RESUMO
Retinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method. One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration.
Assuntos
Proteínas de Drosophila , Proteínas do Olho/genética , Proteínas de Membrana/genética , Retinose Pigmentar/genética , Elementos Alu/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Análise Mutacional de DNA , DNA Complementar/química , DNA Complementar/genética , Drosophila melanogaster/genética , Saúde da Família , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Mutagênese Insercional , Mutação , Linhagem , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Retinose Pigmentar/patologia , Análise de Sequência de DNA , Distribuição TecidualRESUMO
Mitochondrial DNA (mtDNA) was deleted in a patient with Kearns-Sayre syndrome (KSS) presenting with a choroideremia-like fundus picture instead of pigmentary retinopathy. No evidence for X-linked choroideremia was present, and because of the strong association between KSS and deleted mtDNA, we suggest that choroideremia is a phenocopy and can be part of KSS.
Assuntos
Coroideremia/genética , DNA Mitocondrial/análise , Síndrome de Kearns-Sayre/genética , Deleção de Sequência , Adulto , Humanos , Cariotipagem , MasculinoRESUMO
A severely mentally retarded girl is presented, with symptoms as described by Pitt, Rogers, and Danks (pre- and postnatal growth retardation, and unusual facies). Additional manifestations are glaucoma, pre-auricular pits, and an atrial septal defect.
Assuntos
Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Criança , Expressão Facial , Feminino , Humanos , Fenótipo , SíndromeRESUMO
The Axenfeld-Rieger anomaly is a defect of the anterior chamber of the eye affecting the angle structures. If accompanied by hypodontia, midface hypoplasia, and umbilical anomalies, the designation "Rieger syndrome" is appropriate. Both conditions are autosomal dominant traits. The Axenfeld-Rieger anomaly is also known to occur in a variety of other syndromes. We report on two sisters, born to consanguineous parents, who presented with Axenfeld-Rieger anomaly, hydrocephalus, leptomeningeal calcifications, and mild mental retardation. Their height was on and just below the 3rd centile, respectively. One of them suffered from epilepsy and the other from sensorineural hearing loss. Two of their brothers died at young ages of hydrocephalus and possibly had intracranial calcifications as well. The differential diagnosis is discussed. Of the known syndromes associated with Axenfeld-Rieger anomaly, none could be convincingly applied to the propositae. Possibly, they represent a previously unreported autosomal recessive syndrome.
Assuntos
Anormalidades Múltiplas/genética , Câmara Anterior/anormalidades , Encefalopatias/genética , Calcinose/genética , Oftalmopatias Hereditárias/genética , Hidrocefalia/genética , Adulto , Catarata , Consanguinidade , Surdez , Cárie Dentária , Diagnóstico Diferencial , Epilepsia , Feminino , Genes Recessivos , Humanos , Deficiência Intelectual , Masculino , Núcleo Familiar , SíndromeRESUMO
Batten disease, or the juvenile form of neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder manifesting with progressive blindness, seizures, and dementia, leading to an early death. The CLN3 locus which is involved in Batten disease had been localized to chromosome 16p11.2. Linkage disequilibrium has been observed between CLN3 and polymorphic microsatellite markers D16S288, D16S299, and D16S298, making carrier detection and prenatal diagnosis by haplotype analysis possible. For the purpose of carrier detection, haplotypes from Dutch Batten patients and their families were constructed. Most patients share the same D16S298 allele, suggesting the presence of a founder effect in the Dutch population. In a large inbred Dutch family, in which Batten disease occurs with high frequency, haplotype analysis has been carried out with high accuracy for carrier detection.
Assuntos
Cromossomos Humanos Par 16 , Triagem de Portadores Genéticos , Lipofuscinoses Ceroides Neuronais/genética , Alelos , Mapeamento Cromossômico , Feminino , Marcadores Genéticos , Humanos , Endogamia , Desequilíbrio de Ligação , Masculino , Países Baixos , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/epidemiologia , Linhagem , Polimorfismo Genético , Probabilidade , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Retinitis pigmentosa (RP) denotes a group of hereditary retinal dystrophies, characterized by the early onset of night blindness followed by a progressive loss of the visual field. The primary defect underlying RP affects the function of the rod photoreceptor cell, and, subsequently, mostly unknown molecular and cellular mechanisms trigger the apoptotic degeneration of these photoreceptor cells. Retinitis pigmentosa is very heterogeneous, both phenotypically and genetically. In this review we propose a tentative classification of RP based on the functional systems affected by the mutated proteins. This classification connects the variety of phenotypes to the mutations and segregation patterns observed in RP. Current progress in the identification of the molecular defects underlying RP reveals that at least three distinct functional mechanisms may be affected: 1) the daily renewal and shedding of the photoreceptor outer segments, 2) the visual transduction cascade, and 3) the retinol (vitamin A) metabolism. The first group includes the rhodopsin and peripherin/RDS genes, and mutations in these genes often result in a dominant phenotype. The second group is predominantly associated with a recessive phenotype that results, as we argue, from continuous inactivation of the transduction pathway. Disturbances in the retinal metabolism seem to be associated with equal rod and cone involvement and the presence of deposits in the retinal pigment epithelium.
