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Your search keyword '"Fitzpatrick, David"' showing total 5 results
Start Over Author "Fitzpatrick, David" Topic anophthalmia Publication Year Range Last 50 years
5 results on '"Fitzpatrick, David"'

1. Robust Genetic Analysis of the X-Linked Anophthalmic (Ie) Mouse.

Author

Hernandez-Moran, Brianda A., Papanastasiou, Andrew S., Parry, David, Meynert, Alison, Gautier, Philippe, Grimes, Graeme, Adams, Ian R., Trejo-Reveles, Violeta, Bengani, Hemant, Keighren, Margaret, Jackson, Ian J., Adams, David J., FitzPatrick, David R., and Rainger, Joe

Subjects
GENETIC variation, GENE expression, TRANSCRIPTION factors, CIS-regulatory elements (Genetics), MOLECULAR diagnosis, MICE, PHENOTYPES, X chromosome
Abstract

Anophthalmia (missing eye) describes a failure of early embryonic ocular development. Mutations in a relatively small set of genes account for 75% of bilateral anophthalmia cases, yet 25% of families currently are left without a molecular diagnosis. Here, we report our experimental work that aimed to uncover the developmental and genetic basis of the anophthalmia characterising the X-linked Ie (eye-ear reduction) X-ray-induced allele in mouse that was first identified in 1947. Histological analysis of the embryonic phenotype showed failure of normal eye development after the optic vesicle stage with particularly severe malformation of the ventral retina. Linkage analysis mapped this mutation to a ~6 Mb region on the X chromosome. Short- and long-read whole-genome sequencing (WGS) of affected and unaffected male littermates confirmed the Ie linkage but identified no plausible causative variants or structural rearrangements. These analyses did reduce the critical candidate interval and revealed evidence of multiple variants within the ancestral DNA, although none were found that altered coding sequences or that were unique to Ie. To investigate early embryonic events at a genetic level, we then generated mouse ES cells derived from male Ie embryos and wild type littermates. RNA-seq and accessible chromatin sequencing (ATAC-seq) data generated from cultured optic vesicle organoids did not reveal any large differences in gene expression or accessibility of putative cis-regulatory elements between Ie and wild type. However, an unbiased TF-footprinting analysis of accessible chromatin regions did provide evidence of a genome-wide reduction in binding of transcription factors associated with ventral eye development in Ie, and evidence of an increase in binding of the Zic-family of transcription factors, including Zic3, which is located within the Ie-refined critical interval. We conclude that the refined Ie critical region at chrX: 56,145,000–58,385,000 contains multiple genetic variants that may be linked to altered cis regulation but does not contain a convincing causative mutation. Changes in the binding of key transcription factors to chromatin causing altered gene expression during development, possibly through a subtle mis-regulation of Zic3, presents a plausible cause for the anophthalmia phenotype observed in Ie, but further work is required to determine the precise causative allele and its genetic mechanism. [ABSTRACT FROM AUTHOR]

Published
2022
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2. The genetic architecture of microphthalmia, anophthalmia and coloboma.

Author

Williamson, Kathleen A. and FitzPatrick, David R.

Subjects
*MICROPHTHALMIA, *COLOBOMA, *PHENOTYPES, *EYE development, *EYE abnormalities, *GENETIC mutation
Abstract

Microphthalmia, anophthalmia and coloboma (MAC) are distinct phenotypes that represent a continuum of structural developmental eye defects. In severe bilateral cases (anophthalmia or severe microphthalmia) the genetic cause is now identifiable in approximately 80 percent of cases, with de novo heterozygous loss-of-function mutations in SOX2 or OTX2 being the most common. The genetic cause of other forms of MAC, in particular isolated coloboma, remains unknown in the majority of cases. This review will focus on MAC phenotypes that are associated with mutation of the genes SOX2, OTX2, PAX6, STRA6, ALDH1A3, RARB, VSX2, RAX, FOXE3, BMP4, BMP7, GDF3, GDF6, ABCB6, ATOH7, C12orf57, TENM3 (ODZ3), and VAX1. Recently reported mutation of the SALL2 and YAP1 genes are discussed in brief. Clinical and genetic features were reviewed in a total of 283 unrelated MAC cases or families that were mutation-positive from these 20 genes. Both the relative frequency of mutations in MAC cohort screens and the level of confidence in the assignment of disease-causing status were evaluated for each gene. [ABSTRACT FROM AUTHOR]

Published
2014
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3. Study of ophthalmo acromelic syndromes in human and mouse

Author

Rainger, Joe, Fitzpatrick, David., and Jackson, Ian

Subjects
616.042, ophthalmo-acromelic syndrome, anophthalmia, oligodactyly, ocular development
Abstract

