Behar D.M.,Raphael Recanati Genetics Institute |
Behar D.M.,Rambam Medical Center |
Davidov B.,Raphael Recanati Genetics Institute |
Brownstein Z.,Tel Aviv University |
And 4 more authors.
Genetic Testing and Molecular Biomarkers | Year: 2014
Dramatic progress has been made in our understanding of the highly heterogeneous molecular bases of sensorineural hearing loss (SNHL), demonstrating the involvement of all known forms of inheritance and a plethora of genes tangled in various molecular pathways. This progress permits the provision of prognostic information and genetic counseling for affected families, which might, nevertheless, be exceedingly challenging. Here, we describe an intricate genetic investigation that included Sanger-type sequencing, BeadArray technology, and next-generation sequencing to resolve a complex case involving one family presenting syndromic and nonsyndromic SNHL phenotypes in two consecutive generations. We demonstrate and conclude that such an effort can be completed during pregnancy. © Copyright 2014, Mary Ann Liebert, Inc. 2014.
Yang Y.J.,Boston Childrens Hospital |
Yang Y.J.,The Broad Institute of MIT and Harvard |
Yang Y.J.,Harvard University |
Yang Y.J.,Howard Hughes Medical Institute |
And 40 more authors.
Cell | Year: 2012
Microcephaly is a neurodevelopmental disorder causing significantly reduced cerebral cortex size. Many known microcephaly gene products localize to centrosomes, regulating cell fate and proliferation. Here, we identify and characterize a nuclear zinc finger protein, ZNF335/NIF-1, as a causative gene for severe microcephaly, small somatic size, and neonatal death. Znf335 null mice are embryonically lethal, and conditional knockout leads to severely reduced cortical size. RNA-interference and postmortem human studies show that ZNF335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. ZNF335 is a component of a vertebrate-specific, trithorax H3K4-methylation complex, directly regulating REST/NRSF, a master regulator of neural gene expression and cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF and provide the first direct genetic evidence that this pathway regulates human neurogenesis and neuronal differentiation. © 2012 Elsevier Inc.
Borck G.,University of Ulm |
Shin B.-S.,U.S. National Institutes of Health |
Stiller B.,University of Ulm |
Mimouni-Bloch A.,Loewenstein Rehabilitation Hospital |
And 23 more authors.
Molecular Cell | Year: 2012
Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the yeast eIF2γ mutation impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpressing eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function. © 2012 Elsevier Inc.
Eytan O.,Tel Aviv Sourasky Medical Center |
Eytan O.,Tel Aviv University |
Sarig O.,Tel Aviv Sourasky Medical Center |
Israeli S.,Tel Aviv Sourasky Medical Center |
And 6 more authors.
Clinical and Experimental Dermatology | Year: 2014
Background Palmoplantar keratoderma punctata (PPKP) is a heterogeneous group of disorders characterized by hyperkeratotic papules occurring over the palms and soles during adolescence. PPKP type 1, also known as PPKP Buschke-Fischer-Brauer type, was recently found to result from mutations in the AAGAB gene, encoding the p34 protein. PPKP type 1 is usually not associated with extracutaneous features. Aim To investigate a large family in which PPKP1 was present in association with congenital dysplasia of the hip (CDH). Methods A combination of direct sequencing of candidate genes and reverse-transcription PCR was used to identify the molecular basis underlying the clinical features displayed by the patients. Results Direct sequencing showed a novel intronic mutation in AAGAB, which was found to cosegregate with PPKP and CDH throughout the family. The mutation was found to result in aberrant RNA splicing, leading to exon 4 skipping. Conclusions This observation suggests either the existence of a CDH-associated gene in the vicinity of AAGAB, or a hitherto unrecognized role for p34 during skeletal development. © 2013 British Association of Dermatologists.
Straussberg R.,Tel Aviv University |
Goldberg-Stern H.,Tel Aviv University |
Tzur S.,Molecular Medicine Laboratory |
Behar D.M.,Raphael Recanati Genetics Institute |
And 8 more authors.
European Journal of Paediatric Neurology | Year: 2015
We describe two siblings born to consanguineous Arab-Muslim parents who presented in early infancy with myoclonic seizures, hypertonia and contractures, arrested head growth, inability to swallow, and bouts of apnea-bradycardia, culminating in cardiac arrest and death. Whole-genome sequencing yielded a c.1173delG mutation in the BRAT1 gene. Three recent reports identified mutations in the same gene in three infants from three Amish sibships, one Mexican neonate and two Japanese siblings with similar clinical manifestations. The authors speculated that the destabilization of the encoded protein may underlie the catastrophic epilepsy and corticobasal neuronal degeneration. We suggest that BRAT1 be added to the growing list of genes that are related to severe early infantile (neonatal) epileptic encephalopathy. © 2014 European Paediatric Neurology Society.