Assuntos
Retinose Pigmentar/genética , Apoptose , Proteínas do Olho/genética , Humanos , Mutação , Retinose Pigmentar/metabolismo , Retinose Pigmentar/fisiopatologia , Segmento Externo da Célula Bastonete/metabolismo , Segmento Externo da Célula Bastonete/fisiopatologia , Visão Ocular/genética , Visão Ocular/fisiologia , Vitamina A/genética , Vitamina A/metabolismoRESUMO
Retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium is a rare form of retinitis pigmentosa that starts early in life with preservation of retinal pigment epithelium adjacent to and under the retinal arterioles and that has hitherto been described as an isolated form. We examined 22 patients from one large family, together with two isolated patients, and confirmed the presumed autosomal recessive mode of inheritance in this type of retinitis pigmentosa. New findings associated with retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium were asteroid hyalosis in four (17%) of 24 patients, tortuosity of retinal arterioles in 11 (46%) of 24 patients, peripheral regions of opacified vessels in eight (33%) of 24 patients, and preservation not only of the para-arteriolar pigment epithelium, but also of the peripheral retinal pigment epithelium in 13 (54%) of 24 patients. Previously reported signs present in these patients were nystagmus in six (25%) of 24 patients, hypermetropia in 23 (96%) of 24 patients, optic nerve head drusen in nine (38%) of 24 patients, vascular sheathing in 11 (46%) of 24 patients, maculopathy in all 24 patients (100%), yellow round deposits in the posterior pole in nine (38%) of 24 patients, exudates resembling those in Coats' disease in two (8%) of 24 patients, visual field defects in all 24 patients (100%), and nondeductible electroretinograms in 21 (91%) of 23 patients. Linkage analysis carried out in the large family resulted in the assignment of a gene for retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium to chromosome 1q31-q32.1.
Assuntos
Epitélio Pigmentado Ocular/patologia , Artéria Retiniana/patologia , Retinose Pigmentar/genética , Adolescente , Adulto , Arteríolas/patologia , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Eletrorretinografia , Feminino , Angiofluoresceinografia , Fundo de Olho , Ligação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Retinose Pigmentar/patologia , Retinose Pigmentar/fisiopatologia , Estudos Retrospectivos , Acuidade VisualRESUMO
Thirty-seven patients, comprising 24 familial cases and 13 isolated patients with Usher syndrome type II (USH2), underwent ophthalmologic examination. Based on the degree of hearing loss, normal vestibular function, and gene-linkage analysis, familial cases were assumed to have USH2A. An analysis of genetic heterogeneity failed to reveal the presence of a second locus in the Dutch population. Although the patients appear to belong to a genetically homogeneous group, remarkable ophthalmologic variability was found. Corrected visual acuity decreased with age and remarkable differences in visual acuity were found within one family. Fundoscopic findings were classified as type A if attenuated vessels and bone corpuscles in all quadrants were found or as type B if findings other than these were found. The prevalence of type A significantly increased with age.
Assuntos
Surdez/complicações , Perda Auditiva Neurossensorial/complicações , Doenças Retinianas/etiologia , Retinose Pigmentar/complicações , Adolescente , Adulto , Surdez/genética , Eletroculografia , Eletrorretinografia , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Retinose Pigmentar/genética , Síndrome , Acuidade Visual , Campos VisuaisRESUMO
A mother and daughter with autosomal dominant retinitis pigmentosa (adRP) were found to carry a cytosine-to-adenine transversion mutation at codon 4 of the rhodopsin gene. This mutation predicts a substitution of lysine for threonine at one of the glycosylation sites in the rhodopsin molecule (Thr4Lys). Both patients presented with a similar phenotype including a tigroid pattern of the posterior pole and a regional predilection for degenerative pigmentary changes in the inferior retina with corresponding visual field defects. The electroretinographic pattern was suggestive of RP of the cone-rod type. This report documents the clinical findings associated with this defined mutation of the rhodopsin gene.
