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Research Interests: Medicine, Estrogen Receptor, Humans, Internal Medicine, Diabetes mellitus, and 15 moreHaplotypes, Female, Male, Gene Dosage, Clinical Sciences, Middle Aged, Gene Polymorphism, Coronary Angiography, Adult, Genetic Polymorphism, Coronary Artery Disease, Haplotype, Estrogen receptor alpha, Gene frequency, and Paediatrics and reproductive medicine
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Research Interests: Molecular Biology, Mass Spectrometry, Biology, Medicine, Extracellular Matrix, and 15 moreHumans, Mice, Female, Animals, Male, Mandible, Phosphorylation, Nickel, Biological activity, Microspheres, Amino Acid Sequence, Base Sequence, Biochemistry and cell biology, Molecular Sequence Data, and Agarose
INTRODUCTION Regenerative medicine research has evolved significantly in recent years. There is a great un-met clinical need for developing new treatments that will induce regeneration of injured skeletal tissues in cases such as large... more
INTRODUCTION Regenerative medicine research has evolved significantly in recent years. There is a great un-met clinical need for developing new treatments that will induce regeneration of injured skeletal tissues in cases such as large bony defects caused by trauma or tumor resection, articular cartilage defects and torn or degenerate tendons and ligaments. Except for bone that can regenerate small defects, all other skeletal tissues do not hold the natural capability for regeneration after injury and rather form a less functional scar tissue. In order to induce tissue regeneration, it is now believed that three crucial elements must reach the injured zone: a) multipotent cells that can rapidly proliferate and differentiate to form the injured tissues, such as mesenchymal stem cells for skeletal tissues; b) extra-cellular matrix that will support the newly built tissues, and c) the correct molecular signals. Using diverse research tools and expertise, our department focused its rese...
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To assess the main causes leading to childhood visual impairment/blindness in a center for low vision in Israel and to analyze the literature on pediatric blinding diseases in developed countries. Retrospective study based on... more
To assess the main causes leading to childhood visual impairment/blindness in a center for low vision in Israel and to analyze the literature on pediatric blinding diseases in developed countries. Retrospective study based on observational case series. Data were obtained from medical records of visually impaired children, seen at a national referral low vision center. Children were divided into two groups: moderate visual impairment (6/18 to 6/60) and severe visual impairment (SVI)/blindness (<6/60). Inherited eye diseases (IED) were grouped together for analysis. Data from the Israeli blind registry from the same period of time were analyzed for comparison. A review of literature on childhood blindness in developed countries since 2000 was conducted. A total of 1393 children aged 0–18 years were included in the study. Moderate visual impairment was seen in 1025 (73.6%) and SVI/blindness in 368 (26.4%) of the studied children. Among blind children, IED accounted for at least 51% of all diagnoses, including mainly albinism and retinal dystrophies. IED prevalence was equally high in both main ethnic groups (Jewish and Arab Muslims). Non-IED (22.6%) included mainly patients with cerebral visual impairment and retinopathy of prematurity. The leading cause of childhood visual impairment and blindness in our patient cohort was IED. Analyses of the literature from the last two decades show that IED are a major cause for SVI/childhood blindness in other developed countries as well. Updated patterns of global childhood blindness may suggest a need for new approach for screening programs and modern tactics for prevention.
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<b>Copyright information:</b>Taken from "A novel de novo mutation in an Ashkenazi-Jewish family with aniridia"Molecular Vision 2008;14():142-145.Published online 28 Jan 2008PMCID:PMC2255027. A schematic... more
<b>Copyright information:</b>Taken from "A novel de novo mutation in an Ashkenazi-Jewish family with aniridia"Molecular Vision 2008;14():142-145.Published online 28 Jan 2008PMCID:PMC2255027. A schematic representation of family MOL0407 is shown. The black filled shapes denote individuals affected with aniridia. The numbers above the symbols indicate the recruited individuals, and the numbers within the symbols indicate the number of siblings. The arrow indicates the index patient. The haplotype of each individual is represented below the individual symbol. Numbers represent the size of the PCR product containing the microsatellite sequence, "M" represents the mutant allele, and "+" represents the normal allele. Sequence analysis of exon 6 in is shown. The upper chromatogram represents the wild-type sequence of an unaffected family member, and the lower chromatogram represents a heterozygous mutation (patient II-3). The position of the insertion is indicated by an arrow. The wild type PAX6 amino acid sequence is shown above the upper chromatogram and the mutant amino acid sequence is shown below the lower chromatogram.
