Eyal Reinstein

Eyal Reinstein

MD PhD

About

53
Publications
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2,873
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Publications

Publications (53)
Article
Full-text available
Multiple clinical trials of allogeneic T cell therapy use site-specific nucleases to disrupt T cell receptor (TCR) and other genes1–6. In this study, using single-cell RNA sequencing, we investigated genome editing outcomes in primary human T cells transfected with CRISPR–Cas9 and guide RNAs targeting genes for TCR chains and programmed cell death...
Article
Mutations in the BRCA1 and BRCA2 genes increase the risk for various cancers including breast, ovarian, prostate, pancreas and melanoma. Identifying BRCA1/2 mutation carriers enables risk assessment, surveillance, early detection and risk reduction. In certain Israeli sub-populations recurring and founder mutations have been identified and for thes...
Article
Pathogenic variants in ZBTB18 gene have been described only postnatally with a variable phenotypic spectrum that includes intellectual disability, microcephaly, hypotonia, poor growth, corpus callosum abnormalities, seizures, and dysmorphic facial features. These features overlap with the phenotype of 1q43-q44 deletion syndrome (OMIM #612337). Ther...
Preprint
Full-text available
Multiple ongoing clinical trials use site-specific nucleases to disrupt T cell receptor (TCR) genes in order to allow for allogeneic T cell therapy. In particular, the first U.S. clinical trial using CRISPR-Cas9 entailed the targeted disruption of the TCR chains and programmed cell death protein 1 (PDCD1) in T cells of refractory cancer patients. H...
Article
Background: Chromosomal microarray analysis (CMA) is preferred for genetic work-up when fetal malformations are detected prenatally. Objectives: To assess the detection rate of CMA after pregnancy termination due to abnormal ultrasound findings. Methods: CMA was successfully performed in 71 pregnancies using fetal DNA (mainly from skin) or placenta...
Article
The purpose of this study was to analyse the association between free beta hCG (fβhCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fβhCG and second trimester intact hCG (ih...
Article
Introduction: Whole exome sequencing is a diagnostic approach for the identification of molecular etiology in patients with suspected monogenic diseases. In this article we report on our experience with whole-exome sequencing (WES) of DNA samples taken from patients referred for genetic evaluation due to suspected undiagnosed genetic conditions....
Article
BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) is considered a sporadic disease occurring in approximate to 22.5 cases per 10 000 in the general population. We define the prevalence and characteristics of familial AVNRT among patients who underwent radiofrequency ablation. METHODS AND RESULTS: Ablation reports of all patients with...
Article
The Ehlers–Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for cli...
Article
Arthrogryposis multiplex congenita (AMC) is heterogeneous group of disorders characterized by non-progressive joint contractures from birth that involve more than one part of the body. There are various etiologies for AMC including genetic and environmental depends on the specific type, however, for most types, the cause is not fully understood. We...
Article
Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, a...
Article
Background: Atrioventricular nodal reentrant tachycardia (AVNRT) is considered a sporadic disease occurring in ≈22.5 cases per 10 000 in the general population. We define the prevalence and characteristics of familial AVNRT among patients who underwent radiofrequency ablation. Methods and results: Ablation reports of all patients with familial A...
Article
Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 i...
Article
Full-text available
Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 i...
Article
In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unrepor...
Article
Pathogenic variants in the NONO gene have been most recently implicated in X-linked intellectual disability syndrome. This observation has been supported by studies of NONO-deficient mice showing that NONO has an important role in regulating inhibitory synaptic activity. Thus far, the phenotypic spectrum of affected patients remains limited. We app...
Article
Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autos...
Article
Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the...
Article
Objective: To evaluate the association between aberrant right subclavian artery (ARSA), with or without additional risk factors for aneuploidy or ultrasound abnormality, and results of chromosomal microarray analysis (CMA). Methods: This was a multicenter study of fetuses diagnosed with ARSA that underwent genetic analysis by CMA, all samples be...
Article
The increasing use of chromosomal microarray studies in patients with intellectual disability has led to the description of new microdeletion and microduplication syndromes. We report terminal microdeletions in 13q34 chromosome region in 5 adult patients of two unrelated families. Patients harboring 13q34 microdeletions display common clinical feat...
Article
Whole-genome and whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. The term newborn screening refers to public health programs designed to screen newborns for various treatable metabolic conditions, by measuring levels of circulating blood metabolites. The availability and significant decrease in...
Article
The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in childre...
Article
We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ-containing protein implicated in regulation of the Wnt/β-catenin signaling pathway, as the causative mutation. The mu...
Article
The presence of cardiovascular abnormalities in patients with spontaneous cerebrospinal fluid (CSF) leaks are not well-documented in the literature, as cardiovascular evaluation is not generally pursued if a patient does not exhibit additional clinical features suggesting an inherited connective tissue disorder. We aimed to assess this association,...
Article
Importance Marfan syndrome (MFS) is a dominantly inherited disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). The most common skin finding in MFS is striae distensae. Particular individuals referred for suspected MFS who do not completely fulfill the MFS diagnostic criteria are classified as having a MASS phenotype....
