The Experts below are selected from a list of 5460 Experts worldwide ranked by ideXlab platform
Begoña Merinero - One of the best experts on this subject based on the ideXlab platform.
-
Genotype–phenotype correlations in sepiapterin reductase deficiency. A Splicing Defect accounts for a new phenotypic variant
neurogenetics, 2011Co-Authors: Luisa Arrabal, Libertad Teresa, Rocío Sánchez-alcudia, Margarita Castro, Celia Medrano, Luis Gutiérrez-solana, Susana Roldán, Aida Ormazábal, Celia Pérez-cerdá, Begoña MerineroAbstract:Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype–phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects Splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.
-
genotype phenotype correlations in sepiapterin reductase deficiency a Splicing Defect accounts for a new phenotypic variant
Neurogenetics, 2011Co-Authors: Luisa Arrabal, Libertad Teresa, Margarita Castro, Celia Medrano, Susana Roldán, Aida Ormazábal, Rocio Sanchezalcudia, Luis Gonzalez Gutierrezsolana, Celia Perezcerda, Begoña MerineroAbstract:Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype–phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects Splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.
Elliot M Meyerowitz - One of the best experts on this subject based on the ideXlab platform.
-
temperature sensitive Splicing in the floral homeotic mutant apetala3 1
The Plant Cell, 1998Co-Authors: Robert Sablowski, Elliot M MeyerowitzAbstract:The floral homeotic gene APETALA3 (AP3) is required for stamen and petal development in Arabidopsis. The previously described ap3-1 allele is temperature sensitive and carries a missense mutation near a 5′ splice site. The missense mutation lies within a domain of the AP3 protein that is thought to be important for protein–protein interactions, which suggests that temperature sensitivity of ap3-1 could reflect an unstable interaction with cofactors. Here, we show instead that the ap3-1 mutation causes a temperature-dependent Splicing Defect and that temperature sensitivity is not a property of the protein products of ap3-1 but of RNA processing, possibly because of unstable base pairing between the transcript and small nuclear RNAs. The unexpected Defect of the ap3-1 mutant offers unique opportunities for genetic and molecular studies of splice site recognition in plants.
Eric Boerwinkle - One of the best experts on this subject based on the ideXlab platform.
-
In silico tools for Splicing Defect prediction: a survey from the viewpoint of end users
Genetics in Medicine, 2014Co-Authors: Xueqiu Jian, Eric BoerwinkleAbstract:RNA Splicing is the process during which introns are excised and exons are spliced. The precise recognition of Splicing signals is critical to this process, and mutations affecting Splicing comprise a considerable proportion of genetic disease etiology. Analysis of RNA samples from the patient is the most straightforward and reliable method to detect Splicing Defects. However, currently, the technical limitation prohibits its use in routine clinical practice. In silico tools that predict potential consequences of Splicing mutations may be useful in daily diagnostic activities. In this review, we provide medical geneticists with some basic insights into some of the most popular in silico tools for Splicing Defect prediction, from the viewpoint of end users. Bioinformaticians in relevant areas who are working on huge data sets may also benefit from this review. Specifically, we focus on those tools whose primary goal is to predict the impact of mutations within the 5′ and 3′ Splicing consensus regions: the algorithms used by different tools as well as their major advantages and disadvantages are briefly introduced; the formats of their input and output are summarized; and the interpretation, evaluation, and prospection are also discussed. Genet Med 16 7, 497–503.
-
In silico tools for Splicing Defect prediction: a survey from the viewpoint of end users.
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Xueqiu Jian, Eric Boerwinkle, Xiaoming LiuAbstract:RNA Splicing is the process during which introns are excised and exons are spliced. The precise recognition of Splicing signals is critical to this process, and mutations affecting Splicing comprise a considerable proportion of genetic disease etiology. Analysis of RNA samples from the patient is the most straightforward and reliable method to detect Splicing Defects. However, currently, the technical limitation prohibits its use in routine clinical practice. In silico tools that predict potential consequences of Splicing mutations may be useful in daily diagnostic activities. In this review, we provide medical geneticists with some basic insights into some of the most popular in silico tools for Splicing Defect prediction, from the viewpoint of end users. Bioinformaticians in relevant areas who are working on huge data sets may also benefit from this review. Specifically, we focus on those tools whose primary goal is to predict the impact of mutations within the 5' and 3' Splicing consensus regions: the algorithms used by different tools as well as their major advantages and disadvantages are briefly introduced; the formats of their input and output are summarized; and the interpretation, evaluation, and prospection are also discussed.
Sweetman Larry - One of the best experts on this subject based on the ideXlab platform.
-
Squalene synthase deficiency: clinical, biochemical, and molecular characterization of a Defect in cholesterol biosynthesis
'Elsevier BV', 2018Co-Authors: Coman David, Vissers, Lisenka E. L. M., Riley, Lisa G., Kwint, Michael P., Hauck Roxanna, Koster Janet, Geuer Sinje, Hopkins Sarah, Hallinan Barbra, Sweetman LarryAbstract:Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of\ua0cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis Defect. The metabolite profile in plasma and\ua0urine suggested that their Defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial Splicing Defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady\ua0state
-
Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis
Elsevier, 2018Co-Authors: Coman David, Hauck Roxanna, Koster Janet, Geuer Sinje, Hopkins Sarah, Hallinan Barbra, Vissers Lisenka, Riley Lisa, Kwint Michael, Sweetman LarryAbstract:Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis Defect. The metabolite profile in plasma and urine suggested that their Defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial Splicing Defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.Griffith Health, School of MedicineNo Full Tex
Daniel Schumperli - One of the best experts on this subject based on the ideXlab platform.
-
spinal muscular atrophy smn2 pre mrna Splicing corrected by a u7 snrna derivative carrying a Splicing enhancer sequence
Molecular Therapy, 2007Co-Authors: Julien Marquis, Kathrin Meyer, Larissa Angehrn, Sacha S Kampfer, Barbara Rothenrutishauser, Daniel SchumperliAbstract:Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous deletion/inactivation of the survival of motoneuron 1 (SMN1) gene. The nearby SMN2 gene, despite its identical coding capacity, is only an incomplete substitute, because a single nucleotide difference impairs the inclusion of its seventh exon in the messenger RNA (mRNA). This Splicing Defect can be corrected (transiently) by specially designed oligonucleotides. Here we have developed a more permanent correction strategy based on bifunctional U7 small nuclear RNAs (snRNAs). These carry both an antisense sequence that allows specific binding to exon 7 and a Splicing enhancer sequence that will improve the recognition of the targeted exon. When expression cassettes for these RNAs are stably introduced into cells, the U7 snRNAs become incorporated into small nuclear ribonucleoprotein (snRNP) particles that will induce a durable Splicing correction. We have optimized this strategy to the point that virtually all SMN2 pre-mRNA becomes correctly spliced. In fibroblasts from an SMA patient, this approach induces a prolonged restoration of SMN protein and ensures its correct localization to discrete nuclear foci (gems).