Purpose The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to... more
Purpose The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to compare it to albinism. Subjects and Methods We retrospectively collected molecular, ophthalmic, and electrophysiological data of 28 patients molecularly confirmed with FHONDA from the Netherlands (9), Israel (13), France (2), and the United States of America (4). We compared the data to that of 133 Dutch patients with the 3 most common types of albinism in the Netherlands: oculocutaneous albinism type 1 (49), type 2 (41), and ocular albinism (43). Results Patients with FHONDA had a total of 15 different mutations in SLC38A8, of which 6 were novel. Excluding missing data, all patients had moderate to severe visual impairment (median visual acuity [VA] = 0.7 logMAR, interquartile range [IQR] = 0.6–0.8), nystagmus (28/28), and grade 4 foveal hypoplasia (17/17). Misrouting was present in all nine tested patients. None of the patients had any signs of hypopigmentation of skin and hair. VA in albinism was better (median = 0.5 logMAR, IQR = 0.3–0.7, P 0.006) and the phenotypes were more variable: 14 of 132 without nystagmus, foveal hypoplasia grades 1 to 4, and misrouting absent in 16 of 74. Conclusions Compared to albinism, the FHONDA syndrome appears to have a more narrow phenotypic spectrum, consisting of nonprogressive moderately to severely reduced VA, nystagmus, severe foveal hypoplasia, and misrouting. The co-occurrence of nystagmus, foveal hypoplasia, and misrouting in the absence of hypopigmentation implies that these abnormalities are not caused by lack of melanin, which has important implications for understanding the pathogenesis of these features.
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Purpose Although most (or even all) genes that can cause achromatopsia (ACHM) when mutated are known, some patients are still negative for mutations even after screening the coding sequence of all known genes. Our aim was to characterize... more
Purpose Although most (or even all) genes that can cause achromatopsia (ACHM) when mutated are known, some patients are still negative for mutations even after screening the coding sequence of all known genes. Our aim was to characterize the genetic and clinical aspects of a deep intronic (c.1663–1205G>A, IVS14–1205G>A) CNGB3 variant. Methods Clinical evaluation included visual acuity testing, refractive error, a full clinical eye exam, full-field electroretinography (ffERG), color vision testing, and retinal imaging. Genetic analysis of CNGB3 exons, as well as part of intron 14, was performed by Sanger sequencing of PCR products. Results Screening for the CNGB3 c.1663–1205G>A variant revealed 17 patients belonging to 12 unrelated families who were either homozygous for this variant (7 cases, 5 families) or heterozygous in combination with another heterozygous known CNGB3 mutation (10 cases, 7 families). All patients were diagnosed with cone-dominated disease, mainly comple...
