Whole-exome study to identify the causative germline mutations of congenital macrothrombocytopenia
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PROVIDER: EGAS00001000371 | EGA |
REPOSITORIES: EGA
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Project description:Leber congenital amaurosis (LCA) includes congenital or early-onset blinding diseases, characterized by vision loss together with nystagmus and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA. While most LCA is recessive, mutations in the homeodomain transcription factor gene CRX lead to autosomal dominant LCA. The mechanism of CRX-LCA is not understood. Here, we report a new spontaneous mouse mutant carrying a frameshift mutation in Crx (CrxRip). We show that, unlike Crx-/- mouse retina, the dominant Crx c.763del1 mutation in CrxRip results in congenital blindness with complete loss of ERG, yet the photoreceptors do not degenerate. Dominant CRX frameshift mutations associated with LCA mimic the CrxRip phenotype that can be rescued by Crx. RNA-Seq profiling reveals progressive and complete loss of rod differentiation factor Nrl in CrxRip, while residual Nrl remains in Crx-/- retina. Moreover, Nrl partially restores the rod phenotype in CrxRip/+ mice. We show that the binding of Otx2 to Nrl promoter is obliterated in CrxRip mutant, and ectopic Otx2 can rescue the rod phenotype. Therefore, Otx2 is required to maintain Nrl expression in developing rods to consolidate rod fate. Our studies provide the mechanism of congenital blindness caused by dominant CRX mutations and should assist in therapeutic design. Retinal samples were harvested from WT, CrxRip/+, CrxRip/Rip, Crx-/- and Nrl-/- retina at postnatal days 2 and 21 for whole transcriptome sequencing (RNAseq). Each sample included 2 independent frozen retina and experiments were performed in duplicates. RNA-seq transcriptome libraries were constructed from 1 ?g of total RNA.
2014-01-13 | E-GEOD-52006 | biostudies-arrayexpress
Project description:Leber congenital amaurosis (LCA) includes congenital or early-onset blinding diseases, characterized by vision loss together with nystagmus and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA. While most LCA is recessive, mutations in the homeodomain transcription factor gene CRX lead to autosomal dominant LCA. The mechanism of CRX-LCA is not understood. Here, we report a new spontaneous mouse mutant carrying a frameshift mutation in Crx (CrxRip). We show that, unlike Crx-/- mouse retina, the dominant Crx c.763del1 mutation in CrxRip results in congenital blindness with complete loss of ERG, yet the photoreceptors do not degenerate. Dominant CRX frameshift mutations associated with LCA mimic the CrxRip phenotype that can be rescued by Crx. RNA-Seq profiling reveals progressive and complete loss of rod differentiation factor Nrl in CrxRip, while residual Nrl remains in Crx-/- retina. Moreover, Nrl partially restores the rod phenotype in CrxRip/+ mice. We show that the binding of Otx2 to Nrl promoter is obliterated in CrxRip mutant, and ectopic Otx2 can rescue the rod phenotype. Therefore, Otx2 is required to maintain Nrl expression in developing rods to consolidate rod fate. Our studies provide the mechanism of congenital blindness caused by dominant CRX mutations and should assist in therapeutic design.
2014-01-13 | GSE52006 | GEO
Project description:Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia
| PRJNA565728 | ENA
Project description:Branchio-otic (BOS) and Branchio-oto-renal (BOR) syndromes are autosomal dominant disorders featuring multiple birth defects including ear, renal and branchial malformations. Mutations in the homeodomain transcription factor SIX1 and its co-factor EYA1 have been identified in about 50% of BOS/BOR patients, while causative mutations are unknown in the other half. We hypothesise that SIX1 target genes represent new BOS/BOR candidates. Using published transcriptomic and epigenomic data from chick ear progenitors, we first identify putative Six1 targets. Next, we provide evidence that Six1 directly regulates these targets: Six1 binds to their enhancers and functional experiments in Xenopus and chick confirm that Six1 controls their expression. Finally, we show that most chick Six1 targets are also expressed in the human developing ear and are associated with known deafness loci. Together, our results not only characterise the molecular mechanisms that mediate Six1 function in the developing ear, but also provide new candidates for human congenital deafness.
2025-03-13 | GSE278932 | GEO
Project description:In this study, we conducted integrative high-throughput analyses of peripheral blood and placental tissue from naturally infected patients in Bolivia, the country with the highest prevalence of Chagas disease and, consequently, the population with the greatest potential for congenital transmission worldwide. We compared T. cruzi-infected and uninfected patients to characterize parasite-associated alterations. Infected mothers were further classified as transmitters or non-transmitters based on the infant’s infection status, determined by serological and molecular tests. Transmitter and non-transmitter mothers were compared to understand the molecular mechanism associated with congenital transmission risk.
