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Biomedical subjects

H Peretz

Publications and source records attributed to H Peretz.

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

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

Screening for tumour suppressor p16(CDKN2A) germline mutations in Israeli melanoma families.

Approximately ten percent of patients with malignant melanoma have family histories of the disease, suggesting a genetic predisposition. Germline mutations in tumour suppressor p16 gene have been implicated as disease causing mutations in some of the melanoma families. The frequency of families with p16 germline mutations among melanoma prone families varies from eight to fifty percent. The range of the variability is influenced apparently by the number of melanoma affected individuals within the family, as well as by other, yet unidentified factors. Ethnic background is known to determine both the frequency and the nature of germline alterations. Recently, specific mutations in tumour suppressor genes involved in breast cancer and in colon cancer were found at elevated frequency among Ashkenazi Jews. This report describes results of a screening for p16 germline alterations in a collection of Israeli melanoma families. We have analyzed genomic DNA from thirty one Ashkenazi and non-Ashkenazi Jewish melanoma families, as well as from thirty melanoma patients without an apparent family history of the disease. The entire coding region of the p16 gene was screened by single strand conformation polymorphism analysis and direct DNA sequencing. We have detected a number of carriers with the Ala148 Thr polymorphism at the end of the second exon and several instances of 500(G=>C) substitution at the 3' untranslated portion of the gene.

Female↗
PubMed1997

[Macroenzymes: an interesting laboratory finding, without clinical relevance].

Macroenzymes are complexes of serum enzymes with proteins which have a higher molecular weight and longer plasma half-life than the normal enzyme. The presence of macroenzymes is suggested by finding increased serum enzyme activity, not associated with symptoms. Thus, macroenzymes can cause diagnostic errors and the performance of unnecessary tests or invasive procedures. We describe 2 patients with highly elevated serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) due to formation of complexes with immunoglobulin G. 1 patient had LDH of 4500 u/L but was otherwise normal and in the second CK was elevated with no evidence of ischemic heart disease. Awareness of the phenomenon of macroenzymes may save the patient long and sometimes invasive investigation.

Adult↗
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

Highly elevated lactate dehydrogenase level in a healthy individual: a case of macro-LDH.

Macroenzymes are complexes of serum enzymes with a plasmatic protein. They have a higher molecular weight and a more prolonged serum half-life than those of unbound enzymes. Although macroenzymes may be found in the serum of post-myocardial infarction patients, they are not usually associated with any specific disease. Their presence, however, can cause an elevation in the serum levels of an enzyme, possibly leading to errors in diagnosis. We report a patient with extremely elevated serum levels of lactate dehydrogenase (LDH) due to the formation of complexes with immunoglobulin G. She had undergone a myriad of clinical examinations until the macroenzyme responsible for this finding was detected. We also review the literature on the clinical significance of macro-LDH. We propose that awareness of this rare and probably benign phenomenon can spare the patient from the distress of exhaustive investigations.

Blood Proteins↗
PubMed1997

Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting.

The multiple endocrine neoplasia type 2 (MEN2) syndromes and Hirschsprung's disease (HSCR) are inherited neurocristopathies characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid disease, and gastrointestinal neuromatosis. Mutations in the RET proto-oncogene are the underlying cause of the MEN2 syndromes and some cases of HSCR. In this report, we show that Cys 618 Arg mutation cosegregates with familial MTC and HSCR in two Moroccan Jewish families in which no involvement of pheochromocytoma or parathyroidism was observed. A single haplotype shared by chromosomes bearing the Cys 618 Arg mutation in both families strongly suggests a founder effect for this mutation. We have observed in our and in several other previously reported families, an excess of maternal over paternal mutated RET alleles in offsprings affected by HSCR. We suggest that parental imprinting may play a role in the ethiology of HSCR caused by mutations in the RET protooncogene.

Arginine↗
PubMed1997

Pheochromocytoma due to unilateral adrenal medullary hyperplasia.

