Congenital anterior staphyloma associated with Peters' anomaly and aphakia in a Holstein calf.
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ABSTRACT:
SUBMITTER: Sato R
PROVIDER: S-EPMC5559356 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Mutations within the RIEG1 homeobox gene on chromosome 4q25 have previously been reported in association with Rieger syndrome. We report a 3' splice site mutation within the 3rd intron of the RIEG1 gene which is associated with unilateral Peters' anomaly. The mutation is a single base substition of A to T at the invariant -2 site of the 3' splice site. Peters' anomaly, which is characterised by ocular anterior segment dysgenesis and central corneal opacification, is distinct from Rieger anomaly. This is the first description of a RIEG1 mutation associated with Peters' anomaly.
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Project description:Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the first study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.
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Project description:FOXE3 is a lens specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, we have identified DNAJB1 as a transcriptional target of FOXE3 in a novel pathway that is crucial for development of the anterior segment of the eye.
2016-03-24 | GSE76389 | GEO
Project description:FOXE3 is a lens specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, we have identified DNAJB1 as a transcriptional target of FOXE3 in a novel pathway that is crucial for development of the anterior segment of the eye. Human Embryonic Kidney (HEK293FT) cells were transfected with the expression vector (pT-RexTM-DEST30) harboring either the wild type or the mutant (C240*) FOXE3 ORF (open reading frame). The experimental design included a total of eight biological replicates of cells expressing the wild type and eight replicates of mutant FOXE3 along with eight non-transfected controls. Cells were harvested 24-hour post-transfection and subjected to total RNA isolation for the preparation of whole transcriptome next-generation sequencing libraries. Initially, we examined the quality of transcriptome libraries on a MiSeq genome analyzer. Subsequent to confirmation of the quality, all libraries were paired-end sequenced (2 x 100 bp) using Illumina TruSeq Cluster V3 flow cell at a concentration of 13.0 pM in two separate lanes (12 bar-coded mRNA pooled libraries in each lane) on a HiSeq 2000 genome analyzer.
2016-03-24 | E-GEOD-76389 | biostudies-arrayexpress
Project description:Anterior segment dysgenesis (ASD) is a spectrum of disorders that affect the anterior ocular chamber. Clinical studies on a Newfoundland family over the past 30 years show that 11 relatives have a variable ocular phenotype ranging from microcornea to Peters anomaly, segregating as an autosomal dominant trait. To determine the molecular etiology of the variable ASD in this family, we sequenced nine functional candidate genes and identified 44 variants. A point mutation in FOXE3, which codes for a transcription factor involved in the formation of the lens and surrounding structures, co-segregated with the variable ocular phenotype. This novel mutation (c.959G>T) substitutes the stop codon for a leucine residue, predicting the addition of 72 amino acids to the C-terminus of FOXE3. Two recent reports have also identified non-stop mutations in FOXE3 in patients with variable ocular phenotypes and predict an extended protein. Although FOXE3 is a lens-specific gene, we successfully isolated complementary DNA from lymphoblasts of an affected family member, and our sequencing results show that the c.959T allele is absent, suggesting that it may be degraded at the RNA level. Though preliminary, our results challenge the notion that an extended FOXE3 protein causes ASD, and instead suggests a mechanism of haploinsufficiency in the case of non-stop mutations. This study adds to several reports that suggest that autosomal-dominant mutations within FOXE3 cause ASD and has important clinical utility, especially for the diagnosis of mildly affected patients.
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Project description:FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye.
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Project description:Complex molecular interactions dictate the developmental steps that lead to a mature and functional cornea and lens. Peters anomaly is one subtype of anterior segment dysgenesis especially due to abnormal development of the cornea and lens. MSX2 was recently implicated as a potential gene that is critical for anterior segment development. However, the role of MSX2 within the complex mechanisms of eye development remains elusive. Our present study observed the morphologic changes in conventional Msx2 knockout (KO) mice and found phenotypes consistent with Peters anomaly and microphthalmia seen in humans. The role of Msx2 in cornea and lens development was further investigated using IHC, in situ hybridization, and quantification of proliferative and apoptotic lens cells. Loss of Msx2 down-regulated FoxE3 expression and up-regulated Prox1 and crystallin expression in the lens. The FoxE3 and Prox1 malfunction and precocious Prox1 and crystallin expression contribute to a disturbed lens cell cycle in lens vesicles and eventually to cornea-lentoid adhesions and microphthalmia in Msx2 KO mice. The observed changes in the expression of FoxE3 suggest that Msx2 is an important contributor in controlling transcription of target genes critical for early eye development. These results provide the first direct genetic evidence of the involvement of MSX2 in Peters anomaly and the distinct function of MSX2 in regulating the growth and development of lens vesicles.