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Little is known about tuftelin expression in the developing embryo, previously it was thought to play a role in tooth enamel mineralization. In this study we show tuftelin's spatio-temporal expression in mineralizing and... more
Little is known about tuftelin expression in the developing embryo, previously it was thought to play a role in tooth enamel mineralization. In this study we show tuftelin's spatio-temporal expression in mineralizing and nonmineralizing tissues of the craniofacial complex in the developing mouse embryo. Embryos aged E10.5-E18.5 and newborns aged P3 were used in this study. Polymerase chain reaction (PCR), Real-time PCR, sequencing, and in-situ hybridization were used to detect and quantify messenger RNA (mRNA) expression in different developmental stages. We applied indirect immunohistochemistry and western-blot analyses to investigate protein expression. Two tuftelin mRNA transcripts and a single 64KDa protein were detected throughout embryonic development. Tuftelin was detected in tissues which develop from different embryonic origins; ectoderm, ectomesenchyme, and mesoderm. Tuftelin mRNA and protein were expressed already at E10.5, before the initiation of tooth formation and earlier than previously described. The expression pattern of tuftelin mRNA and protein exhibits dynamic spatio-temporal changes in various tissues. Tuftelin is expressed in neuronal tissues, thus fitting with its described correlation to nerve growth factor. A shift between cytoplasmatic and perinuclear/nuclear expression implies a possible role in regulation of transcription. Recent studies showed tuftelin is induced under hypoxic conditions in-vitro and in-vivo, through the hypoxia-inducible factor 1-α pathway. These results led to the hypothesis that tuftelin is involved in adaptation to hypoxic conditions. The fact that much of mammalian embryogenesis occurs at O 2 concentrations of 1-5%, raises the possibility that tuftelin expression throughout development is due to its role in the adaptive mechanisms in response to hypoxia.
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Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due... more
Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of ...
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Aniridia is a rare panocular disorder caused by mutations in the PAX6 gene and characterized mainly by iris hypoplasia. Here, we present six families with a history of low vision/blindness with a previously undiagnosed mild aniridia... more
Aniridia is a rare panocular disorder caused by mutations in the PAX6 gene and characterized mainly by iris hypoplasia. Here, we present six families with a history of low vision/blindness with a previously undiagnosed mild aniridia phenotype with minimal iris changes. Retrospective case series of patients diagnosed with a subtle aniridia phenotype characterized by minimal iris abnormalities, foveal hypoplasia, and an identified mutation in PAX6. Data collection from patient's charts included ocular examination findings, visual acuity, refraction, and clinical pictures when available. Genetic analysis was performed by isolation of genomic DNA from peripheral blood. The main outcome was the identification of patients with mild aniridia harboring a PAX6 mutation. In all six families, the phenotype included minimal corectopia and foveal hypoplasia; nystagmus was present in 10 out of 11 patients. A PAX6 mutation was identified in all six families; three of these mutations were ident...
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To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype-phenotype correlations. Cohort study. Retinitis pigmentosa patients from 230 families of AJ... more
To analyze the genetic and clinical findings in retinitis pigmentosa (RP) patients of Ashkenazi Jewish (AJ) descent, aiming to identify genotype-phenotype correlations. Cohort study. Retinitis pigmentosa patients from 230 families of AJ origin. Sanger sequencing was performed to detect specific founder mutations known to be prevalent in the AJ population. Ophthalmologic analysis included a comprehensive clinical examination, visual acuity (VA), visual fields, electroretinography, color vision testing, and retinal imaging by OCT, pseudocolor, and autofluorescence fundus photography. Inheritance pattern and causative mutation; retinal function as assessed by VA, visual fields, and electroretinography results; and retinal structural changes observed on clinical funduscopy as well as by pseudocolor, autofluorescence, and OCT imaging. The causative mutation was identified in 37% of families. The most prevalent RP-causing mutations are the Alu insertion (c.1297_8ins353, p.K433Rins31*) in ...
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Inherited retinal diseases (IRDs) are heterogeneous phenotypes caused by variants in a large number of genes. Disease prevalence and the frequency of carriers in the general population have been estimated in only a few studies, but are... more
Inherited retinal diseases (IRDs) are heterogeneous phenotypes caused by variants in a large number of genes. Disease prevalence and the frequency of carriers in the general population have been estimated in only a few studies, but are largely unknown. To this end, we developed two parallel methods to calculate carrier frequency for mutations causing autosomal-recessive (AR) IRDs in the Israeli population. We created an SQL database containing information on 178 genes from gnomAD (including genotyping of 5706 Ashkenazi Jewish (AJ) individuals) and our cohort of >2000 families with IRDs. Carrier frequency for IRD variants and genes was calculated based on allele frequency values and the Hardy-Weinberg (HW) equation. We identified 399 IRD-causing variants in 111 genes in Israeli patients and AJ controls. For the AJ subpopulation, gnomAD and HW-based regression analysis showed high correlation, therefore allowing one to use HW-based data as a reliable estimate of carrier frequency. ...