We describe two male patients, aged 17 and 47 years, with clinical and biochemical features of pheochromocytoma. Both patients had normal-sized adrenal glands on abdominal CT scan and abnormal unilateral uptake of I-123 metaiodobenzylguanidine (MIBG) on scintigraphy. The surgical adrenalectomy revealed normal macroscopic glands in both patients. Histological examination showed adrenal medullary hyperplasia with adrenal cortico-medullary ratios of 2:1 and 4:1. Unilateral adrenalectomy resulted in amelioration of symptoms and normalization of catecholamines excretion. DNA examination for RET protooncogene revealed no mutations in exons 10, 11, 13, 14 and 16. Our results suggest that diffuse adrenal medullary hyperplasia may be the initial pathological change in the adrenal gland leading, subsequently, to the development of nodular hyperplasia and adrenal medullary tumor. These results indicate that the syndrome of pheochromocytoma may occur as an unilateral adrenal medullary hyperplasia in patients without evidence for multiple endocrine neoplasia.

Adolescent↗
PubMed1995

Glanzmann's thrombasthenia associated with deletion-insertion and alternative splicing in the glycoprotein IIb gene.

Glanzmann's thrombasthenia is a bleeding disorder characterized by a decrease or absence of the functional platelet membrane glycoprotein (GP) complex, GPIIb/IIIa (alpha IIb beta 3). We describe a new deletion-insertion mutation in the GPIIb gene causing type I Glanzmann's thrombasthenia in two siblings of a consanguineous Iranian-Jewish family. The proband's platelets bound more antibodies against the vitronectin receptor-alpha V beta 3 than normal platelets, suggesting a normal GPIIIa (beta 3) gene and a defect in the GPIIb gene. Sequencing of amplified cDNA and genomic DNA fragments showed a 6-bp deletion and 31-bp insertion in exon 25 of the GPIIb gene. The predominant platelet GPIIb mRNA of the proband was a product of the splicing of exon 24 to a cryptic AG acceptor site in the insertion and encoded for deletion of amino acids Leu817-Asn826 and insertion of eight different amino acids. Cotransfection of COS-7 cells with expression vectors containing wild-type GPIIIa cDNA and the mutated GPIIb cDNA failed to produce detectable amounts of GPIIb/IIIa on the surface of the cells. Allele-specific restriction analysis of genomic DNA of family members showed homozygosity for the mutation in the affected siblings, heterozygosity in the parents, and homozygosity for the normal allele in an unaffected sibling. The observed mutation is in a region that is conserved from rodents to humans and has been suggested to be involved in the interaction between GPIIb and GPIIIa when these GPs are complexed in solution.

Adult↗
PubMed1995

One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews.

In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi-Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.

Aged↗
PubMed1991

Detection of the Glanzmann's thrombasthenia mutations in Arab and Iraqi-Jewish patients by polymerase chain reaction and restriction analysis of blood or urine samples.

Severe Glanzmann's thrombasthenia is relatively frequent in Iraqi-Jews and Arabs residing in Israel. We have recently described the mutations responsible for the disease in Iraqi-Jews--an 11 base pair deletion in exon 12 of the glycoprotein IIIa gene, and in Arabs--a 13 base pair deletion at the AG acceptor splice site of exon 4 on the glycoprotein IIb gene. In this communication we show that the Iraqi-Jewish mutation can be identified directly by polymerase chain reaction and gel electrophoresis. With specially designed oligonucleotide primers encompassing the mutation site, an 80 base pair segment amplified in healthy controls was clearly distinguished from the 69 base pair segment produced in patients. Patients from 11 unrelated Iraqi-Jewish families had the same mutation. The Arab mutation was identified by first amplifying a DNA segment consisting of 312 base pairs in controls and of 299 base pairs in patients, and then digestion by a restriction enzyme Stu-1, which recognizes a site that is absent in the mutant gene. In controls the 312 bp segment was digested into 235 and 77 bp fragments, while in patients there was no change in the size of the amplified 299 bp segment. The mutation was found in patients from 3 out of 5 unrelated Arab families. Both Iraqi-Jewish and Arab mutations were detectable in DNA extracted from blood and urine samples. The described simple methods of identifying the mutations should be useful for detection of the numerous potential carriers among the affected kindreds and for prenatal diagnosis using DNA extracted from chorionic villi samples.

Base Sequence↗