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Project description:This case report describes the clinical signs, magnetic resonance imaging (MRI) findings and associated (histo)pathological findings in a crossbred Belgian Blue calf with congenital complex brain anomaly. The calf was presented with non-progressive signs (including cerebellar ataxia) since it was born, suggestive of a multifocal intracranial lesion. A congenital anomaly was suspected and after hematology, biochemistry, serology, and cerebrospinal fluid analysis, a magnetic resonance imaging study was performed. The following suspected abnormalities were the principal changes identified: severe hydrocephalus, porencephaly, suspected partial corpus callosum agenesis (CCA), and increased fluid signal between the folia of the cerebellum. Post-mortem examination predominately reflected the MRI findings. The origin for these malformations could not be identified and there was no evidence of a causative infectious agent. Corpus callosum abnormalities have been reported in bovids before and have been linked to bovine viral diarrhea virus (BVDV) infections, as have several other central nervous system anomalies in this species. In this case, BVDV was deemed an unlikely causative agent based on serology test results and lack of typical histopathological signs. The etiology of the congenital anomaly present in this bovine calf remains unknown.
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Project description:Peters anomaly is a form of anterior segment dysgenesis characterized by central ocular opacity and corneo-lenticular adhesions. Isolated and syndromic Peters anomaly can be observed and demonstrate significant genetic heterogeneity. We report the identification of overlapping 8q21.11 deletions in two patients with syndromic Peters anomaly via whole exome sequencing and chromosomal microarray analyses. Microdeletions of 8q21.11 were recently reported in 10 patients with highly variable phenotypes involving craniofacial features, ptosis, intellectual disability, abnormalities of the hands/feet and other defects; sclerocornea and/or microphthalmia were reported in three cases. The two additional cases presented in this report expand the phenotypic spectrum of 8q21.11 microdeletions to include Peters anomaly (seen in both patients) and persistent primary dentition (seen in one patient with a larger deletion). The two novel deletions include the ZFHX4 and PEX2 genes, which were also affected in all three previous cases involving ocular anomalies. Screening of the remaining alleles of ZFHX4 and PEX2 did not identify any additional likely pathogenic variants in either patient, suggesting a dominant mechanism (haploinsufficiency) for the identified deletion. This report provides further insight into the phenotypes associated with 8q21.11 deletions and, for the first time, reports Peters anomaly as an additional ocular feature; screening for copy number variations of the 8q21.11 region should be considered in patients with Peters anomaly and related syndromic features. © 2016 Wiley Periodicals, Inc.
| S-EPMC5119633 | biostudies-other
Project description:Background: Neuromusculoskeletal anomalies generally in combination with severe clinical symptoms, comprise a heterogeneous group of fairly common and mostly fatal disorders in man and animals. Osteogenesis imperfecta (OI), also known as brittle bone disease, causes bone fragility and deformity. Prominent extra-skeletal accessory manifestations of OI comprise blue/gray sclerae, hearing impairment, lung abnormalities and hypercalciuria. Cases of OI in cattle have been reported. However, no causative mutations have been identified in cattle so far.Aim: To report a possible oligogenic origin identified in a calf from clinically healthy parents suffering from OI.Materials and Methods: A neonatal embryo transfer male Holstein calf developing multiple fractures with bone tissue showing marked osteopenia was used for whole genome re-sequencing as well as its parents. In addition, 2,612 randomly chosen healthy Holstein cattle were genotyped as well as controls.Results: Sixteen candidate genes with potential protein-altering variants were selected revealing non-synonymous variants only within IFITM5 and CRTAP genes. However, in-depth gene analysis did not result in the identification of a single causative mutation in the OI calf.Conclusion: The analysis of the OI case revealed a possible oligogenic origin of the disease attributable to additive effects of three candidate genes, i.e., ABCA13, QRFPR, and IFTIM5.Clinical relevance: Most OI cases in humans and domestic animals reported so far are caused by distinct dominant or recessive monogenic mutations, therefore a potential oligogenic additive genetic effect is a novel finding. Furthermore, the case presented here demonstrates that cross-species genetic analyses might not always be straightforward.
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