22 results on '"Abidi FE"'
Search Results
2. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.
- Author
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Hiatt SM, Trajkova S, Sebastiano MR, Partridge EC, Abidi FE, Anderson A, Ansar M, Antonarakis SE, Azadi A, Bachmann-Gagescu R, Bartuli A, Benech C, Berkowitz JL, Betti MJ, Brusco A, Cannon A, Caron G, Chen Y, Cochran ME, Coleman TF, Crenshaw MM, Cuisset L, Curry CJ, Darvish H, Demirdas S, Descartes M, Douglas J, Dyment DA, Elloumi HZ, Ermondi G, Faoucher M, Farrow EG, Felker SA, Fisher H, Hurst ACE, Joset P, Kelly MA, Kmoch S, Leadem BR, Lyons MJ, Macchiaiolo M, Magner M, Mandrile G, Mattioli F, McEown M, Meadows SK, Medne L, Meeks NJL, Montgomery S, Napier MP, Natowicz M, Newberry KM, Niceta M, Noskova L, Nowak CB, Noyes AG, Osmond M, Prijoles EJ, Pugh J, Pullano V, Quélin C, Rahimi-Aliabadi S, Rauch A, Redon S, Reymond A, Schwager CR, Sellars EA, Scheuerle AE, Shukarova-Angelovska E, Skraban C, Stolerman E, Sullivan BR, Tartaglia M, Thiffault I, Uguen K, Umaña LA, van Bever Y, van der Crabben SN, van Slegtenhorst MA, Waisfisz Q, Washington C, Rodan LH, Myers RM, and Cooper GM
- Subjects
- Humans, Male, Female, Phenotype, Gene Expression Regulation, Face, Nuclear Proteins genetics, Histone Demethylases genetics, Neurodevelopmental Disorders genetics, Intellectual Disability genetics, Nervous System Malformations
- Abstract
Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene., Competing Interests: Declaration of interests J.L.B., Y.C., B.R.L., M.P.N., A.G.N., and H.Z.E. are employees of GeneDx, LLC. S.E.A. is a cofounder and CEO of MediGenome, the Swiss Institute of Genomic Medicine. All other authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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3. Angelman syndrome with a 15q11q13 deletion in a mother and daughter.
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Bell S, Butler KM, Drazba KT, Lynch J, Abidi FE, DuPont B, and Stevenson RE
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- Chromosome Deletion, Chromosomes, Human, Pair 15 genetics, Female, Humans, Mothers, Nuclear Family, Angelman Syndrome diagnosis, Angelman Syndrome genetics
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- 2022
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4. Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C.
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Grafodatskaya D, Chung BH, Butcher DT, Turinsky AL, Goodman SJ, Choufani S, Chen YA, Lou Y, Zhao C, Rajendram R, Abidi FE, Skinner C, Stavropoulos J, Bondy CA, Hamilton J, Wodak S, Scherer SW, Schwartz CE, and Weksberg R
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- Blood Cell Count, Brain metabolism, Calcium-Binding Proteins blood, Calcium-Binding Proteins genetics, Chromosomes, Human, X, Chromosomes, Human, Y, CpG Islands, Epigenesis, Genetic, F-Box Proteins blood, F-Box Proteins genetics, Female, Histone Demethylases, Histones genetics, Histones metabolism, Humans, Male, Mutation, Polycomb-Group Proteins blood, Polycomb-Group Proteins genetics, Promoter Regions, Genetic, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases blood, Ubiquitin-Protein Ligases genetics, DNA Methylation, Oxidoreductases, N-Demethylating genetics
- Abstract
Background: A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment., Results: Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP., Conclusions: We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.
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- 2013
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5. CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.
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Hackett A, Tarpey PS, Licata A, Cox J, Whibley A, Boyle J, Rogers C, Grigg J, Partington M, Stevenson RE, Tolmie J, Yates JR, Turner G, Wilson M, Futreal AP, Corbett M, Shaw M, Gecz J, Raymond FL, Stratton MR, Schwartz CE, and Abidi FE
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- Amino Acid Sequence, Base Sequence, Case-Control Studies, Chromosomes, Human, X genetics, Cohort Studies, DNA Mutational Analysis, Facies, Family, Female, Genetic Diseases, X-Linked genetics, Guanylate Kinases chemistry, Humans, Male, Mental Retardation, X-Linked complications, Microcephaly complications, Microcephaly genetics, Middle Aged, Molecular Sequence Data, Nystagmus, Congenital enzymology, Pedigree, Phenotype, X Chromosome Inactivation genetics, Genetic Diseases, X-Linked complications, Guanylate Kinases genetics, Mental Retardation, X-Linked enzymology, Mental Retardation, X-Linked genetics, Mutation genetics, Nystagmus, Congenital complications, Nystagmus, Congenital genetics
- Abstract
Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
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- 2010
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6. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.
