Biomedical subjects

Eli Hershkovitz

Publications and source records attributed to Eli Hershkovitz.

18 recordsLinked to original sources

PubMed2006

Parathyroid development and the role of tubulin chaperone E.

The development of the parathyroid glands involves complex embryonic processes of cell-specific differentiation and migration of the glands from their sites of origin in the pharynx and pharyngeal pouches to their final positions along the ventral midline of the pharyngeal and upper thoracic region. The recognition of several distinct genetic forms of isolated and syndromic hypoparathyroidism led us to review the recent findings on the molecular mechanisms of the development of the parathyroid glands. Although far from being understood, a special emphasis was given to the possible role of tubulin chaperone E (TBCE), which was implicated in the pathogenesis of the hypopathyroidism, retardation and dysmorphism (HRD) syndrome. The novel finding that TBCE plays a critical role in the formation of the parathyroid opens a novel domain of research, not anticipated previously, into the complex process of parathyroid development.

Gene Expression Regulation↗

PubMed2006

Single nucleotide RNA choreography.

New structural analysis methods, and a tree formalism re-define and expand the RNA motif concept, unifying what previously appeared to be disparate groups of structures. We find RNA tetraloops at high frequencies, in new contexts, with unexpected lengths, and in novel topologies. The results, with broad implications for RNA structure in general, show that even at this most elementary level of organization, RNA tolerates astounding variation in conformation, length, sequence and context. However the variation is not random; it is well-described by four distinct modes, which are 3-2 switches (backbone topology variations), insertions, deletions and strand clips.

Models, Molecular↗

PubMed2005

Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion.

The mitochondrial DNA (mtDNA) depletion syndrome is a quantitative defect of mtDNA resulting from dysfunction of one of several nuclear-encoded factors responsible for maintenance of mitochondrial deoxyribonucleoside triphosphate (dNTP) pools or replication of mtDNA. Markedly decreased succinyl-CoA synthetase activity due to a deleterious mutation in SUCLA2, the gene encoding the beta subunit of the ADP-forming succinyl-CoA synthetase ligase, was found in muscle mitochondria of patients with encephalomyopathy and mtDNA depletion. Succinyl-CoA synthetase is invariably in a complex with mitochondrial nucleotide diphosphate kinase; hence, we propose that a defect in the last step of mitochondrial dNTP salvage is a novel cause of the mtDNA depletion syndrome.

Alleles↗

PubMed2005

Nerve growth factor-tyrosine kinase A pathway is involved in thermoregulation and adaptation to stress: studies on patients with hereditary sensory and autonomic neuropathy type IV.

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is caused by mutations in the tyrosin kinase A (TrkA) gene, encoding for the high-affinity receptor of nerve growth factor (NGF). The NGF-TrkA system is expressed in many endocrine glands. We hypothesized that HSAN IV represents a natural model for impaired NGF effect on the neuroendocrine system in humans. We have documented the clinical outcome of 31 HSAN IV patients in a single medical center, and investigated their basal endocrine system status. The endocrine system response to thirst was compared between six patients and six healthy children. High rates of mortality (22%) and severe morbidity (30%) have been found in HSAN IV patients. Hypothermia was noted in 40% of the patients and unexplained fever was observed in 56%. Subnormal adrenal function was demonstrated in six (30%) of the patients studied. Furthermore, we found lower plasma norepinephrine (NE) levels in six HSAN IV patients compared with a control group after the thirst test. Our findings emphasize the importance of NGF-TrkA pathway in the physiology of the neuroendocrine system and its response to stress. Inadequate response to stress might contribute to the observed significant mortality, morbidity, and temperature instability in HSAN IV patients.

Body Temperature Regulation↗

PubMed2005

The 2p21 deletion syndrome: characterization of the transcription content.