The combination of severe ocular and distal limb malformations is rare. Ophthalmo-acromelic syndrome (OAS; MIM 206920) is characterised by anophthalmia with lower limb oligodactyly. To date <40 cases of this autosomal recessive disorder have been reported. Genome-wide analysis of ~10,000 SNPs typed on two apparently unrelated families - comprising a total of three affected individuals, four unaffected siblings and their consanguineous parents - identified a large region of overlapping autozygosity on chromosome 14q. Adding data from a third consanguineous family gave a combined LOD score of >5 with no evidence of locus heterogeneity. Collaborative data from a further 6 individuals refined the critical interval to a 3.4 Mb region on chromosome14:69,652,605-73,059,612 Mb. To sequence all 19 known protein-coding genes in the region, the 238 exons were ranked by evolutionary sequence conservation and divided equally between the Edinburgh and Nijmegen groups. Complete sequence coverage has been obtained for 61% of the “Edinburgh” exons but no potentially causative mutations have been identified. Further mutation analysis of the OAS locus is on-going. Mice homozygous for the X-ray induced Mp mutation were reportedly anophthalmic with hind limb oligodactyly and thus represented a potential model for human OAS. This line was rederived in Edinburgh and phenotypic analysis of Mp/Mp homozygotes showed runting, malformed pinnae with microphthalmia but not anophthalmia. The apparent hind-limb oligodactyly was due to osseous syndactyly. Mp heterozygotes had milder microphthalmia and pinnae deformities, but lacked the syndactyly. In both heterozygotes and homozygotes the eye malformations were fully penetrant, pan-ocular and characterised by failure of both the ciliary apparatus and vitreous body to form and abnormal retinal lamination. Genome-wide microsatellite marker analysis showed linkage of the Mp phenotype to chromosome 18. Fbn2 mapped within the linkage interval and was a good candidate for Mp based on the finding of hind limb osseous syndactyly in Fbn2-null mice. However, Fbn2-null mice have no eye phenotype. 3’-RACE identified that Mp was as a 660 kb inversion affecting the 3’-regions of Fbn2 and the adjacent gene Isoc1. This created two aberrant reciprocal fusion transcripts: Fbn2 exons 1-63 are fused to Isoc1 exon 5; and Isoc1 exons 1-4 are fused to Fbn2 exons 64-65. This predicts nonsense-mediated decay of the Isoc1 Mp transcript and production of a truncated Fbn2 Mp protein. Ocular development was analysed in homozygote and wild type embryos to define the basis of the “worse than null phenotype” seen in Mp mice. RNA in situ hybridisations (ISH) failed to detect expression of Isoc1 in the embryonic eye. In contrast, normal expression of Fbn2 in the ciliary body and retina was consistent with the Mp phenotype. A combination of EM and immunocytochemistry showed that truncated Fbn2 (Fbn2Mp) was retained within the ER. Fbn2Mp co-localised with markers of ER stress: Grp78 expression and UPR-specific Xbp1 splicing. Signalling by Wnt2b is thought to be critical for ciliary development and Lef1, a Wnt-responsive transcription factor, showed increased and ectopic ocular expression in the region affected by ER stress. Sox2 is a direct transcriptional target of Lef1 and we observed apparent ectopic expression of Sox2 in the ciliary body. Throughout the developing retina in mutant embryos we also observed individual cells that were ectopically expressing the transcription factor Chx10 and other cells expressing the apoptotic marker Activated- Caspase-3. The apoptotic marker did not specifically co-localise with Fbn2Mp. Taken together, these findings suggest that the ocular malformations in Mp are a direct result of the ER stress induced by Fbn2Mp in a specific group of cells in the early ciliary body. The ER stress presumably halts post-translational modification of a developmentally critical signaling molecule, possibly Wnt2b, which happens to be expressed in the same cells. We have termed the resulting pathological mechanism a synodiporic effect (synodiporia = the ones walking the street together or fellow travellers). Such effects may have significant implications for human genetic disease analysis, and may provide an explanation for other “worse than null” mutations.