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Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A, Stephens P, Blow M, Greenman C, Xue Y, Tyler-Smith C, Thompson D, Gray K, Andrews J, Barthorpe S, Buck G, Cole J, Dunmore R, Jones D, Maddison M, Mironenko T, Turner R, Turrell K, Varian J, West S, Widaa S, Wray P, Teague J, Butler A, Jenkinson A, Jia M, Richardson D, Shepherd R, Wooster R, Tejada MI, Martinez F, Carvill G, Goliath R, de Brouwer AP, van Bokhoven H, Van Esch H, Chelly J, Raynaud M, Ropers HH, Abidi FE, Srivastava AK, Cox J, Luo Y, Mallya U, Moon J, Parnau J, Mohammed S, Tolmie JL, Shoubridge C, Corbett M, Gardner A, Haan E, Rujirabanjerd S, Shaw M, Vandeleur L, Fullston T, Easton DF, Boyle J, Partington M, Hackett A, Field M, Skinner C, Stevenson RE, Bobrow M, Turner G, Schwartz CE, Gecz J, Raymond FL, Futreal PA, and Stratton MR
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- Chromosome Mapping, Female, Genetic Variation, Humans, Male, Pedigree, Chromosomes, Human, X genetics, Exons genetics, Mental Retardation, X-Linked genetics, Sequence Analysis, DNA methods
- Abstract
Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
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- 2009
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7. ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.
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Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, Schwartz CE, and Sherr EH
- Abstract
We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome. We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others. Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient.
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- 2009
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8. Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia.
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Abidi FE, Holloway L, Moore CA, Weaver DD, Simensen RJ, Stevenson RE, Rogers RC, and Schwartz CE
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- Adolescent, Adult, Amino Acid Sequence, Cohort Studies, DNA Mutational Analysis, Histone Demethylases, Humans, Male, Middle Aged, Pedigree, Young Adult, Growth Disorders genetics, Mental Retardation, X-Linked genetics, Mutation, Oxidoreductases, N-Demethylating genetics, Reflex, Abnormal genetics
- Abstract
Background: Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively more common causes of XLMR with a frequency of approximately 3% in males with proven or probable XLMR. The JARID1C protein functions as a histone 3 lysine 4 (H3K4) demethylase and is involved in the demethylation of H3K4me3 and H3K4me2., Methods: Mutation analysis of the JARID1C gene was conducted in the following cohorts: probands from 23 XLMR families linked to Xp11.2, 92 males with mental retardation and short stature, and 172 probands from small XLMR families with no linkage information., Results: Four novel mutations consisting of two missense mutations, p.A77T and p.V504M, and two frame shift mutations, p.E468fsX2 and p.R1481fsX9, were identified in males with mental retardation. Two of the mutations, p.V504M and p.E468fsX2, are located in the JmjC domain of the JARID1C gene where no previous mutations have been reported. Additional studies showed that the missense mutation, p.V504M, was a de novo event on the grandpaternal X chromosome of the family. Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%). The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%)., Conclusion: Based on the clinical observations, male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene.
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- 2008
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9. ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.
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Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, Schwartz CE, and Sherr EH
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- Adolescent, Arousal physiology, Chromosome Breakage, Chromosomes, Human, X genetics, Female, Humans, In Situ Hybridization, Fluorescence, Mental Retardation, X-Linked psychology, Rho Guanine Nucleotide Exchange Factors, Arousal genetics, Guanine Nucleotide Exchange Factors genetics, Mental Retardation, X-Linked genetics
- Abstract
Introduction: We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome., Objective: We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others., Results: Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). The telomeric break lies in a gene poor region. We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. Consequently, we sequenced the coding exons and intron/exon borders of the ARHGEF9 gene in 99 probands from families with X linked mental retardation (XLMR) and 477 mentally retarded males in whom a diagnosis of Fragile X syndrome had been excluded. We did not identify any pathogenic changes; however, we did identify intronic nucleotide changes that might alter splicing., Conclusion: ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the developing and adult brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient. While ARHGEF9 appears to be an uncommon cause of mental retardation in males, it should be considered in patients with mental retardation and sensory hyperarousal.