2026-03-12 | GSE311812 | GEO
Project description:Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal dominant inheritance. Here, we describe a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation affecting the rod domain of the protein. To demonstrate pathogenicity of this homozygous FLNC-mutation described, ultra-morphological, proteomic and functional investigations were performed in addition to immunological studies of known marker proteins for dominant filaminopathies. Our results showed that the mutant protein is expressed to similar quantities as the wildtype variant in control skeletal muscle fibres, alters the proteomic signature of quadriceps muscle, and results in the presence of ultrastructural perturbations. Moreover, comparable findings for filaminopathy marker proteins were found in both, our homozygous and a dominant case. The mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wildtype variant. These combined findings extend the currently recognized clinical, genetic and biochemical spectrum of filaminopathies. The unusual congenital presentation of the disease indicates that homozygosity for a mutation in filamin C severely aggravates the phenotype.
2020-07-24 | PXD016657 | Pride
Project description:Purpose: We identify the genetic cause of autosomal dominant congenital cataract in a large family and to define how a CRYBB2 splice-site variant perturbs lens development and associated ocular phenotypes. Methods: Whole-exome sequencing and Sanger sequencing were used for variant identification and segregation. Wild-type (WT) or mutant CRYBB2 was expressed in lens epithelial cells to assess splicing and downstream transcriptional changes by RNA sequencing and qRT-PCR. Extracellular matrix (ECM) organization and cell–matrix interactions were examined by immunostaining and adhesion assays. In zebrafish, crybb2 disruption was evaluated using lens structural assays, hyaloid vasculature imaging in Tg(flk1:EGFP) larvae, tracer distribution assays, and mRNA rescue. Single-cell RNA sequencing at 48 hpf was performed to profile lens and vascular populations and infer pathway-level changes. Results: We identified a novel CRYBB2 splice-site variant in affected members of a family with congenital cataract, consistent with an association with the disease in this pedigree. The variant disrupted normal splicing and was associated with altered βB2-crystallin–linked transcriptional programs and ECM homeostasis, including changes in collagen IV/laminin deposition and impaired cell–matrix adhesion. In zebrafish, crybb2 disruption caused lens fiber cell differentiation defects and was accompanied by abnormal hyaloid vascular patterning and altered tracer distribution around the lens; these phenotypes were partially improved by crybb2 mRNA rescue. Single-cell transcriptomic analyses suggested coordinated changes in ECM and junction/adhesion-related pathways across lens and vascular compartments, consistent with a lens-associated, non-cell-autonomous influence on adjacent vasculature. Conclusions: A novel CRYBB2 splice-site mutation is associated with autosomal dominant congenital cataract and disrupts lens homeostasis with accompanying changes in hyaloid vascular remodeling. These findings expand the pathogenic spectrum of CRYBB2 and support a model in which lens abnormalities are associated with altered lens–vascular interactions during development.
2026-05-28 | GSE333421 | GEO
Project description:Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by defective adipose tissue, extreme insulin resistance, and early onset of diabetes. There are four types of congenital generalized lipodystrophy based on the causative genetic alterations. The symptoms and the degrees of disease progression are varied among all affected individuals, which might be due to unknown genetic modifiers. To identify potential predictive biomarkers associated with the disease progressions, we recruited 7 patients (cgl2_p1,cgl2_p2,cgl2_p3,cgl2_p4,cgl2_p5,cgl2_p6,cgl2_p7),as well as gender/aged-matched controls (cgl2_c1,cgl2_c2,cgl2_c3,cgl2_c4,cgl2_c5,cgl2_c6,cgl2_c7).The total RNA samples were extracted from the participants' peripheral blood mononuclear cells, followed by RNA-Seq. To find the molecular signatures that might be associated with disease progression, patients were further categorized into sub-groups based on the results of biochemical analysis and their clinical symptoms (e.g. diabetes, metabolic syndrome and metal retardation). DEGs were identified for each sub-groups of patients, and pathway analysis was performed to explore the underlying dysregulated mechanisms.
2021-08-18 | GSE159337 | GEO
Project description:Purpose: Comorbid familial non-obstructive azoospermia (NOA) and congenital cataract (CC) has not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose is to uncover novel human mutations and genes causing familial NOA and CC. Methods: We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family.The proband was also carried out SNP array analysis. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. Results: Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and (c.688-689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient’s seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. Conclusions: We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.
2017-06-15 | GSE100019 | GEO
Project description:No major predisposing gene for familial myeloproliferative neoplasms (MPN) has been identified. Here, we demonstrate that the autosomal dominant transmission of a 700 kb duplication in four geographically-related families predisposes to MPN rapidly progressing to acute leukemia. Using induced pluripotent stem and primary cells to explore hematopoietic differentiation, we demonstrate that overexpressed ATG2B and GSKIP enhance hematopoietic progenitor differentiation, including megakaryocytic through increasing their sensitivity to TPO. ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication changes the fitness of cells harboring signaling mutations and increases the probability of disease development.
2015-08-05 | GSE67938 | GEO