The vast majority of small-deletion syndromes are caused by haploinsufficiency of one or several genes and are transmitted as dominant traits. We have previously identified a homozygous deletion of 179,311 bp on chromosome 2p21 as the cause of a unique syndrome, inherited in a recessive mode, consisting of cystinuria, neonatal seizures, hypotonia, severe somatic and developmental delay, facial dysmorphism, and reduced activity of all the respiratory chain enzymatic complexes that are encoded in the mitochondria. We now present the transcription content of this region: Multiple splicing variants of the genes protein phosphatase 1B (formerly 2C) magnesium-dependent, beta isoform (PPM1B), SLC3A1, and KIAA0436 (approved gene symbol PREPL) were identified and their patterns of expression analyzed. The spliced variants are predicted to have additional functions compared to the known variants and their patterns of expression fit the tissues affected by the syndrome. The first exon of an additional gene (C2orf34) is encoded in the deleted region and the gene is not expressed in the patients. In addition several transcripts with very short open reading frames are also encoded in the deletion. The identification of all transcripts encoded in the region deleted in the patients is the first step in the study of the genotype-phenotype correlation of the 2p21 patients.

Alternative Splicing↗

PubMed2005

Treatment of X-linked childhood cerebral adrenoleukodystrophy by the use of an allogeneic stem cell transplantation with reduced intensity conditioning regimen.

Childhood cerebral form of X-linked adrenoleukodystrophy (X-ALD) is a rapidly progressive demyelinating condition affecting the cerebral white matter, which rapidly leads to total disability and death. The only known curative treatment for this condition is allogeneic hematopoietic stem cell transplantation (HSCT). Procedure-related toxicity is assumed to be the cause of death of patients with X-ALD. Three cases of ALD successfully transplanted with the use of non-myeloablative fludarabine based conditioning are described. Patients showed smooth peri-bone marrow transplantation course with fast and stable engraftment. In the 3- to 5 yr follow-up period, patients showed no deterioration in their clinical and neurological condition. Levels of very long chain fatty acids were very variable and had a tendency to decrease in at least one of the three patients. In another patient, an improvement of magnetic resonance imaging changes was found. Non-myeloablative HSCT should be considered as an early treatment for X-ALD.

Adrenoleukodystrophy↗

PubMed2005

Decreased first phase insulin response in children with congenital insensitivity to pain with anhidrosis.

Nerve growth factor (NGF) and its receptor tyrosine kinase A (TrkA) participate in endocrine pancreas morphogenesis and insulin secretion in vitro. Mutations in the TrkA gene cause the syndrome of congenital insensitivity to pain with anhydrosis (CIPA). We hypothesized that CIPA may represent a natural model for impaired NGF effect on insulin secretion in humans. Glucose challenge tests were performed in seven children with CIPA. We calculated the first phase insulin response (FPIR), the second phase insulin response (SPIR) and glucose disposal rate. FPIR was impaired in four and borderline in two patients. SPIR and glucose disposal rate were within the normal range. Oral glucose tolerance test was normal in all patients. Low FPIR in. CIPA suggests for the first time that the NGF-TrkA pathway may play a role in insulin secretion in response to glucose challenge in humans. Additional studies on the clinical significance of NGF-TrkA effects on insulin secretion are required.

Adolescent↗

PubMed2004

Childhood obesity.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Child↗

PubMed2004

X-linked spondyloepiphyseal dysplasia tarda: a novel SEDL mutation in a Jewish Ashkenazi family and clinical intervention considerations.

X-linked spondyloepiphyseal dysplasia tarda (SEDT; MIM 313400) is a late onset progressive skeletal disorder, which manifests in childhood and is characterized by disproportionate short stature with a short trunk, barrel chest and absence of systemic complications. We found a single-nucleotide deletion in position 613 of the SEDL gene in two brothers of Jewish-Ashkenazi ancestry afflicted with the disease. This is the first description of SEDL mutations in a Jewish family. Following this finding, an eight-month old second cousin of the brothers, who had yet no clinical or radiological signs of the disease, was found to carry the deletion. Another relative, 24-years old, carrying the same mutation was 1.61 m tall and had only minimal signs of the disease. These findings raise the dilemma of pre-natal counseling in SEDL and the need for exploring means of early intervention in pre-symptomatic cases.

Base Sequence↗

PubMed2004

Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation.

