Dataset Information

New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates.

ABSTRACT: Central areolar choroidal dystrophy (CACD) is a rare hereditary disease that mainly affects the macula, resulting in progressive and usually profound visual loss. Being part of congenital retinal dystrophies, it may have an autosomal dominant or recessive inheritance and, until now, has no effective treatment. Given the shortage of genotypic information about the disease, this work systematically reviews the literature for CACD-causing genes. Three independent researchers selected 33 articles after carefully searching and filtering the Scielo, Pubmed, Lilacs, Web of Science, Scopus, and Embase databases. Mutations of six genes (PRPH2, GUCA1A, GUCY2D, CDHR1, ABCA4, and TTLL5) are implicated in the monogenic dominant inheritance of CACD. They are functionally related to photoreceptors (either in the phototransduction process, as in the case of GUCY2D, or the recovery of retinal photodegradation in photoreceptors for GUCA1A, or the formation and maintenance of specific structures within photoreceptors for PRPH2). The identified genetic variants do not explain all observed clinical features, calling for further whole-genome and functional studies for this disease. A network analysis with the CACD-related genes identified in the systematic review resulted in the identification of another 20 genes that may influence CACD onset and symptoms. Furthermore, an enrichment analysis allowed the identification of 13 transcription factors and 4 long noncoding RNAs interacting with the products of the previously mentioned genes. If mutated or dysregulated, they may be directly involved in CACD development and related disorders. More than half of the genes identified by bioinformatic tools do not appear in commercial gene panels, calling for more studies about their role in the maintenance of the retina and phototransduction process, as well as for a timely update of these gene panels.

SUBMITTER: Kazmierczak de Camargo JP

PROVIDER: S-EPMC9152281 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates.

Kazmierczak de Camargo João Paulo JP Prezia Giovanna Nazaré de Barros GNB Shiokawa Naoye N Sato Mario Teruo MT Rosati Roberto R Beate Winter Boldt Angelica A

Frontiers in genetics 20220517

Central areolar choroidal dystrophy (CACD) is a rare hereditary disease that mainly affects the macula, resulting in progressive and usually profound visual loss. Being part of congenital retinal dystrophies, it may have an autosomal dominant or recessive inheritance and, until now, has no effective treatment. Given the shortage of genotypic information about the disease, this work systematically reviews the literature for CACD-causing genes. Three independent researchers selected 33 articles af ...[more]

PMID: 35656327

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Project description:Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration and is usually associated with mutations in the PRPH2 gene. We aimed to generate and characterize a mouse model with the p.Arg195Leu mutation previously described in patients. Heterozygous (Prph2WT/KI) and homozygous (Prph2KI/KI) mice were generated using the CRISPR/Cas9 system to introduce the p.Arg195Leu mutation. Retinal function was assessed by electroretinography and optomotor tests at 1, 3, 6, 9, 12, and 20 months of age. The structural integrity of the retinas was evaluated at the same ages using optical coherence tomography. Immunofluorescence and transmission electron microscopy images of the retina were also analyzed. Genetic sequencing confirmed that both Prph2WT/KI and Prph2KI/KI mice presented the p.Arg195Leu mutation. A progressive loss of retinal function was found in both mutant groups, with significantly reduced visual acuity from 3 months of age in Prph2KI/KI mice and from 6 months of age in Prph2WT/KI mice. Decreased amplitudes in the electroretinography responses were observed from 1 month of age in Prph2KI/KI mice and from 6 months of age in Prph2WT/KI mice. Morphological analysis of the retinas correlated with functional findings, showing a progressive decrease in retinal thickness of mutant mice, with earlier and more severe changes in the homozygous mutant mice. We corroborated the alteration of the outer segment structure, and we found changes in the synaptic connectivity in the outer plexiform layer as well as gliosis and signs of microglial activation. The new Prph2WT/KI and Prph2KI/KI murine models show a pattern of retinal degeneration similar to that described in human patients with central areolar choroidal dystrophy and appear to be good models to study the mechanisms involved in the onset and progression of the disease, as well as to test the efficacy of new therapeutic strategies.

Project description:BackgroundNetwork-based approaches for the analysis of large-scale genomics data have become well established. Biological networks provide a knowledge scaffold against which the patterns and dynamics of 'omics' data can be interpreted. The background information required for the construction of such networks is often dispersed across a multitude of knowledge bases in a variety of formats. The seamless integration of this information is one of the main challenges in bioinformatics. The Semantic Web offers powerful technologies for the assembly of integrated knowledge bases that are computationally comprehensible, thereby providing a potentially powerful resource for constructing biological networks and network-based analysis.ResultsWe have developed the Gene eXpression Knowledge Base (GeXKB), a semantic web technology based resource that contains integrated knowledge about gene expression regulation. To affirm the utility of GeXKB we demonstrate how this resource can be exploited for the identification of candidate regulatory network proteins. We present four use cases that were designed from a biological perspective in order to find candidate members relevant for the gastrin hormone signaling network model. We show how a combination of specific query definitions and additional selection criteria derived from gene expression data and prior knowledge concerning candidate proteins can be used to retrieve a set of proteins that constitute valid candidates for regulatory network extensions.ConclusionsSemantic web technologies provide the means for processing and integrating various heterogeneous information sources. The GeXKB offers biologists such an integrated knowledge resource, allowing them to address complex biological questions pertaining to gene expression. This work illustrates how GeXKB can be used in combination with gene expression results and literature information to identify new potential candidates that may be considered for extending a gene regulatory network.

Project description:BackgroundDespite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, behavior and social functioning has not been studied systematically in CG patients.MethodsTo determine if CG patients demonstrate a specific neuropsychological and psychosocial profile, we investigated intelligence, functioning on multiple cognitive domains, behavior and social functioning with a comprehensive neuropsychological test battery and questionnaires (self- and proxy-reported).ResultsThe data of 48 patients, aged 4-47 years are reported. FSIQ ranged from 45 to 103 (mean 77 ± 14). A negative correlation between age and FSIQ was demonstrated (p = 0.037) which resulted directly from the inclusion of four young 'milder' patients detected by newborn screening (NBS) with an expected better clinical outcome. Compared to normative data, patients had significantly lower but highly variable scores on all cognitive domains, especially on tests requiring mental speed. In the context of the FSIQ, 43% of the cognitive test results exceeded IQ based expectations. Overall, the patients' scores on social functioning were in the normal range but internalizing problems were frequently reported. In our cohort, an early initiation of dietary treatment due to NBS or family screening did not result in a more favorable neuropsychological outcome.ConclusionsIn this study, we demonstrated that as a cohort, CG patients have a below average intelligence and impaired cognitive functioning without a distinctive neuropsychological profile. The effect of age on neurocognitive functioning should be assessed in longitudinal studies. Social functioning was not impaired, but patients may be at risk for internalizing problems. Considering the large variability in cognitive, behavioral and social functioning and the finding that cognitive outcomes may exceed IQ based expectations, an individual evaluation and follow-up is warranted in all CG patients to ensure timely support if needed.

Dataset Information

New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates.

Publications

New Insights on the Regulatory Gene Network Disturbed in Central Areolar Choroidal Dystrophy-Beyond Classical Gene Candidates.

Similar Datasets

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