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Received June 17, 1993; Revised and Accepted August 29, 1993 ... Epidermolysis bullosa simplex (EBS) is a dominantly inherited disorder of the epidermis in which fragility of keratinocytes of the basal layer underlies the development of... more
Received June 17, 1993; Revised and Accepted August 29, 1993 ... Epidermolysis bullosa simplex (EBS) is a dominantly inherited disorder of the epidermis in which fragility of keratinocytes of the basal layer underlies the development of non-scarring blisters of the skin. This fragility ...
Research Interests: Biological Sciences, Humans, Mutation, Epidermolysis Bullosa, Human Molecular Genetics, and 12 morePolymerase Chain Reaction, Proteins, Introns, Protein Secondary Structure Prediction, Genetic Polymorphism, Amino Acid Sequence, Base Sequence, Glutamic Acid, Nucleotides, Keratins, Molecular Sequence Data, and Medical and Health Sciences
Purpose: To report a novel de novo PAX6 mutation in an Ashkenazi-Jewish family with autosomal dominant aniridia. Methods: A mother and her daughter of Ashkenazi-Jewish origin were diagnosed with aniridia. Blood samples were drawn from... more
Purpose: To report a novel de novo PAX6 mutation in an Ashkenazi-Jewish family with autosomal dominant aniridia. Methods: A mother and her daughter of Ashkenazi-Jewish origin were diagnosed with aniridia. Blood samples were drawn from family members and DNA was analyzed by direct sequencing and microsatellite marker analysis. Results: The index patient and her daughter were affected with aniridia accompanied by congenital cataract, nystagmus, and glaucoma. A heterozygous PAX6 frameshift mutation in exon 6 (c.577_578insG, insG@Gly72) was identified in the affected individuals and not in any of the unaffected family members including the parents of the index patient. Microsatellite analysis revealed that the index patient inherited the disease haplotype from her unaffected father. A sequence analysis of human PAX6 expressed sequence tags revealed the identification of spliced transcripts initiating from introns 4, 6, 7, 8, and 11. Conclusions: A novel de novo frameshift mutation in PAX6, which presumably occurred in the paternal gamete, was found in a family with autosomal dominant aniridia. The location of the mutation suggests that only full-length PAX6 isoforms would be disrupted, indicating that the normal expression of shorter, paired-less, protein isoforms cannot prevent manifestation of the disease.
Research Interests: Humans, Expressed Sequence Tags, Female, Blood sampling, Male, and 15 moreJews, Infant, Introns, Middle Aged, Optometry and Ophthalmology, Aniridia, Indexation, Amino Acid Sequence, Base Sequence, Full Length Movies, Molecular Sequence Data, DNA mutational analysis, Autosomal Dominant, frameshift mutation, and Direct sequence
Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years.... more
Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual-energy X-ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5.6 years was determined in 19 patients. Serum 25-hydroxyvitamin D, insulin growth factor-1 (IGF-1), bone formation markers bone-alkaline phosphatase, osteocalcin and the resorption marker urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z-score &lt; -2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF-1 in 72% and increased urinary NTx in 84% of patients. Serum IGF-1 correlated with spine and hip BMD (r = 0.4, r = 0.39, P &lt; 0.01 respectively), and NTx correlated with the hip BMD Z-score (r = 0.35 P &lt; 0.05). The mean annual percentage change in spine BMD was -1.36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF-1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.