The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded. The synthesis of these 13 proteins requires many nuclear-encoded proteins that participate in mitochondrial DNA replication, transcript production, and a distinctive mitochondrial translation apparatus. We report a patient with agenesis of corpus callosum, dysmorphism, and fatal neonatal lactic acidosis with markedly decreased complex I and IV activity in muscle and liver and a generalized mitochondrial translation defect identified in pulse-label experiments. The defect was associated with marked reduction of the 12S rRNA transcript level likely attributed to a nonsense mutation in the MRPS16 gene. A new group of mitochondrial respiratory chain disorders is proposed, resulting from mutations in nuclear encoded components of the mitochondrial translation apparatus.

Alkyl and Aryl Transferases↗

PubMed2004

Thyroglossal duct carcinoma in children: case presentation and review of the literature.

Carcinoma within the thyroglossal duct (TGDCa) is a very rare pediatric tumor. This report presents the case of a 15-year-old girl with TGDCa, reviews the previously published pediatric cases of this tumor, and provides diagnostic and therapeutic considerations in TGDCa in children. Twenty one cases of TGDCa have been reported, 12 of them in females. Mean age at presentation was approximately 13 years for females and approximately 12 years for males. The duration of a midcervical mass prior to the diagnosis of TGDCa varied from 3 weeks to 8 years. The size of the neck mass at presentation averaged 2 cm-4 cm. All masses were asymptomatic, and the diagnosis of TGDCa was incidental following surgery. All pediatric cases of TGDCa reported thus far were of the papillary type, except for 3 patients who presented with a mixed papillary-follicular carcinoma. Capsular invasion was detected in 10 (45%) patients. Local invasive disease was found in 5 (23%) patients, but all removed thyroid glands (12) were free of carcinoma. One patient had lung metastases. Thyroidectomy with subsequent radioiodine ablation was the treatment of choice in the majority of the cases. The reported prognosis for TGDCa in children was favorable, with only one reported death.

Adolescent↗

PubMed2004

Hypoparathyroidism-retardation-Dysmorphism (HRD) syndrome--a review.

Hypoparathyroidism, retardation, and dysmorphism (HRD) is a newly recognized genetic syndrome, described in patients of Arab origin. The syndrome consists of permanent congenital hypoparathyroidism, severe prenatal and postnatal growth retardation, and profound global developmental delay. The patients are susceptible to severe infections including life-threatening pneumococcal infections especially during infancy. The main dysmorphic features are microcephaly, deep-set eyes or microphthalmia, ear abnormalities, depressed nasal bridge, thin upper lip, hooked small nose, micrognathia, and small hands and feet. A single 12-bp deletion (del52-55) in the second coding exon of the tubulin cofactor E (TCFE) gene, located on the long arm of chromosome 1, is the cause of HRD among Arab patients. Early recognition and therapy of hypocalcemia is important as is daily antibiotic prophylaxis against pneumococcal infections.

Abnormalities, Multiple↗

PubMed2003

Automated identification of RNA conformational motifs: theory and application to the HM LSU 23S rRNA.

We develop novel methods for recognizing and cataloging conformational states of RNA, and for discovering statistical rules governing those states. We focus on the conformation of the large ribosomal subunit from Haloarcula marismortui. The two approaches described here involve torsion matching and binning. Torsion matching is a pattern-recognition code which finds structural repetitions. Binning is a classification technique based on distributional models of the data. In comparing the results of the two methods we have tested the hypothesis that the conformation of a very large complex RNA molecule can be described accurately by a limited number of discrete conformational states. We identify and eliminate extraneous and redundant information without losing accuracy. We conclude, as expected, that four of the torsion angles contain the overwhelming bulk of the structural information. That information is not significantly compromised by binning the continuous torsional information into a limited number of discrete values. The correspondence between torsion matching and binning is 99% (per residue). Binning, however, does have several advantages. In particular, we demonstrate that the conformation of a large complex RNA molecule can be represented by a small alphabet. In addition, the binning method lends itself to a natural graphical representation using trees.

Automation↗

PubMed2003

Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA.