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- 2008
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10. Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene.
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Lubs H, Abidi FE, Echeverri R, Holloway L, Meindl A, Stevenson RE, and Schwartz CE
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- Adolescent, Adult, Amino Acid Sequence, Carrier Proteins chemistry, Conserved Sequence, DNA Mutational Analysis, DNA-Binding Proteins, Heart Septal Defects, Atrial diagnosis, Heart Septal Defects, Atrial genetics, Humans, Male, Mental Retardation, X-Linked diagnosis, Mental Retardation, X-Linked mortality, Microcephaly diagnosis, Microcephaly genetics, Molecular Sequence Data, Nuclear Proteins chemistry, Pedigree, Protein Structure, Tertiary, Sequence Alignment, Syndrome, Carrier Proteins genetics, Mental Retardation, X-Linked genetics, Mutation, Missense, Nuclear Proteins genetics
- Abstract
Background: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984., Methods: This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene., Results: A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C)., Conclusions: This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator.
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- 2006
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11. A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor.
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Ramser J, Abidi FE, Burckle CA, Lenski C, Toriello H, Wen G, Lubs HA, Engert S, Stevenson RE, Meindl A, Schwartz CE, and Nguyen G
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- Alternative Splicing, Amino Acid Sequence, Enhancer Elements, Genetic, Epilepsy metabolism, Exons, Female, Humans, Male, Mental Retardation, X-Linked metabolism, Molecular Sequence Data, Mutation, Pedigree, Receptors, Cell Surface metabolism, Renin-Angiotensin System genetics, Renin-Angiotensin System physiology, Vacuolar Proton-Translocating ATPases metabolism, Epilepsy genetics, Mental Retardation, X-Linked genetics, Receptors, Cell Surface genetics, Vacuolar Proton-Translocating ATPases genetics
- Abstract
The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.
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- 2005
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12. Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.
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Abidi FE, Cardoso C, Lossi AM, Lowry RB, Depetris D, Mattéi MG, Lubs HA, Stevenson RE, Fontes M, Chudley AE, and Schwartz CE
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- Amino Acid Sequence, Chromosomes, Human, X genetics, Female, Humans, Male, Molecular Sequence Data, Pedigree, Phenotype, RNA Splice Sites genetics, X-linked Nuclear Protein, Alternative Splicing genetics, DNA Helicases genetics, Exons genetics, Frameshift Mutation genetics, Genes, Recessive genetics, Mental Retardation, X-Linked genetics, Nuclear Proteins genetics
- Abstract
The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.
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- 2005
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13. Family MRX9 revisited: further evidence for locus heterogeneity in MRX.
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Winnepenninckx B, Errijgers V, Reyniers E, De Deyn PP, Abidi FE, Schwartz CE, and Kooy RF
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- Base Sequence, DNA Primers, Female, Humans, Male, Pedigree, Chromosomes, Human, X, Genetic Heterogeneity, Genetic Linkage, Intellectual Disability genetics
- Abstract
Nonspecific X-linked mental retardation (MRX) patients are characterized by mental retardation, without additional distinguishing features. Consequently, MRX families can only be distinguished by mapping studies; yet, due to imprecise mapping studies performed in the past, the number of genes causing MRX is debatable, and a more precise localization for families is necessary to estimate this number. MRX 9 has been mapped to the pericentromeric region Xp21-q13. We refined the mapping of the MRX9 family to Xp11.22-Xp11.4. A sequencing analysis of three likely candidate genes in Xp11, SREB3, synapsin I, and TM4SF2, revealed no mutations., (Copyright 2002 Wiley-Liss, Inc.)
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- 2002
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14. A novel 2 bp deletion in the TM4SF2 gene is associated with MRX58.
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Abidi FE, Holinski-Feder E, Rittinger O, Kooy F, Lubs HA, Stevenson RE, and Schwartz CE
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- Base Sequence, DNA Mutational Analysis, Genetic Linkage, Humans, Male, Membrane Proteins, Pedigree, Tetraspanins, Intellectual Disability genetics, Nerve Tissue Proteins genetics, Sequence Deletion, X Chromosome
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- 2002
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15. Molecular cloning and characterization of TRPC5 (HTRP5), the human homologue of a mouse brain receptor-activated capacitative Ca2+ entry channel.