Article
The criteria for diagnosing and distinguishing between Weill-Marchesani syndrome (WMS) and geleophysic dysplasia (GD) are inexact and often overlap. We report the clinical findings and evolving phenotype for a period of 18 years in a patient whose diagnosis, and distinguishing characteristics, transformed from GD to WMS. Molecular testing demonstra...
Article
Arterial complications are common in vascular type Ehlers-Danlos syndrome (EDS), accounting for 66% of first complications. Several cases in the literature have documented acute compartment syndrome (ACS) following vascular rupture in vascular type EDS. Other disorders of connective tissue have also demonstrated vascular fragility, leading to arter...
Article
The spondylometaphyseal dysplasias (SMDs) is a large heterogeneous group of skeletal dysplasias characterized radiologically by vertebral abnormalities and metaphyseal changes in the tubular bones (Maroteaux and Spranger 1991; Taybi and Lachman 2007; Warman et al. 2011; Rimoin et al. 2007; Marik et al. 2012). There are five well-described distinct...
Article
Full-text available
Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associa...
Article
We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissu...
Article
Periventricular heterotopia (PH) is a disorder of neuronal migration during fetal development that is characterized by morphologically normal neurons being located in an anatomically abnormal position in the mature brain. PH is usually diagnosed in patients presenting with a seizure disorder, when neuroimaging demonstrates the ectopically placed no...
Article
Gastrointestinal complications are common in patients with Ehlers-Danlos syndrome, affecting up to 50% of individuals depending on the subtype. The spectrum of gastrointestinal manifestations is broad and ranges from life threatening spontaneous perforation of the visceral organs to a more benign functional symptoms. Here we describe the clinical a...
Article
Ehlers-Danlos syndrome (EDS) type VIII (periodontitis type) is a distinct form of EDS characterized by periodontal disease leading to precocious dental loss and a spectrum of joint and skin manifestations. EDS type VIII is transmitted in an autosomal dominant pattern; however, the mutated gene has not been identified. There are insufficient data on...
Article
Klaassens M, Reinstein E, Hilhorst-Hofstee Y, Schrander JJP, Malfait F, Staal H, ten Have LC, Blaauw J, Roggeveen HCJ, Krakow D, De Paepe A, van Steensel MAM, Pals G, Graham JM Jr, Schrander-Stumpel CTRM. Ehlers–Danlos arthrochalasia types (VIIA–B) – expanding the phenotype: from prenatal life through adulthood. The Ehlers–Danlos syndromes (EDS) fo...
Article
The periodontitis type of Ehlers-Danlos syndrome (EDS type VIII) is distinguished from other subtypes of EDS by severe periodontitis leading to premature loss of permanent teeth. A limited number of patients and pedigrees with this condition have been described. We report a four-generation EDS VIII kindred with a phenotype of joint hypermobility, n...
Article
Allergy and autoimmunity are complex inflammatory processes caused by dysregulation of the immune system. There are select situations in which allergy and autoimmunity coexist pathologically. Traditionally considered unrelated, recent evidence suggests unexpected roles for allergic mediators in several autoimmune diseases. This review presents upda...
Article
Thrombosis is a frequent complication of cancer that is a substantial cause of morbidity and mortality. The association of antiphospholipid antibodies (aPL) and cancer has been under investigation for several years. Recent findings suggest an increased prevalence of certain cancers in aPL-positive patients; thus, an intensive search for an occult m...
Article
Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several indep...
Article
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins; but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several in...
Article
The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins that are degraded by the system are those involved in the control of inflammation, cell cycle regulation, and gene expression. With so many important cellular pathways affected, derangements in the ubiquitin system have bee...
Article
The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins degraded by the system are those involved in the control of inflammation, cell cycle regulation and gene expression. With numerous important cellular pathways affected, derangements in the ubiquitin system were shown to res...
Article
Full-text available
Many short-lived nuclear proteins are targeted for degradation by the ubiquitin-proteasome pathway. The role of the nucleus in regulating the turnover of these proteins is not well defined, although many components of the ubiquitin-proteasome system are localized in the nucleus. We have used nucleoplasm from highly purified HeLa nuclei to examine t...
Article
The E7 oncoprotein of the high risk human papillomavirus type 16 (HPV-16), which is etiologically associated with uterine cervical cancer, is a potent immortalizing and transforming agent. It probably exerts its oncogenic functions by interacting and altering the normal activity of cell cycle control proteins such as p21WAF1, p27KIP1 and pRb, trans...
Article
Mutant ataxin-1, the expanded polyglutamine protein causing spinocerebellar ataxia type 1 (SCA1), aggregates in ubiquitin-positive nuclear inclusions (NI) that alter proteasome distribution in affected SCA1 patient neurons. Here, we observed that ataxin-1 is degraded by the ubiquitin-proteasome pathway. While ataxin-1 [2Q] and mutant ataxin-1 [92Q]...
Article
Full-text available
We have previously shown that the degradation of c-myc and N-myc in vitro is mediated by the ubiquitin system. However, the role of the system in targeting the myc proteins in vivo and the identity of the conjugating enzymes and possible ancillary proteins involved has remained obscure. Here we report that the degradation of the myc proteins in cel...
Article
Full-text available
We have previously shown that the degradation of c-myc and N-myc in vitro is mediated by the ubiquitin system. However, the role of the system in targeting the myc proteins in vivo and the identity of the conjugating enzymes and possible ancillary proteins involved has remained obscure. Here we report that the degradation of the myc proteins in cel...

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