The Experts below are selected from a list of 1758 Experts worldwide ranked by ideXlab platform
Joe Rainger - One of the best experts on this subject based on the ideXlab platform.
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a secreted wnt ligand binding domain of fzd5 generated by a frameshift mutation causes autosomal dominant coloboma
Human Molecular Genetics, 2016Co-Authors: Chunqiao Liu, Joe Rainger, Sonya A Widen, Kathleen A Williamson, Rinki Ratnapriya, Christina Gerthkahlert, Ramakrishna P Alur, Erin Strachan, Souparnika H Manjunath, Archana BalakrishnanAbstract:Ocular coloboma is a common Eye Malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt-Frizzled (FZD) signaling in ocular development and directly implicate WNT-FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma.
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A Trans-Acting Protein Effect Causes Severe Eye Malformation in the Mp Mouse
PLOS Genetics, 2013Co-Authors: D.r. Keene, N.l. Charbonneau, Joe Rainger, Margaret A. Keighren, Malcolm E Fisher, Jeffrey T.-j. Huang, Sébastien Mella, Lorraine RoseAbstract:Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that Mp is caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 and Isoc1. The Isoc1-Fbn2 fusion gene (Isoc1 Mp ) mRNA has a frameshift and early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support a significant developmental role for this gene. The Fbn2-Isoc1 fusion gene (Fbn2 Mp ) predicted protein consists of the N-terminal Fibrillin-2 (amino acids 1–2646, exons 1– 62) lacking the C-terminal furin-cleavage site with a short out-of-frame extension encoded by the final exon of Isoc1. The Mp limb phenotype is consistent with that reported in Fbn2 null embryos. However, severe Eye Malformations, a defining feature of Mp, are not seen in Fbn2 null animals. Fibrillin-2 Mp forms large fibrillar structures within the rough endoplasmic reticulum (rER) associated with an unfolded protein response and quantitative mass spectrometry shows a generalised defect in protein secretion in conditioned media from mutant cells. In the embryonic Eye Fbn2 is expressed within the peripheral ciliary margin (CM). Mp embryos show reduced canonical Wnt-signalling in the CM – known to be essential for ciliary body development - and show subsequent aplasia of CM-derived structures. We propose that the Mp ‘‘worse-thannull’’ Eye phenotype plausibly results from a failure in normal trafficking of proteins that are co-expressed with Fbn2 within the CM. The prediction of similar trans-acting protein effects will be an important challenge in the medical interpretation of human mutations from whole exome sequencing.
Shijie Zhang - One of the best experts on this subject based on the ideXlab platform.
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a new gestational diabetes mellitus model hyperglycemia induced Eye Malformation via inhibition of pax6 in the chick embryo
Disease Models & Mechanisms, 2016Co-Authors: Shijie Zhang, Ruirong Tan, Bun Tsoi, Wenshan Huang, Yihua Huang, Xiaolong Tang, Nan Yao, Xuesong Yang, Hiroshi Kurihara, Qi WangAbstract:Gestational diabetes mellitus (GDM) is one of the leading causes of fetal Malformations. However, few models have been developed to study the underlying mechanisms of GDM-induced fetal Eye Malformation. In this study, a high concentration of glucose (0.2 mmol per egg) was injected into the air sac of chick embryos on embryo development day (EDD) 1 to develop a hyperglycemia model. Results showed that 47.3% of embryonic Eye Malformation happened on EDD 5. In this model, the key genes regulating Eye development, Pax6, Six3 and Otx2, were downregulated by hyperglycemia. Among these genes, the expression of Pax6 was the most vulnerable to hyperglycemia, being suppressed by 70%. A reduction in Pax6 gene expression induced Eye Malformation in chick embryos. However, increased expression of Pax6 in chick embryos could rescue hyperglycemia-induced Eye Malformation. Hyperglycemia stimulated O-linked N-acetylglucosaminylation, which caused oxidative stress in chick embryos. Pax6 was found to be vulnerable to free radicals, but the antioxidant edaravone could restore Pax6 expression and reverse Eye Malformation. These results illustrated a successful establishment of a new chick embryo model to study the molecular mechanism of hyperglycemia-induced Eye Malformation. The suppression of the Pax6 gene is probably mediated by oxidative stress and could be a crucial target for the therapy of GDM-induced embryonic Eye Malformation.
