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B Bonne-Tamir

Publications and source records attributed to B Bonne-Tamir.

At least 19 recordsLinked to original sources
PubMed2004

COMT haplotypes suggest P2 promoter region relevance for schizophrenia.

A recent study found, in a large sample of Ashkenazi Jews, a highly significant association between schizophrenia and a particular haplotype of three polymorphic sites in the catechol-O-methyl transferase, COMT, gene: an IVS 1 SNP (dbSNP rs737865), the exon 4 functional SNP (Val158Met, dbSNP rs165688), and a downstream SNP (dbSNP rs165599). Subsequently, this haplotype was shown to be associated with lower levels of COMT cDNA derived from normal cortical brain tissue, most likely due to cis-acting element(s). As a first step toward evaluating whether this haplotype may be relevant to schizophrenia in populations other than Ashkenazi Jews, we have studied this haplotype in 38 populations representing all major regions of the world. Adding to our previous data on four polymorphic sites in the COMT gene, including the Val158Met polymorphism, we have typed the IVS 1 rs737865 and 3' rs615599 sites and also included a novel IVS 1 indel polymorphism, yielding seven-site haplotype frequencies for normal individuals in the 38 globally distributed populations, including a sample of Ashkenazi Jews. We report that the schizophrenia-associated haplotype is significantly heterogeneous in populations worldwide. The three-site, schizophrenia-associated haplotype frequencies range from 0% in South America to 37.1% in Southwest Asia, despite the fact that schizophrenia occurs at roughly equal frequency around the world. Assuming that the published associations found between the exon 4 Val158Met SNP and schizophrenia are due to linkage disequilibrium, these new haplotype data support the hypothesis of a relevant cis variant linked to the rs737865 site, possibly just upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain. The previously described HindIII restriction site polymorphism, located within the P2 promoter, varies within all populations and may provide essential information in future studies of schizophrenia.

Catechol O-Methyltransferase↗
PubMed2001

Distinctive genetic signatures in the Libyan Jews.

Unlinked autosomal microsatellites in six Jewish and two non-Jewish populations were genotyped, and the relationships among these populations were explored. Based on considerations of clustering, pairwise population differentiation, and genetic distance, we found that the Libyan Jewish group retains genetic signatures distinguishable from those of the other populations, in agreement with some historical records on the relative isolation of this community. Our methods also identified evidence of some similarity between Ethiopian and Yemenite Jews, reflecting possible migration in the Red Sea region. We suggest that high-resolution statistical methods that use individual multilocus genotypes may make it practical to distinguish related populations of extremely recent common ancestry.

Arabs↗
PubMed2001

Isolation and characterization of the UBASH3A gene on 21q22.3 encoding a potential nuclear protein with a novel combination of domains.

In order to identify candidate genes for Down syndrome phenotypes or monogenic disorders that map to human chromosome 21q22.3, we have used genomic sequence and expressed sequence tags mapping to an autosomal recessive deafness (DFNB10) critical region to isolate a novel 2.5-kb cDNA that maps between TFF1 and D21S49. A semi-quantitative reverse transcription/polymerase chain reaction method revealed that UBASH3A gene expression is limited to only a few tissues, with its highest expression in spleen, peripheral blood leukocytes, and bone marrow. The putative 661-amino-acid protein shows considerable homology to a hypothetical protein from Drosophila melanogaster but only domain homologies to other organisms. Both the human and D. melanogaster proteins contain protein-protein interaction domains, viz., SH3 and ubiquitin-associated (UBA) domains, in addition to a novel domain also containing a nuclear localization signal. This is the first protein described containing both UBA and SH3 domains. The gene, thus called UBASH3A, spans 40 kb and is divided into 15 exons. Mutation analysis excluded UBASH3A as being responsible for DFNB10.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness.

