutation by polymerase chain reaction (PCR) amplification of exon 9 and restriction analysis using Mae III and for the FV R506Q mutation by PCR amplification of exon 10 and restriction analysis using Mnl I. VTE was observed in five of 11 members who were heterozygous for both PC and FV mutations. In contrast, VTE was not observed for the PC mutation in 13 heterozygotes who had normal FV, including the parents of the deceased proband, 10 heterozygotes for the FV mutation who had normal PC, and 12 individuals bearing neither mutation. These observations extend recent evidence of an increased thrombotic risk conferred by the coexistence of heterozygous PC deficiency and heterozygous activated PC resistance and support the paradigm in which hereditary thrombophilia is often a multigenic disease.

Adult↗