Leigh syndrome (LS) is a mitochondrial encephalopathy that is caused by a mutation either in the mitochondrial DNA (mtDNA) or in the nuclear encoded genes of the mitochondrial proteins. Prenatal diagnosis of defects in the mtDNA is usually problematic because of mtDNA heteroplasmy and tissue specificity. However, the mutations T8993 G/C in the ATP synthase subunit 6 gene of the mtDNA show a more even tissue distribution and do not appear to change significantly over time. There are only few reports of prenatal diagnosis of the T8993G mutation in Leigh disease. Here we describe the first prenatal genetic testing of T8993C in a fetus of a mother whose previous child had died of Leigh syndrome due to the T8993C mutation. Mutant load in the chorionic villus sample (CVS) as well as in amniocytes was undetectable, thus predicting a very high likelihood of an unaffected outcome, indicative of a healthy baby. The diagnosis was confirmed after birth. Gathering data on the prenatal diagnosis of mtDNA mutations is of great importance so that prenatal diagnosis of both T8993G and T8993C mutations can be offered routinely.

Adult↗

PubMed2003

Retinol concentration in maternal and cord serum: its relation to birth weight in healthy mother-infant pairs.

BACKGROUND: Vitamin A is an essential micronutrient for the development and growth of the fetus. The objective of this study was to identify a possible association between low serum retinol and birth weight in healthy mother-infant pairs in Southern Israel. A secondary objective was to examine ethnic differences in maternal and cord serum retinol. METHODS: Serum retinol was measured at delivery from pairs of healthy mothers and healthy mature newborns. RESULTS: Of the 313 mother-infant pairs studied, 56% were Jews and 44% Bedouins. The proportion of infants with birth weight of 2500-2999 g was greater among mothers with lower serum retinol (<0.7 micromol/l) compared to mothers with normal serum retinol (> or =0.7 micromol/l) (p<0.001). Cord retinol <0.7 micromol/l was more frequent in infants with birth weight 2500-2990 g compared to infants with birth weight > or =3000 g (p=0.006). Using a split model and stepwise multiple regression analysis, infant's birth weight was significantly influenced by cord retinol concentration in infants born to mothers with low serum retinol; gestational age and cord retinol alone explained 27% of the variability of birth weight in this group. A higher proportion of Bedouin than Jewish infants had serum retinol <0.7 and <0.35 micromol/l (both p<0.001). CONCLUSION: Low cord and maternal serum retinol may reflect poor vitamin A status of the newborn and the mother, which in turn may affect fetal growth.

Adult↗

PubMed2002

Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome.

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

Amino Acid Sequence↗

PubMed2002

Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-Ter deletion.

An 8.5-year-old girl with a pathogenic mutation (515insC) of the ATP-binding cassette, subfamily D, member 1 gene (ABCD1) on her maternally derived X chromosome showed clinical, biochemical, and magnetic resonance imaging abnormalities similar to those in affected males. Cytogenetic studies led to the surprise finding of a de novo deletion of Xq27 on the paternally derived X chromosome. A bone marrow transplant had an apparently favorable effect. Cytogenetic studies should be performed in all severely symptomatic X-linked adrenoleukodystrophy heterozygotes.

Adrenoleukodystrophy↗

PubMedDate not supplied

Statistical analysis of RNA backbone.

Local conformation is an important determinant of RNA catalysis and binding. The analysis of RNA conformation is particularly difficult due to the large number of degrees of freedom (torsion angles) per residue. Proteins, by comparison, have many fewer degrees of freedom per residue. In this work, we use and extend classical tools from statistics and signal processing to search for clusters in RNA conformational space. Results are reported both for scalar analysis, where each torsion angle is separately studied, and for vectorial analysis, where several angles are simultaneously clustered. Adapting techniques from vector quantization and clustering to the RNA structure, we find torsion angle clusters and RNA conformational motifs. We validate the technique using well-known conformational motifs, showing that the simultaneous study of the total torsion angle space leads to results consistent with known motifs reported in the literature and also to the finding of new ones.

Base Sequence↗