Approximately 50% of childhood deafness is caused by mutations in specific genes. Autosomal recessive loci account for approximately 80% of nonsyndromic genetic deafness. Here we report the identification of a new transmembrane serine protease (TMPRSS3; also known as ECHOS1) expressed in many tissues, including fetal cochlea, which is mutated in the families used to describe both the DFNB10 and DFNB8 loci. An 8-bp deletion and insertion of 18 monomeric (approximately 68-bp) beta-satellite repeat units, normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes, causes congenital deafness (DFNB10). A mutation in a splice-acceptor site, resulting in a 4-bp insertion in the mRNA and a frameshift, was detected in childhood onset deafness (DFNB8). This is the first description of beta-satellite insertion into an active gene resulting in a pathogenic state, and the first description of a protease involved in hearing loss.

Adult↗
PubMed2000

Cloning and characterization of a putative human glycerol 3-phosphate permease gene (SLC37A1 or G3PP) on 21q22.3: mutation analysis in two candidate phenotypes, DFNB10 and a glycerol kinase deficiency.

Using multiple exons trapped from human chromosome 21 (HC21)-specific cosmids with homology to a putative Arabidopsis thaliana glycerol 3-phosphate permease, we have determined the full-length cDNA sequence of a novel HC21 gene encoding a putative sugar-phosphate transporter (HGMW-approved symbol SLC37A1, aka G3PP). The predicted protein has 12 putative transmembrane domains and is also highly homologous to bacterial glpT proteins. The transcript was precisely mapped to 21q22.3 between D21S49 and D21S113. Comparison of the SLC37A1 cDNA to genomic sequence revealed that the gene encompasses 82 kb, and it is split into 19 coding exons and 7 untranslated exons, which are alternatively spliced in a complex and tissue-specific manner. Glycerol 3-phosphate (G3P) is produced by glycerol kinase (GK) and is found in several biochemical pathways in different cellular compartments, such as the glycerol phosphate shuttle and glycerophospholipid synthesis. Thus SLC37A1 mutations may cause a phenotype similar to GK deficiency. Mutational analyses of SLC37A1 in seven patients with no mutations in the GK gene and low GK activity revealed only nonpathogenetic sequence variants, excluding SLC37A1 as the gene for the phenotype in these patients. SLC37A1 maps in the refined critical region of the autosomal recessive deafness locus, DFNB10, on 21q22.3. Mutation analyses also excluded SLC37A1 as the gene for DFNB10.

Amino Acid Sequence↗
PubMed2000

Isolation and characterization of a human chromosome 21q22.3 gene (WDR4) and its mouse homologue that code for a WD-repeat protein.

To identify candidate genes for Down syndrome phenotypes or disorders that map to human chromosome 21q22.3, trapped exons are being used to isolate full-length transcripts. We isolated a full-length cDNA (WDR4) encoding a novel WD-repeat protein and its mouse homologue. Two RNA species of 1.5 and 2.1 kb were observed in human, with the 1.5-kb transcript being produced by a splicing event after the stop codon, and thus both transcripts encode the same putative 412-amino-acid protein containing four guanine nucleotide-binding WD repeats. The more highly expressed 1.5-kb transcript was expressed mainly in fetal tissues while the 2.1-kb transcript showed a faint expression in most tissues. Two additional alternative splicing events of 270 and 52 nt within the coding region were observed. The WDR4 gene spans 37 kb and is divided into 11 coding exons. WDR4 maps between PDE9A and NDUFV3, a region where several genetic disorders, including a form of manic-depressive psychosis, also map, and seven sequence variants observed in the WDR4 gene could be used in association studies.

Alternative Splicing↗
PubMed2000

Jewish and Middle Eastern non-Jewish populations share a common pool of Y-chromosome biallelic haplotypes.

