The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform
Klaus Rohrschneider - One of the best experts on this subject based on the ideXlab platform.
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photoreceptor progenitor mrna analysis reveals exon skipping resulting from the abca4 c 5461 10t c mutation in stargardt disease
Ophthalmology, 2016Co-Authors: Riccardo Sangermano, Miriam Bauwens, Ingeborgh L Van Den Born, Elfride De Baere, Alejandro Garanto, Rob W J Collin, Angelique S A Goercharnramlal, Anke Den Engelsmanvan H A Dijk, Klaus Rohrschneider, Carel B HoyngAbstract:Purpose To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1). Design Case series. Participants Seventeen persons with STGD1 carrying ABCA4 variants and 1 Control Participant. Methods Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C. Main Outcome Measures Haplotype and rare variant data for ABCA4 , RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. Results The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone–rod dystrophy before 20 years of age and were legally blind by 25 years of age. Conclusions The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.
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photoreceptor progenitor mrna analysis reveals exon skipping resulting from the abca4 c 5461 10t c mutation in stargardt disease
Ophthalmology, 2016Co-Authors: Riccardo Sangermano, Miriam Bauwens, Elfride De Baere, Alejandro Garanto, Rob W J Collin, Angelique S A Goercharnramlal, Anke Den Engelsmanvan H A Dijk, Nathalie M Bax, Ingeborgh L Van Den Born, Klaus RohrschneiderAbstract:Purpose To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1). Design Case series. Participants Seventeen persons with STGD1 carrying ABCA4 variants and 1 Control Participant. Methods Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C. Main Outcome Measures Haplotype and rare variant data for ABCA4 , RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. Results The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone–rod dystrophy before 20 years of age and were legally blind by 25 years of age. Conclusions The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.
Riccardo Sangermano - One of the best experts on this subject based on the ideXlab platform.
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photoreceptor progenitor mrna analysis reveals exon skipping resulting from the abca4 c 5461 10t c mutation in stargardt disease
Ophthalmology, 2016Co-Authors: Riccardo Sangermano, Miriam Bauwens, Ingeborgh L Van Den Born, Elfride De Baere, Alejandro Garanto, Rob W J Collin, Angelique S A Goercharnramlal, Anke Den Engelsmanvan H A Dijk, Klaus Rohrschneider, Carel B HoyngAbstract:Purpose To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1). Design Case series. Participants Seventeen persons with STGD1 carrying ABCA4 variants and 1 Control Participant. Methods Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C. Main Outcome Measures Haplotype and rare variant data for ABCA4 , RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. Results The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone–rod dystrophy before 20 years of age and were legally blind by 25 years of age. Conclusions The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.
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photoreceptor progenitor mrna analysis reveals exon skipping resulting from the abca4 c 5461 10t c mutation in stargardt disease
Ophthalmology, 2016Co-Authors: Riccardo Sangermano, Miriam Bauwens, Elfride De Baere, Alejandro Garanto, Rob W J Collin, Angelique S A Goercharnramlal, Anke Den Engelsmanvan H A Dijk, Nathalie M Bax, Ingeborgh L Van Den Born, Klaus RohrschneiderAbstract:Purpose To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1). Design Case series. Participants Seventeen persons with STGD1 carrying ABCA4 variants and 1 Control Participant. Methods Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C. Main Outcome Measures Haplotype and rare variant data for ABCA4 , RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. Results The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone–rod dystrophy before 20 years of age and were legally blind by 25 years of age. Conclusions The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.
Rebecca M Reynolds - One of the best experts on this subject based on the ideXlab platform.
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glibenclamide and metformin versus standard care in gestational diabetes graces a feasibility open label randomised trial
BMC Pregnancy and Childbirth, 2017Co-Authors: Rebecca M Reynolds, Fiona C Denison, Ed Juszczak, Jennifer L Bell, Jessica Penneycard, Mark W J Strachan, Robert Lindsay, Claire I AlexanderAbstract:Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and Participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM. We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks’ gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic Control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic Control, Participant satisfaction and clinical outcomes. Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6–90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic Control to metformin and glibenclamide, with fewer blood glucose readings <3.5 mmol/l (median [IQR] difference/woman/week of treatment 0.58 [0.03–1.87]). A large randomised Controlled trial comparing glibenclamide or insulin in combination with metformin for women with GDM would be feasible but is unlikely to be worthwhile, given the poorer glycaemic Control with glibenclamide and metformin in this pilot study. The combination of metformin and glibenclamide should be reserved for women with GDM with true needle phobia or inability to use insulin therapy. www.clinicaltrials.gov registration number:NCT02080377 February 11th 2014.