Published
2009

4. A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation.

Author

Horn, Denise, Prescott, Trine, Houge, Gunnar, Brække, Kristin, Rosendahl, Karen, Nishimura, Gen, FitzPatrick, David R., and Spranger, Jürgen

Subjects
*SKELETAL dysplasia, *PHENOTYPES, *INTELLECTUAL disabilities, *MICROPHTHALMIA, *COLOBOMA, *MISSENSE mutation
Abstract

We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Recent exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2. [ABSTRACT FROM AUTHOR]

Published
2015
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5. Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Author

Kishan Sokhi, Jacqueline Ramsay, Tanya Bardakjian, Adele Schneider, Nursel Elcioglu, Raoul C.M. Hennekam, C. Nur Semerci, Ferda Ozkinay, Joe Rainger, David Sexton, Andrea Superti Furga, Anita Saponari, Lina Ramos, Ellen van Beusekom, Malcolm E. Fisher, Gabriele Gillessen-Kaesbach, Anita Wischmeijer, Ian J. Jackson, Sérgio B. Sousa, Hans van Bokhoven, Rainer Koenig, Lihadh Al-Gazali, Paul Perry, Peter Branney, Louise S. Bicknell, Harris Morrison, Livia Garavelli, Dagmar Wieczorek, André Mégarbané, Rosanna Pallotta, Han G. Brunner, Lisa McKie, Saemah Nuzhat Zafar, Philippe Gautier, Ayesha Khan, David R. FitzPatrick, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, Ege Üniversitesi, Rainger, Joe, van Beusekom, Ellen, Ramsay, Jacqueline K., McKie, Lisa, Al-Gazali, Lihadh, Pallotta, Rosanna, Saponari, Anita, Branney, Peter, Fisher, Malcolm, Morrison, Harris, Bicknell, Louise, Gautier, Philippe, Perry, Paul, Sokhi, Kishan, Sexton, David, Bardakjian, Tanya M., Schneider, Adele S., Elcioglu, Nursel, Ozkinay, Ferda, Koenig, Rainer, Megarbane, Andre, Semerci, C. Nur, Khan, Ayesha, Zafar, Saemah, Hennekam, Raoul, Sousa, Sergio B., Ramos, Lina, Garavelli, Livia, Furga, Andrea Superti, Wischmeijer, Anita, Jackson, Ian J., Gillessen-Kaesbach, Gabriele, Brunner, Han G., Wieczorek, Dagmar, van Bokhoven, Hans, FitzPatrick, David R., and Faculteit der Geneeskunde

Subjects
ANOMALIES, DNA Mutational Analysis, PROTEIN, anophthalmia, gene targeting, Bone Morphogenetic Protein 1, hindlimb, Mice, Xenopus laevis, genetic linkage, BINDING, genetics, Waardenburg's Syndrome, Waardenburg Syndrome, clinical article, C57BL mouse, adult, Mus, microsatellite marker, DEFECTS, gene expression regulation, Disease gene identification, BMP1 protein, human, Pedigree, Medicine, down regulation, mutational analysis, drug antagonism, medicine.medical_specialty, SMOC1 protein, human, embryo, Bone morphogenetic protein, animal tissue, loss of function mutation, Smoc1 gene, Genetics, Humans, human, Biology, Molecular Biology, Waardenburg syndrome, mouse, Ecology, Evolution, Behavior and Systematics, MUTATIONS, animal model, Correction, SMOC-1 protein, mouse, school child, medicine.disease, Mice, Inbred C57BL, Human Reproduction [NCEBP 12], gene function, Endocrinology, decapentaplegic protein, Genetics and epigenetic pathways of disease Functional Neurogenomics [NCMLS 6], Mutation, Cancer Research, frameshift mutation, Medizin, nonsense mutation, Gene Expression, mouse mutant, Eye, Bmp1 protein, mouse, Autosomal Recessive, bone morphogenetic protein, Missense mutation, animal, Osteonectin, SPECIFICATION, Genetics (clinical), RECESSIVE ANOPHTHALMIA, limb, cleft palate, Mice, Knockout, child, Coloboma, ABNORMALITIES, messenger RNA, article, pedigree, female, Mammalia, Models, Animal, Drosophila, Research Article, gene locus, lcsh:QH426-470, Nonsense mutation, procollagen C proteinase, male, ddc:570, Internal medicine, medicine, Animalia, Animals, gene, SMOC 1 protein, mouse, gene identification, growth, development and aging, Clinical Genetics, Phenocopy, nonhuman, Anophthalmia, missense mutation, syndactyly, Anophthalmos, nucleotide sequence, Human Genetics, Extremities, infant, lcsh:Genetics, XENOPUS, CELL-DEATH, adolescent, Genetics of Disease, Syndactyly, homozygosity, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], metabolism, Animal Genetics
Abstract

WOS: 000293338600004, PubMed ID: 21750680, Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site-and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc(1tm1a)) that reduces mRNA to similar to 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc(1tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc(1tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice., Medical Research Council (UK)Medical Research Council UK (MRC); Medical Research CouncilMedical Research Council UK (MRC) [MC_U127561093, MC_PC_U127561112, MC_U127561112], Funding for this project was provided as an intramural program grant from the Medical Research Council (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2011

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