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1.
Genes Cells ; 28(7): 482-495, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37073980

RESUMO

Histone methylation plays a vital role in retinal development. However, the role of histone H3K36 methylation in retinal development is not clear. We examined the role of H3K36 methylation by loss-of-function analysis of H3K36me1/2 demethylases, Fbxl10, and Fbxl11. We analyzed the effect of knockout of these genes in the developing and mature retina on retinal development. Knockout of Fbxl10 specifically in the developing retina did not result in gross developmental abnormalities. Although adult rod photoreceptor-specific knockout of Fbxl11 in mature retinas did not result in morphological abnormalities, Fbxl11 knockout in developing retinas increased apoptosis, suppressed the proliferation of retinal progenitor cells, and resulted in microphthalmia. Morphological analysis revealed perturbed differentiation of rod photoreceptor and bipolar cells. RNA-seq of retinas at P7 showed markedly decreased expression of genes characterizing rod photoreceptor and bipolar cells in Fbxl11-knockout retinas. In addition, perturbation of alternative splicing increased intron retention in Fbxl11-knockout retinas. Genome-wide evaluation of the H3K36 methylation status revealed that Fbxl11 knockout altered the distribution of H3K36me2/3 in genes important for rod photoreceptor development. Taken together, we show that Fbxl11 plays pivotal roles in the development of retinal late-born cell types and may contribute to tight control of H3K36 methylation during retinal development.


Assuntos
Histona Desmetilases , Histonas , Diferenciação Celular/genética , Histona Desmetilases/genética , Histonas/genética , Histonas/metabolismo , Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes , Animais , Camundongos
2.
Biochem Biophys Res Commun ; 503(4): 3023-3030, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30146259

RESUMO

We found that the Zhx2 gene (whose product is known to act as a tumor suppressor in hepatocellular carcinoma) is expressed in embryonic retinal progenitors and in developing cone bipolar cells in the postnatal retina, as well as in Müller glia in the mature retina. To examine the functions of Zhx2 protein during retinal development, we performed loss- and gain-of-function analyses using a retinal explant culture system. We introduced a plasmid encoding Zhx2 shRNA into isolated mouse retinas at E17.5, and the retinas were cultured as explants. After 3 days of culture, proliferation was slightly enhanced, leading to retinas thicker than in the control, but this phenomenon was observed only transiently. After 14 days of the culture, the thickness and gross morphology of retinas expressing sh-Zhx2 were indistinguishable from those of the control. The numbers of rod cells, amacrine cells, and Müller glia were the same in both groups. However, although the total number of bipolar cells was the same, the experimental group saw an increased population of ON bipolar cells, and decreased numbers of a subset of OFF bipolar cells. We also examined the effects of overexpression of Zhx2. Although Zhx2 acts as a tumor suppressor, its overexpression in developing retinas did not lead to any discernible difference in retinal thickness, suggesting that proliferation activity was not affected. After 14 days of explant culture, the total number of bipolar cells decreased, and subset composition was altered. Taken together, these results suggest that Zhx2 plays roles in the regulation of bipolar cell subset fate determination during retinal development.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Retina/citologia , Retina/crescimento & desenvolvimento , Células Amácrinas/citologia , Células Amácrinas/metabolismo , Animais , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/metabolismo , Camundongos Endogâmicos ICR , Neurogênese , Neuroglia/citologia , Neuroglia/metabolismo , Retina/embriologia , Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/citologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo
3.
J Hum Genet ; 63(8): 893-900, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29760528

RESUMO

The macula is a unique structure in higher primates, where cone and rod photoreceptors show highest density in the fovea and the surrounding area, respectively. The hereditary macular dystrophies represent a heterozygous group of rare disorders characterized by central visual loss and atrophy of the macula and surrounding retina. Here we report an atypical absence of ON-type bipolar cell response in a Japanese patient with autosomal dominant macular dystrophy (adMD). To identify a causal genetic mutation for the adMD, we performed whole-exome sequencing (WES) on four affected and four-non affected members of the family for three generations, and identified a novel p.C538Y mutation in a post-synaptic gene, LRRTM4. WES analysis revealed seven rare genetic variations in patients. We further referred to our in-house WES data from 1360 families with inherited retinal diseases, and found that only p.C538Y mutation in LRRTM4 was associated with adMD-affected patients. Combinatorial filtration using public database of single-nucleotide polymorphism frequency and genotype-phenotype annotated database identified novel mutation in atypical adMD.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Degeneração Macular/patologia , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Células Bipolares da Retina/patologia , Adulto , Sequência de Aminoácidos , Animais , Povo Asiático , Pré-Escolar , Eletrorretinografia , Família , Feminino , Genes Dominantes , Haplorrinos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/química , Linhagem , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Sequenciamento do Exoma
4.
Psychiatry Clin Neurosci ; 62(2): 152-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18412836