Research Interests: Minerals, Humans, Collagen, Female, Male, and 15 moreBone Density, Osteocalcin, Alkaline phosphatase, Middle Aged, Longitudinal Studies, Adult, Biological markers, Chi Square Distribution, Beta Thalassemia, Femur Neck, Bone and Bones, lumbar vertebrae, hydroxyvitamin D, Cardiovascular medicine and haematology, and Collagen type I
Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous hereditary retinal diseases that result in blindness due to photoreceptor degeneration. Mutations in the rhodopsin (RHO) gene are the most common cause of... more
Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous hereditary retinal diseases that result in blindness due to photoreceptor degeneration. Mutations in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP) and are responsible for 16% to 35% of adRP cases in the Western population. Our purpose was to investigate the contribution of RHO to adRP in the Israeli and Palestinian populations. Thirty-two adRP families participated in the study. Mutation detection was performed by whole exome sequencing (WES) and Sanger sequencing of RHO exons. Fluorescence PCR reactions of serially diluted samples were used to predict the percentage of mosaic cells in blood samples. Eight RHO disease-causing mutations were identified in nine families, with only one novel mutation, c.548-638dup91bp, identified in a family where WES failed to detect any causal variant. Segregation analysis revealed that the origin of the mutation is in a mosaic health...
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Research Interests: Biomarkers, Wound Healing, Proprioception, Humans, Female, and 13 moreAnimals, Clinical Sciences, Amelogenin, Rats, Alginates, Cellular and Molecular Medicine, Cell Proliferation, Tensile Strength, Recombinant Proteins, Drug Carriers, Mesenchymal Stromal Cells, Biochemistry and cell biology, and Nerve Endings
Received June 17, 1993; Revised and Accepted August 29, 1993 ... Epidermolysis bullosa simplex (EBS) is a dominantly inherited disorder of the epidermis in which fragility of keratinocytes of the basal layer underlies the development of... more
Received June 17, 1993; Revised and Accepted August 29, 1993 ... Epidermolysis bullosa simplex (EBS) is a dominantly inherited disorder of the epidermis in which fragility of keratinocytes of the basal layer underlies the development of non-scarring blisters of the skin. This fragility ...
Research Interests: Biological Sciences, Humans, Mutation, Epidermolysis Bullosa, Human Molecular Genetics, and 12 morePolymerase Chain Reaction, Proteins, Introns, Protein Secondary Structure Prediction, Genetic Polymorphism, Amino Acid Sequence, Base Sequence, Glutamic Acid, Nucleotides, Keratins, Molecular Sequence Data, and Medical and Health Sciences
Research Interests: Obstetrics, Birth Weight, Pregnancy, Humans, Female, and 15 moreEuropean, Gynecology, Adult, Pregnancy Complication, Gestational Age, Case Control Study, Intrauterine Growth Restriction, Case Control Studies, Pre Eclampsia, Factor V Leiden, Pregnancy complications, Methylenetetrahydrofolate Reductase, Paediatrics and reproductive medicine, Abruptio placentae, and Fetal Growth Retardation
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To report a novel de novo PAX6 mutation in an Ashkenazi-Jewish family with autosomal dominant aniridia. A mother and her daughter of Ashkenazi-Jewish origin were diagnosed with aniridia. Blood samples were drawn from family members and... more
To report a novel de novo PAX6 mutation in an Ashkenazi-Jewish family with autosomal dominant aniridia. A mother and her daughter of Ashkenazi-Jewish origin were diagnosed with aniridia. Blood samples were drawn from family members and DNA was analyzed by direct sequencing and microsatellite marker analysis. The index patient and her daughter were affected with aniridia accompanied by congenital cataract, nystagmus, and glaucoma. A heterozygous PAX6 frameshift mutation in exon 6 (c.577_578insG, insG@Gly72) was identified in the affected individuals and not in any of the unaffected family members including the parents of the index patient. Microsatellite analysis revealed that the index patient inherited the disease haplotype from her unaffected father. A sequence analysis of human PAX6 expressed sequence tags revealed the identification of spliced transcripts initiating from introns 4, 6, 7, 8, and 11. A novel de novo frameshift mutation in PAX6, which presumably occurred in the pat...