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Sossey-Alaoui K, Lyon JA, Jones L, Abidi FE, Hartung AJ, Hane B, Schwartz CE, Stevenson RE, and Srivastava AK
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- Amino Acid Sequence, Animals, Brain, Calcium Channels isolation & purification, Cloning, Molecular, DNA Mutational Analysis, Doublecortin Protein, Exons, Gene Expression, Humans, Intellectual Disability genetics, Mice, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Polymorphism, Single-Stranded Conformational, TRPC Cation Channels, X Chromosome genetics, Calcium Channels genetics, Cation Transport Proteins, Sequence Alignment
- Abstract
A novel human gene, TRPC5, was cloned from the region of Xq23 that contains loci for nonsyndromic mental retardation (MRX47 and MRX35) and two genes, DCX and HPAK3, implicated in two X-linked disorders (LISX and MRX30). Within a single YAC, we have determined the order cen-HPAK3(5'-3')-DCX(3'-5')-DXS7012E-TRPC5(3'-5' )-ter. TRPC5 encodes a 974-residue novel human protein (111.5 kDa predicted mass) and displays 99% homology with mouse TRP5, (MGD-approved symbol Trrp5) a novel member of a family of receptor-activated Ca2+ channels. It contains eight transmembrane domains, including a putative pore region. A transcript larger than 9.5 kb is observed only in fetal and adult human brain, with a relatively higher level in the adult human cerebellum. We devised an efficient method, Incorporation PCR SSCP (IPS), for detection of gene alterations. Five single-nucleotide variations in the TRPC5 gene were identified in males with mental retardation. However, these were found to be polymorphic variants. Exclusive expression of the TRPC5 gene in developing and adult brain suggests a possible role during development and provides a candidate gene for instances of mental retardation and other developmental defects., (Copyright 1999 Academic Press.)
- Published
- 1999
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16. Identification and characterization of a phase-specific, nuclear DNA binding protein from the dimorphic pathogenic fungus Histoplasma capsulatum.
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Abidi FE, Roh H, and Keath EJ
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- Base Sequence, DNA, Fungal, DNA-Binding Proteins genetics, Deoxyribonucleases, Type II Site-Specific, Molecular Sequence Data, Nuclear Proteins genetics, DNA-Binding Proteins metabolism, Fungal Proteins genetics, Histoplasma metabolism, Nuclear Proteins metabolism, Regulatory Sequences, Nucleic Acid
- Abstract
Genes expressed in the parasitic yeast (Y) phase of the dimorphic fungal pathogen Histoplasma capsulatum which are transcriptionally silent in the mycelial (M) phase have recently been cloned and analyzed. To understand the molecular regulation of genes involved in the transition to and maintenance of the Y phase, the presumptive 5' regulatory regions of two Y phase-specific genes (yps-3 and yps 21:E-9) were PCR amplified as labelled probes to identify nuclear DNA binding proteins which may influence phase-specific gene transcription. Protein-DNA interactions were assessed by Southwestern blot analysis in which sodium dodecyl sulfate-polyacrylamide gel electrophoresis-separated protein extracts from Y and M phases of the virulent G217B strain of H. capsulatum were visualized by their capability for in situ binding to the labelled 517-bp (G217B yps-3) or the 395-bp (G217B yps 21:E-9) putative 5' regulatory regions. A 30-kDa nuclear protein unique to the M-phase extracts of the highly virulent G217B strain, but absent in the Y phase of the same organism, was identified. In contrast, the low-virulence, thermal-sensitive Downs strain of H. capsulatum lacked detectable p30 binding activity in either yeast- or mycelial phase extracts, regardless of the source of labelled probe (395-bp G217B yps 21:E-9 probe or 512-bp HindIII-EcoRI-labelled Downs yps21:E-9). A decanucleotide motif, TCCTTTTTTT, was identified in the upstream regulatory regions of these yps genes, as well as in the putative alpha-tubulin promoter, and was conserved with 70 to 100% homology. This recognition sequence was sufficient for p30M binding with 32P-labelled ligated oligonucleotides when used in the Southwestern assay. These findings describe the first nuclear DNA binding factor identified in H. capsulatum which binds to target sequences in a phase-specific manner, suggesting that p30M may govern aspects of gene transcription in this pathogenic fungus, in which a temperature-sensitive switch influences morphology and virulence.