RESUMO

AIM: Although recent epidemiological studies on the pervasive development disorders (PDD) appear to be reporting higher rates of incidence than previously believed, great variation in the reported figures suggests a need for review of the methodology involved. As such, a survey on the incidence of PDD was conducted and compared with data from a previous survey to examine the effects of screening and diagnostic methodology on incidence. METHODS: The incidence of pervasive developmental disorders was surveyed in all children (12 589) born between January 1994 and December 1996 in Toyota, Japan. RESULTS: Incidence was 1.81% and the ratio of boys to girls was 2.80. Definitive diagnoses were made between 13 months and 7 years 2 months, the average age at diagnosis being 3 years 4 months. Among the cases of PDD, children with normal or borderline intelligence amounted to 66.4%, mild mental retardation (MR) 17.5%, moderate MR 10.3% and severe MR 5.8%. CONCLUSION: An approximately 11-fold increase was noted in prevalence of PDD compared to a previous survey two decades ago, and two main factors were believed to account for this apparent sharp increase. First, inclusion of high-functioning subjects detected during infancy, and second, higher rates of diagnosis resulting from an integrated process of screening.


Assuntos
Transtorno Autístico/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Programas de Rastreamento/estatística & dados numéricos , População Urbana/estatística & dados numéricos , Transtorno Autístico/diagnóstico , Transtorno Autístico/psicologia , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/psicologia , Pré-Escolar , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Lactente , Inteligência , Japão , Masculino
5.
Invest Ophthalmol Vis Sci ; 58(14): 6020-6029, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196766

RESUMO

Purpose: To report the clinical characteristics of asymptomatic cases with RP1L1 gene mutations in four families with occult macular dystrophy (OMD). Methods: Four asymptomatic cases from four families were selected from a cohort of 40 subjects (16 families) with RP1L1 pathogenic variants. Clinical data of the four asymptomatic cases and three symptomatic patients in the same families were reviewed. The three asymptomatic cases did not have any visual symptoms in either eye, and one was unilaterally affected. Ophthalmologic examinations, including spectral-domain optical coherence tomography (OCT) were performed, and the morphologic characteristics of the photoreceptor layer of the asymptomatic cases were compared to those of the symptomatic patients within the same family. Results: The OCT images demonstrated photoreceptor abnormalities in the parafoveal regions in all of the four asymptomatic cases (i.e., absence of the interdigitation zone and blurring of the ellipsoid zone). However, these microstructures were preserved at the foveal center. The longitudinal reflectivity profiles clearly identified this distinct pattern in the asymptomatic cases. In contrast, no distinct abnormalities were detected by other examinations including perimetry, fundus autofluorescence images, and multifocal electroretinograms (ERGs). Conclusions: The sparing of the central foveal photoreceptor layer accounts for the well-preserved visual acuity in the asymptomatic patients. The sparing may represent either the initial phase of typical OMD or a subtype of macular lesion associated with OMD. It is necessary to examine asymptomatic subjects in families with OMD because some of them may progress to the typical phenotype of OMD.