Haplotypes constructed from Y-chromosome markers were used to trace the paternal origins of the Jewish Diaspora. A set of 18 biallelic polymorphisms was genotyped in 1,371 males from 29 populations, including 7 Jewish (Ashkenazi, Roman, North African, Kurdish, Near Eastern, Yemenite, and Ethiopian) and 16 non-Jewish groups from similar geographic locations. The Jewish populations were characterized by a diverse set of 13 haplotypes that were also present in non-Jewish populations from Africa, Asia, and Europe. A series of analyses was performed to address whether modern Jewish Y-chromosome diversity derives mainly from a common Middle Eastern source population or from admixture with neighboring non-Jewish populations during and after the Diaspora. Despite their long-term residence in different countries and isolation from one another, most Jewish populations were not significantly different from one another at the genetic level. Admixture estimates suggested low levels of European Y-chromosome gene flow into Ashkenazi and Roman Jewish communities. A multidimensional scaling plot placed six of the seven Jewish populations in a relatively tight cluster that was interspersed with Middle Eastern non-Jewish populations, including Palestinians and Syrians. Pairwise differentiation tests further indicated that these Jewish and Middle Eastern non-Jewish populations were not statistically different. The results support the hypothesis that the paternal gene pools of Jewish communities from Europe, North Africa, and the Middle East descended from a common Middle Eastern ancestral population, and suggest that most Jewish communities have remained relatively isolated from neighboring non-Jewish communities during and after the Diaspora.

Base Sequence↗
PubMed2000

Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus.

About 60% of congenital hearing impairment cases in developed countries are due to genetic defects. Data on the molecular basis of hereditary hearing reflects vast genetic heterogeneity. There are >400 disorders in which hearing impairment is one of the characteristic traits of a syndrome. Linkage studies have identified more than 40 human chromosomal loci associated with non-syndromic hearing loss. So far, 16 of these 40 non-syndromic hearing impairment genes have been identified. We have studied the molecular basis of hearing impairment in four Druze families from the same village in Northern Galilee. The Druze are a small, isolated population in the Middle East practising endogamous marriage. Thus it was expected that a single mutation would account for hearing impairments in all these families. Our results show that at least four different genes are involved. Hearing impairment was caused in one family by a novel mutation in the recently identified OTOF (the DFNB9 gene), by a novel Pendred syndrome mutation (Thr193Ile) in another family, and by a GJB2 mutation (35delG also known as 30delG) in the third family. In the fourth family linkage was excluded from all known hearing impairments loci (recessive and dominant) as well as from markers covering chromosomes 11-22, pointing therefore to the existence of another non-syndromic recessive hearing loss (NSRD) locus on chromosomes 1-10.

Carrier Proteins↗
PubMed1999

Molecular analysis of HLA class II polymorphisms among different ethnic groups in Israel.

The Jewish population in Israel comprises of inhabitants of heterogeneous ethnic backgrounds. Genetic studies classify the Israeli Jewish population into two major groups: Ashkenazi from Central and Eastern Europe and Sephardic or non Ashkenazi, from the Mediterranean and North Africa. The present study was aimed at elucidating the differential influx of HLA class II alleles in Ashkenazi, in various non-Ashkenazi subgroups and in Israeli Moslem Arabs. Using the PCR-SSOP technique, a large number of alleles were detected at each of the loci examined (DRB1, DQA1 and DQB1). In addition, gene frequencies, characteristic DR/DQ linkage disequilibria, population distance and their corresponding dendogram, were used to study the relationship between Israelis as a group, non Jewish Caucasians and Blacks. These populations could be grouped into three main clusters: the first consists of all the Israeli groups with the exception of the Ethiopian Jews; the second consists of non Jewish Caucasians, with a clear distinction seen between Israelis and non Jewish Europeans and U.S. Caucasians; the third, composed of Blacks, is distinctly different from the other populations. Ethiopian Jews were found to be closer to the Blacks than to any of the Israeli Jewish groups. We have shown that Jews share common features, a fact that points to a common ancestry. A certain degree of admixture with their pre-immigration neighbors exists despite the cultural and religious constraints against intermarriage.

Alleles↗
PubMed1999

Genetic variation of three tetrameric tandem repeats in four distinct Israeli ethnic groups.

The allele frequency distributions of three STR loci amplified by PCR have been studied in four Israeli communities: Ashkenazi Jews and three non-Ashkenazi groups, namely Moroccan, Yemenite, and Ethiopian Jews. The loci analyzed were CSF1PO, TPOX, and HUMTHO1. The typing was performed in sequencing polyacrylamide gels under denaturing conditions that could separate alleles with differences of a single base. The population data were analyzed with respect to Hardy-Weinberg (H-W) equilibrium and found that all loci meet the H-W expectations. No-ticeable differences were encountered between the four Jewish ethnic groups studied hereby indicating the importance of establishing a local database to be used in human identity testing in these different Israeli Jewish groups.