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- 1998
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17. Molecular cloning and sequence analysis of yps-3, a yeast-phase-specific gene in the dimorphic fungal pathogen Histoplasma capsulatum.
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Keath EJ and Abidi FE
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- Amino Acid Sequence, Base Sequence, Cloning, Molecular, Histoplasma growth & development, Histoplasma pathogenicity, Molecular Sequence Data, Regulatory Sequences, Nucleic Acid, Sequence Alignment, Sequence Homology, Amino Acid, Virulence genetics, Fungal Proteins genetics, Genes, Fungal, Histoplasma genetics
- Abstract
Genes specifically expressed in the parasitic yeast phase of Histoplasma capsulatum have been cloned to clarify the mechanisms underlying both pathogenesis and morphogenesis in this human dimorphic fungal pathogen. Previous studies have determined that the yeast-phase-specific gene, yps-3, is expressed differentially in two non-isogenic strains which differ in their thermotolerance and virulence. We have cloned the yps-3 homologues from the high virulence (G217B) and low virulence (Downs) strains, and obtained a partial cDNA clone representing the expressed gene from H. capsulatum G217B. The Downs clone harbours a 287 bp insertion sequence that disrupts a long ORF defined by the yps-3 G217B cDNA. Although the insertion sequence contains features reminiscent of mobile genetic elements, including 15 bp direct repeats of flanking sequence, it is not randomly distributed in the H. capsulatum genome. S1 nuclease analysis was utilized to map the 5' end of the expressed yps-3 gene in G217B to potential regulatory regions which are largely homologous in both strains. This finding may point to a deficiency in a temperature inducible regulatory protein in the low virulence, temperature-sensitive Downs strain. The nucleotide sequence of the yps-3 gene and the predicted amino acid sequence of its product represents the first report of phase-specific gene and protein sequences in this widely distributed fungal pathogen. Further analysis of the product encoded by the yps-3 gene may provide significant insight into the pathogenic repertoire of H. capsulatum.
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- 1994
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18. 1.5-Mb YAC contig in Xq28 formatted with sequence-tagged sites and including a region unstable in the clones.
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Palmieri G, Romano G, Casamassimi A, D'Urso M, Little RD, Abidi FE, Schlessinger D, Lagerström M, Malmgren H, and Steen-Bondeson ML
- Subjects
- Base Sequence, Chromosomes, Human, Cloning, Molecular, DNA, Electrophoresis, Gel, Pulsed-Field, Humans, Molecular Sequence Data, Polymerase Chain Reaction, Restriction Mapping, Chromosomes, Fungal, Genome, Human, Sequence Tagged Sites, X Chromosome
- Abstract
A contig of 20 yeast artificial clones (YACs) has been assembled across 1.5 Mb of Xq28 and formatted with nine previously reported probes and nine STSs developed from the sequence of probes and end fragments of YACs. YAC end fragments were obtained by subcloning, Alu-vector PCR, or primer-ligation PCR methods. Eighteen of the YACs were recovered from a library specific for Xq24-q28; two that fill a gap were obtained from a second library made from total human DNA. One region, containing probes pX78c and 2A1.1, was unstable in YACs, but it was possible to generate a self-consistent map of DNA over the entire contig. Overlaps were confirmed by Southern blot analyses of YAC DNAs, and pulsed-field gel electrophoresis confirmed the extent of the contig and identified at least four CpG islands in the region.
- Published
- 1993
- Full Text
- View/download PDF
19. Human glucose-6-phosphate dehydrogenase gene carried on a yeast artificial chromosome encodes active enzyme in monkey cells.
- Author
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D'Urso M, Zucchi I, Ciccodicola A, Palmieri G, Abidi FE, and Schlessinger D
- Subjects
- Animals, Blotting, Southern, Chromosomes, Fungal, Gene Expression, Gene Library, Genes, Genetic Vectors, Genome, Human, Guanosine Diphosphate metabolism, Haplorhini, Humans, Hybrid Cells, Restriction Mapping, Cloning, Molecular, Guanine Nucleotides genetics, Guanosine Diphosphate genetics
- Abstract
Yeast artificial chromosomes (YACs) permit the cloning of large tracts of human DNA. A YAC containing the human glucose-6-phosphate dehydrogenase gene is shown to encode active enzyme, supporting the inference that the YAC conserves the structure of the genomic DNA.