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proanthocyanidins prevent high glucose induced Eye Malformation by restoring pax6 expression in chick embryo
Nutrients, 2015Co-Authors: Ruirong Tan, Shijie Zhang, Bun Tsoi, Wenshan Huang, Nan Yao, Mo Hong, Yujia Zhai, Zhongfu Mao, Luping TangAbstract:Gestational diabetes mellitus (GDM) is one of the leading causes of offspring Malformations, in which Eye Malformation is an important disease. It has raised demand for therapy to improve fetal outcomes. In this study, we used chick embryo to establish a GDM model to study the protective effects of proanthocyanidins on Eye development. Chick embryos were exposed to high glucose (0.2 mmol/egg) on embryo development day (EDD) 1. Proanthocyanidins (1 and 10 nmol/egg) were injected into the air sac on EDD 0. Results showed that both dosages of proanthocyanidins could prevent the Eye Malformation and rescue the high glucose-induced oxidative stress significantly, which the similar effects were showed in edaravone. However, proanthocyanidins could not decrease the glucose concentration of embryo Eye. Moreover, the key genes regulating Eye development, Pax6, was down-regulated by high glucose. Proanthocyanidins could restore the suppressed expression of Pax6. These results indicated proanthocyanidins might be a promising natural agent to prevent high glucose-induced Eye Malformation by restoring Pax6 expression.
Michael P Clarke - One of the best experts on this subject based on the ideXlab platform.
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recurrent heterozygous pax6 missense variants cause severe bilateral microphthalmia via predictable effects on dna protein interaction
Genetics in Medicine, 2020Co-Authors: Kathleen A Williamson, Nikki H Hall, Liusaidh J Owen, Benjamin J Livesey, Isabel M Hanson, Gill Adams, Simon Bodek, Patrick Calvas, Bruce Castle, Michael P ClarkeAbstract:Purpose Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit Eye Malformation cohort (HGUEye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
Kathleen A Williamson - One of the best experts on this subject based on the ideXlab platform.
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recurrent heterozygous pax6 missense variants cause severe bilateral microphthalmia via predictable effects on dna protein interaction
Genetics in Medicine, 2020Co-Authors: Kathleen A Williamson, Nikki H Hall, Liusaidh J Owen, Benjamin J Livesey, Isabel M Hanson, Gill Adams, Simon Bodek, Patrick Calvas, Bruce Castle, Michael P ClarkeAbstract:Purpose Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. Methods We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit Eye Malformation cohort (HGUEye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. Results Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. Conclusion Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
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a secreted wnt ligand binding domain of fzd5 generated by a frameshift mutation causes autosomal dominant coloboma
Human Molecular Genetics, 2016Co-Authors: Chunqiao Liu, Joe Rainger, Sonya A Widen, Kathleen A Williamson, Rinki Ratnapriya, Christina Gerthkahlert, Ramakrishna P Alur, Erin Strachan, Souparnika H Manjunath, Archana BalakrishnanAbstract:Ocular coloboma is a common Eye Malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt-Frizzled (FZD) signaling in ocular development and directly implicate WNT-FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma.
Lorraine Rose - One of the best experts on this subject based on the ideXlab platform.
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A Trans-Acting Protein Effect Causes Severe Eye Malformation in the Mp Mouse
PLOS Genetics, 2013Co-Authors: D.r. Keene, N.l. Charbonneau, Joe Rainger, Margaret A. Keighren, Malcolm E Fisher, Jeffrey T.-j. Huang, Sébastien Mella, Lorraine RoseAbstract:Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that Mp is caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 and Isoc1. The Isoc1-Fbn2 fusion gene (Isoc1 Mp ) mRNA has a frameshift and early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support a significant developmental role for this gene. The Fbn2-Isoc1 fusion gene (Fbn2 Mp ) predicted protein consists of the N-terminal Fibrillin-2 (amino acids 1–2646, exons 1– 62) lacking the C-terminal furin-cleavage site with a short out-of-frame extension encoded by the final exon of Isoc1. The Mp limb phenotype is consistent with that reported in Fbn2 null embryos. However, severe Eye Malformations, a defining feature of Mp, are not seen in Fbn2 null animals. Fibrillin-2 Mp forms large fibrillar structures within the rough endoplasmic reticulum (rER) associated with an unfolded protein response and quantitative mass spectrometry shows a generalised defect in protein secretion in conditioned media from mutant cells. In the embryonic Eye Fbn2 is expressed within the peripheral ciliary margin (CM). Mp embryos show reduced canonical Wnt-signalling in the CM – known to be essential for ciliary body development - and show subsequent aplasia of CM-derived structures. We propose that the Mp ‘‘worse-thannull’’ Eye phenotype plausibly results from a failure in normal trafficking of proteins that are co-expressed with Fbn2 within the CM. The prediction of similar trans-acting protein effects will be an important challenge in the medical interpretation of human mutations from whole exome sequencing.