Assuntos
DNA/genética , Proteínas do Olho/genética , Fóvea Central/patologia , Degeneração Macular/genética , Mutação , Segmento Interno das Células Fotorreceptoras da Retina/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Angiofluoresceinografia , Fóvea Central/metabolismo , Fundo de Olho , Humanos , Degeneração Macular/metabolismo , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Segmento Interno das Células Fotorreceptoras da Retina/metabolismo , Tomografia de Coerência Óptica , Adulto Jovem
6.
Jpn J Ophthalmol ; 61(1): 92-98, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27718025

RESUMO

PURPOSE: The 2 most common causative genes for achromatopsia (ACHM) are CNGA3 and CNGB3; other genes including GNAT2 account for only a small portion of ACHM cases. The cone mosaics in eyes with CNGA3 and CNGB3 variants are severely disrupted; the cone mosaics in patients with GNAT2-associated ACHM; however, have been reported to show a contiguous pattern in adaptive optics (AO) retinal images. The purpose of this study was to analyze the cone mosaic of another case of GNAT2-associated ACHM. PATIENT AND METHODS: The patient was a 17-year-old Japanese boy. Comprehensive ocular examinations including fundus photography, electroretinography (ERGs), optical coherence tomography (OCT), and whole-exome analysis were performed. The cone mosaic was recorded with a flood-illuminated AO fundus camera, and the cone density was compared with those of 10 normal control eyes. RESULTS: The patient had the typical phenotype of ACHM, and a novel homozygous variant, c.730_743del, in GNAT2 was identified. The fundus did not show any specific abnormalities, and the OCT images showed the presence of the ellipsoid zone. The AO fundus image showed a clearly defined cone mosaic around the fovea. The cone density at 500 µm from the fovea was reduced by 15-30 % as compared with those of the normal eyes. CONCLUSIONS: This is the first description of a Japanese patient with ACHM with a novel GNAT2 variant. The eyes of this patient had a preserved cone structure with loss of function.


Assuntos
Defeitos da Visão Cromática/diagnóstico , Proteínas do Olho/genética , Células Fotorreceptoras Retinianas Cones/citologia , Adolescente , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/metabolismo , Eletrorretinografia , Proteínas do Olho/metabolismo , Angiofluoresceinografia , Fundo de Olho , Variação Genética , Humanos , Masculino , Acuidade Visual , Testes de Campo Visual
7.
Invest Ophthalmol Vis Sci ; 57(11): 4837-46, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27623337

RESUMO

PURPOSE: To determine the clinical and genetic characteristics of Japanese patients with occult macular dystrophy (OMD) in a nationwide multicenter study. METHODS: Twenty-three patients from 21 families with clinically diagnosed OMD were studied at 10 institutions throughout Japan. Ophthalmologic examinations including spectral-domain optic coherence tomography were performed. Patients were classified into two phenotype groups: a classical group having both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors, and a nonclassical group lacking at least one of these two features. Whole-exome sequencing, direct sequencing, and in silico molecular analysis were performed to detect the pathogenic RP1L1 variants. Statistical associations between the phenotype and genotypes based on the presence of pathogenic RP1L1 variants were investigated. RESULTS: There were 12 families with the classical findings and 9 families with the nonclassical findings. Nine pathogenic RP1L1 missense variants were identified in 12 families (57%) including three reported variants, namely, p.R45W, p.S1199C, and p.G1200A, and six novel variants, p.G221R, p.T1194M, p.T1196I, p.G1200D, p.G1200V, and p.V1201G. The pathogenic missense variants in seven families (33%) were located between amino acid numbers 1196 and 1201. A significant association was found between the photoreceptor microstructural phenotypes and molecular genotypes. CONCLUSIONS: The spectrum of the morphologic phenotypes and pathogenic RP1L1 variants was documented in a well-characterized Japanese cohort with OMD. A unique motif including six amino acids (1196-1201) downstream of the doublecortin domain could be a hot spot for RP1L1 pathogenic variants. The significant association of the morphologic phenotypes and genotypes indicates that there are two types of pathophysiology underlying the occult macular dysfunction syndrome: a hereditary OMD with the classical phenotype (Miyake's disease), and a nonhereditary OMD-like syndrome with progressive occult maculopathy.


Assuntos
DNA/genética , Proteínas do Olho/genética , Degeneração Macular/genética , Mutação , Retina/patologia , Adolescente , Adulto , Idoso , Análise Mutacional de DNA , Eletrorretinografia , Proteínas do Olho/metabolismo , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Genótipo , Humanos , Incidência , Japão/epidemiologia , Degeneração Macular/epidemiologia , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retina/metabolismo , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
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