Basel-Vanagaite L.,Raphael Recanati Genetics Institute |
Basel-Vanagaite L.,Tel Aviv University
American Journal of Medical Genetics, Part A | Year: 2010
Weaver syndrome comprises pre- and postnatal overgrowth, accelerated osseous maturation, characteristic craniofacial appearance and developmental delay; it is a generally sporadic disorder, although autosomal dominant inheritance has been reported. Some of the manifestations characterize both the Weaver and Sotos syndrome, and distinction between the two is mainly by clinical examination and molecular testing. Most of the patients with Sotos syndrome have NSD1 gene deletions or mutations; however, the molecular basis of most of the Weaver syndrome patients is unknown. Patients with overgrowth syndromes have an increased frequency of tumors; the risk in Sotos syndrome patients has been estimated to be about 2-3%, with leukemia and lymphoma accounting for 44% of the malignancies. We report on a 41/2-year-old girl with typical Weaver syndrome who developed acute lymphoblastic leukemia, an association not previously reported, and review the reported cases of Weaver syndrome patients who developed malignancies. Malignancy inWeaver syndrome has been reported previously in six patients. While searching the literature for all reported cases with Weaver syndrome and counting the cases with malignancy, we found that the frequency of tumors or hematologic malignancy was 10.9%. This is likely to be an overestimate, biased by failure to report cases without tumors and by over-reporting cases with this rare association. While the presence of acute lymphoblastic leukemia in our patient might be incidental, we cannot exclude a possible causative association between Weaver syndrome and hematologic malignancy. © 2010 Wiley-Liss, Inc.
Basel-Vanagaite L.,Raphael Recanati Genetics Institute |
Dobyns W.B.,University of Chicago
Pediatric Neurology | Year: 2010
Microcephaly may be present at birth or develop postnatally. Classification according to the genetic cause cannot always predict the severity of the clinical course. The aim of this research was to group a large cohort of patients with primary microcephaly into more discrete subtypes, to optimize assessment of the patients based on their clinical and brain imaging findings. Medical records and brain images were reviewed for 4442 patients with brain malformations diagnosed and treated over 24 years and identified 247 patients classified as having microcephaly with simplified gyri alone or in association with additional brain abnormalities. For each case, clinical records were retrospectively reviewed for consanguinity, positive family history, sex, associated anomalies, and cranial magnetic resonance imaging. A subset (n = 12) of representative patients with the most complete available data was studied in greater detail, to define the most common subtypes and clinical presentations. Overall, four relatively common brain imaging presentations were identified, involving abnormalities in the gyral pattern, extra-axial space, and small size of the brainstem and cerebellum. Classifying patients with microcephaly according to brain imaging findings could enable more accurate counseling of the families with regard to prognosis.
PubMed | Raphael Recanati Genetics Institute
Type: Journal Article | Journal: Journal of lipid research | Year: 2014
Congenital pancreatic lipase (PNLIP) deficiency is a rare monoenzymatic form of exocrine pancreatic failure characterized by decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. While considered to be an autosomal recessive state affecting a few dozens of individuals world-wide and involving the PNLIP gene, no causative mutations for this phenotype were so far reported. Here, we report the identification of the homozygote missense mutation, Thr221Met [c.662C>T], in two brothers from a consanguineous family of Arab ancestry. The observed genotypes among the family members were concordant with an autosomal recessive mode of inheritance but moreover a clear segregation between the genotype state and the serum PNLIP activity was evident. Based on biophysical computational tools, we suggest the mutation disrupts the proteins stability and impairs its normal function. Although the role of PNLIP is well established, our observations provide genetic evidence that PNLIP mutations are causative for this phenotype.
PubMed | Molecular Medicine Laboratory, Ariel University, Tel Aviv University and Raphael Recanati Genetics Institute
Type: Case Reports | Journal: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | Year: 2015
We describe two siblings born to consanguineous Arab-Muslim parents who presented in earlyinfancy with myoclonic seizures, hypertonia and contractures, arrested head growth, inability to swallow, and bouts of apnea-bradycardia, culminating in cardiac arrest and death. Whole-genome sequencing yielded a c.1173delG mutation in the BRAT1 gene. Three recent reports identified mutations in the same gene in three infants from three Amish sibships, one Mexican neonate and two Japanese siblings with similar clinical manifestations. The authors speculated that the destabilization of the encoded protein may underlie the catastrophic epilepsy and corticobasal neuronal degeneration. We suggest that BRAT1 be added to the growing list of genes that are related to severe early infantile (neonatal) epileptic encephalopathy.
PubMed | Ariel University, Tel Aviv University and Raphael Recanati Genetics Institute
Type: | Journal: Gene | Year: 2017
In this study, we report a family with X-linked recessive syndrome caused by mutated AMMECR1 and characterized by elliptocytosis with or without anemia, midface hypoplasia, proportionate short stature and hearing loss. Recently, mutations in AMMECR1 were reported in two maternal half-brothers, presenting with nephrocalcinosis, midface hypoplasia and, in one of the siblings, deafness and elliptocytosis. AMMECR1 gene is localized in the critical region of contiguous deletion syndrome on Xq22.3 implicated in Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME complex). Interestingly, alternative splicing of exon 2, the same exon harboring the truncating mutation, was observed in the proband and in his unaffected mother. Alternative splicing of this exon is predicted to lead to an in-frame deletion. We provide further evidence that mutated AMMECR1 gene is responsible for this clinically recognizable X-linked condition with variable expressivity.