DNA↗
PubMed1998

Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups.

We characterized microsatellite marker haplotypes and identified mutations in members of 19 ethnically diverse Israeli families affected by Wilson disease (WD). Eighteen unique haplotypes were derived from allelic combinations for four marker loci spanning the WD gene, ATP7B, at chromosome 13q14.3: D13S133, D13S296, D13S301 and D13S295. Most of these haplotypes are population specific and vary among and even within different ethnic groups. Intrafamilial variability of WD haplotypes was observed in two large consanguineous families in which a single origin of WD was expected. In contrast, some WD haplotypes were identified in more than one group. Five novel and four previously described mutations were detected in our sample. The novel mutations include two deletions (845delT and 1639delC) and three missense mutations (E1064A, M645R, and G1213V). Mutations were identified for 11 of the 18 WD haplotypes, suggesting that other mutations may reside in noncoding regions of the ATP7B gene. Identification of all WD mutations will undoubtedly increase our understanding of the normal function of ATP7B as well as lead to more accurate prognosis and genetic counseling.

Adenosine Triphosphatases↗
PubMed1998

A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus.

A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) -- TaqI "A", "B", and "D" sites -- and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI "B" and "A", was highly significant with D' values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI "B" site in all populations, with D' values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an "Out of Africa" model for recent human evolution.

Alleles↗
PubMed1998

Localization of the gene for congenital dyserythropoietic anemia type I to a <1-cM interval on chromosome 15q15.1-15.3.

Congenital dyserythropoietic anemias (CDA) are a rare group of red-blood-cell disorders of unknown etiology that are characterized by ineffective erythropoiesis, pathognomonic cytopathology of the nucleated red blood cells in the bone marrow, and secondary hemochromatosis. In CDA type I, bone-marrow electron microscopy reveals characteristic findings in erythroid precursors, including spongy heterochromatin and enlarged nuclear pores. Since the genetic basis of CDA type I is not evident, we used homozygosity and linkage mapping to localize the genetic defect responsible for CDA type I in 25 Bedouins from four large consanguineous families. We report the linkage of this disease to markers on chromosome 15 located at q15. 1-q15.3. Fourteen markers within a 12-cM interval were typed in the relevant family members. Nine of the markers yielded maximum LOD scores of 1.625-12.928 at a recombination fraction of .00. Linkage disequilibrium was found only with marker D15S779. Haplotype analysis revealed eight different carrier haplotypes and highlighted the existence of a founder haplotype. Identification of historical crossover events further narrowed the gene location to between D15S779 and D15S778. The data suggest localization of the CDA type I gene within a 0.5-cM interval. The founder mutation probably occurred >/= 400 years ago. Sequence analysis of the coding region of protein 4.2, the only known erythroid-specific gene in the locus, did not reveal any change in the CDA type I patients. Future analysis of this locus may lead to the identification of a gene essential to normal erythropoiesis.

Anemia, Dyserythropoietic, Congenital↗
PubMed1998

A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations.

Haplotypes consisting of the (CTG)n repeat, as well as several flanking markers at the myotonic dystrophy (DM) locus, were analyzed in normal individuals from 25 human populations (5 African, 2 Middle Eastern, 3 European, 6 East Asian, 3 Pacific/Australo-Melanesian, and 6 Amerindian) and in five nonhuman primate species. Non-African populations have a subset of the haplotype diversity present in Africa, as well as a shared pattern of allelic association. (CTG)18-35 alleles (large normal) were observed only in northeastern African and non-African populations and exhibit strong linkage disequilibrium with three markers flanking the (CTG)n repeat. The pattern of haplotype diversity and linkage disequilibrium observed supports a recent African-origin model of modern human evolution and suggests that the original mutation event that gave rise to DM-causing alleles arose in a population ancestral to non-Africans prior to migration of modern humans out of Africa.

Alleles↗
PubMed1997

Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins.

Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.

Amino Acid Substitution↗