- Published
- 1990
- Full Text
- View/download PDF
20. Yeast artificial chromosomes containing human Xq24-Xq28 DNA: library construction and representation of probe sequences.
- Author
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Abidi FE, Wada M, Little RD, and Schlessinger D
- Subjects
- Animals, Base Sequence, Chromosome Mapping, Chromosomes, Fungal, Cloning, Molecular, Cricetinae, Genetic Linkage, Genome, Human, Humans, Hybrid Cells, DNA Probes, Gene Library, X Chromosome
- Abstract
A library of yeast artificial chromosomes (YACs) with human DNA inserts has been assembled from a human/hamster somatic cell hybrid containing Xq24-Xqter human DNA. Screening of the agar-embedded transformants for human DNA used a manifold of 3000 stainless-steel pins to transfer colonies onto the surface of media. This facilitated the recovery of the 1 in 300 clones that contained a human DNA insert (the remainder had hamster DNA and were discarded). The library described here consists of about two genomic equivalents (102 Mb) of human DNA in 467 clones: 167 were generated by EcoRI partial digestion and contain 25.5 Mb of human DNA; 252 used partial digestion with TaqI and cover 64.2 Mb; and 48 were from sheared DNA inserts and cover 11.7 Mb. Clones were screened by hybridization with 70 probes previously assigned to Xq24-Xq28. Eleven probes did not hybridize to any YACs in the library, and 16 probes hybridized to one YAC each, 23 to two, 13 to three, and 7 to four. Also, individual YACs large enough to detect features like the clustering of polymorphic sequences in subregions of Xq24-Xqter have been obtained. For example, XY58 contained five probe sequences previously independently isolated. The overall yield of YACs containing probe sequences was indistinguishable from Poisson statistical expectations for random cloning (P = 0.9). Thus, YAC libraries such as the one described here can include most, if not all, of the sequences in the source DNA from which the library is derived. These results support the possibility that YACs may provide a reliable bridge between linkage studies and conventional recombinant DNA analyses in mapping of the human genome.
- Published
- 1990
- Full Text
- View/download PDF
21. Fluorescence anisotropy of IAEDANS-labelled L7/L12 attached to rRNAs and ribosomes.
- Author
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Dash D, Abidi FE, and Burma DP
- Subjects
- Escherichia coli metabolism, Fluorescence Polarization methods, Fluorescent Dyes, Naphthalenesulfonates, Protein Binding, RNA, Ribosomal metabolism, Ribosomal Proteins metabolism, Ribosomes metabolism
- Published
- 1988
22. Lectin-binding assay by polyethylene glycol 8000.
- Author
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Abidi FE, Bishayee S, Bachhawat BK, and Bhadra R
- Subjects
- Drug Stability, Hydrogen-Ion Concentration, Iodine Radioisotopes, Lectins isolation & purification, Sialic Acid Binding Immunoglobulin-like Lectins, Sialoglycoproteins analysis, alpha-Fetoproteins analysis, gamma-Globulins, Lectins analysis, Polyethylene Glycols analysis
- Abstract
A quantitative lectin-binding assay using a precipitation technique and polyethylene glycol 8000 (PEG) as a precipitating agent has been described. Carcinoscorpin, a sialic acid-binding lectin isolated from the hemolymph of Indian horseshoe crab, Carcinoscorpius rotunda cauda, and iodinated fetuin, a sialoglycoprotein, were appropriately incubated as the components of the binding assay. The specific interaction between these two components developed the lectin-glycoprotein-bound complex. This was subsequently precipitated by the addition of PEG together with a coprecipitant gamma-globulin. Radioactivity of the precipitated bound complex was estimated to quantify the binding. The formation of the bound complex was effectively inhibited by a specific sialodisaccharide, O-(N-acetylneuraminyl)-(2----6)-2-acetamido-2-deoxygalactitol, implying the specific interaction for such precipitation. The probable effect of PEG was to stabilize the bound complex, precipitating it along with added gamma-globulin. This was further evident from the prevention of dissociation of the bound complex and increased binding of glycoprotein to the immobilized lectin in the presence of PEG. The assay was also applicable to other sialoglycoproteins such as alpha 1-acid glycoprotein and human chorionic gonadotropin. Moreover, the method yielded a saturation plateau with a characteristic hyperbolic binding curve. The assay was simple, quick, safe, economic, and highly sensitive.
- Published
- 1987
- Full Text
- View/download PDF
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