Marc L. Seal - One of the best experts on this subject based on the ideXlab platform.
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Quantifying individual differences in brain morphometry underlying symptom severity in Autism Spectrum Disorders.
Scientific Reports, 2019Co-Authors: Gareth Ball, Chris Adamson, Stephen C Bowden, Marc L. SealAbstract:The neurobiology of heterogeneous neurodevelopmental disorders such as autism spectrum disorders (ASD) are still unclear. Despite extensive efforts, most findings are difficult to reproduce due to high levels of individual variance in phenotypic expression. To quantify individual differences in brain morphometry in ASD, we implemented a novel subject-level, distance-based method on subject-specific attributes. In a large multi-cohort sample, each subject with ASD (n = 100; n = 84 males; mean age: 11.43 years; mean IQ: 110.58) was strictly matched to a Control Participant (n = 100; n = 84 males; mean age: 11.43 years; mean IQ: 110.70). Intrapair Euclidean distance of MRI brain morphometry and symptom severity measures (Social Responsiveness Scale) were entered into a regularised machine learning pipeline for feature selection, with rigorous out-of-sample validation and permutation testing. Subject-specific structural morphometry features significantly predicted individual variation in ASD symptom severity (19 cortical thickness features, p = 0.01, n = 5000 permutations; 10 surface area features, p = 0.006, n = 5000 permutations). Findings remained robust across subjects and were replicated in validation samples. Identified cortical regions implicate key hubs of the salience and default mode networks as neuroanatomical features of social impairment in ASD. Present results highlight the importance of subject-level markers in ASD, and offer an important step forward in understanding the neurobiology of heterogeneous disorders.
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Quantifying individual differences in brain morphometry underlying symptom severity in Autism Spectrum Disorders
bioRxiv, 2018Co-Authors: Gareth Ball, Chris Adamson, Stephen C Bowden, Marc L. SealAbstract:The neurobiology of heterogeneous neurodevelopmental disorders such as autism spectrum disorders (ASD) are still unclear. Despite extensive efforts, most findings are not reproducible due to high levels of individual variance in phenotypic expression. To quantify individual differences in brain morphometry in ASD, we implemented a novel subject-level, distance-based method using subject-specific attributes. In a large multi- cohort sample, each subject with ASD (n=100; n=84 males; mean age: 11.43 years; mean IQ: 110.58) was strictly matched to a Control Participant (n=100; n=84 males; mean age: 11.43 years; mean IQ: 110.70). Intrapair Euclidean distance of MRI brain morphometry and symptom severity measures were entered into a regularized machine learning pipeline for feature selection, with rigorous out-of-sample validation and bootstrapped permutation testing. Subject-specific cortical thickness (19 features; p=0.01, n=5000 permutations) and surface area (10 features; p=0.006, n=5000 permutations) features significantly predicted individual variation in ASD symptom severity. Findings remained robust across subjects and were replicated in validation samples. Identified cortical regions implicate key hubs of the salience and default mode networks as neuroanatomical features of social impairment in ASD. Present results highlight the importance of subject-level markers in ASD, and offer an important step forward in understanding the neurobiology of heterogeneous disorders.
Carel B Hoyng - One of the best experts on this subject based on the ideXlab platform.
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photoreceptor progenitor mrna analysis reveals exon skipping resulting from the abca4 c 5461 10t c mutation in stargardt disease
Ophthalmology, 2016Co-Authors: Riccardo Sangermano, Miriam Bauwens, Ingeborgh L Van Den Born, Elfride De Baere, Alejandro Garanto, Rob W J Collin, Angelique S A Goercharnramlal, Anke Den Engelsmanvan H A Dijk, Klaus Rohrschneider, Carel B HoyngAbstract:Purpose To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1). Design Case series. Participants Seventeen persons with STGD1 carrying ABCA4 variants and 1 Control Participant. Methods Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C. Main Outcome Measures Haplotype and rare variant data for ABCA4 , RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. Results The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone–rod dystrophy before 20 years of age and were legally blind by 25 years of age. Conclusions The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.