Assuntos
Códon/genética , Células Fotorreceptoras/patologia , Mutação Puntual , Retinose Pigmentar/genética , Rodopsina/genética , Adulto , Eletrorretinografia , Feminino , Fundo de Olho , Humanos , Lisina , Pessoa de Meia-Idade , Países Baixos , Linhagem , Retinose Pigmentar/patologia , Treonina , Testes Visuais , Campos VisuaisRESUMO
Audiograms were traced or additionally performed on 23 Usher's syndrome patients in 10 Dutch multi-affected families, all linked to chromosome 1q (USH2A locus). Serial audiograms, available in 13 patients, were used for a regression analysis of binaural pure tone average on age (follow-up, 9 to 32 years) to test for "significant progression," ie, a significant regression coefficient, here called the "annual threshold increase" (ATI, expressed in decibels per year). A significant ATI (> 1 dB/y) was observed in 3 patients. Analysis of variance of ATI demonstrated significant heterogeneity; hearing loss was either stable or progressive. This implies a significant clinical heterogeneity. A similar analysis performed on our progressive USH2A cases and "type III" cases previously reported by others (ATI of 1 to 5 dB/y), some of which were recently linked to chromosome 3q (USH3 locus), failed to show any significant heterogeneity in the progression of hearing loss.
Assuntos
Cromossomos Humanos Par 1 , Perda Auditiva Neurossensorial/congênito , Retinose Pigmentar/fisiopatologia , Adolescente , Adulto , Audiometria , Criança , Pré-Escolar , Feminino , Genes Recessivos , Ligação Genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Retinose Pigmentar/genética , SíndromeRESUMO
Leber hereditary optic neuropathy (LHON) is a heritable disorder, clinically characterized by rapidly progressive loss of central vision due to severe bilateral optic atrophy. The disease predominantly occurs in men. The clinical picture shows marked interpersonal variation. Recently it has been established that LHON is associated with at least three specific mutations in the mitochondrial DNA, which explains the non-Mendelian, strictly maternal inheritance. The presence of different mutations implies that there is not only clinical but also genetical heterogeneity. Since all matrilinear family members carry the mtDNA mutation involved, but only 30-50% of males and 5-15% of the females develop LHON, other etiological factors, hereditary or exogenous, remain to be discovered. Identification of these factors is of major importance to understand the pathogenesis and to explore the possibilities for therapy and prevention of LHON.
Assuntos
DNA Mitocondrial/genética , Atrofias Ópticas Hereditárias/genética , Adulto , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Mutação Puntual , Cromossomo XAssuntos
Oftalmopatias Hereditárias/complicações , Deficiência Intelectual/epidemiologia , Neoplasias da Retina/genética , Retinoblastoma/genética , Pré-Escolar , Feminino , Humanos , Lactente , Deficiência Intelectual/etiologia , Masculino , Países Baixos/epidemiologia , Prevalência , Sistema de RegistrosAssuntos
Anormalidades Múltiplas , Lentigo/complicações , Anus Imperfurado/cirurgia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Criança , Criptorquidismo/cirurgia , Exoftalmia/complicações , Feminino , Transtornos do Crescimento/complicações , Humanos , Iris , Masculino , Melanócitos , Pele/ultraestrutura , Síndrome , Doenças da Úvea/complicaçõesRESUMO
A 15-year-old male patient with the typical ocular symptoms of Norrie disease is described. Additionally, he presents severe mental retardation, growth disturbances, hypogonadism, and increased susceptibility to infections. This complex syndrome is apparently segregating through three generations: four other male relatives of the patient were blind from birth and died from recurrent infections between the ages of three to 15 months. The DNA sequence of the DXS7 locus (L1.28 probe), known to be closely linked to the Norrie gene, was not found in the patient's DNA. This result suggests that the more complex clinical picture seen is the result of a deletion of the X chromosome spanning DXS7, the Norrie gene, and several neighbouring loci. A detailed clinical description of the patient is given and compared to that of similar cases.
Assuntos
Deleção Cromossômica , Doenças Retinianas/genética , Aberrações dos Cromossomos Sexuais/genética , Cromossomo X/ultraestrutura , Adolescente , Cegueira/genética , Sondas de DNA , Humanos , Hipogonadismo/genética , Deficiência Intelectual/genética , Masculino , Linhagem , Descolamento Retiniano/complicações , SíndromeRESUMO
A hereditary malformation of the metatarsophalangeal joints, called here "tear drop" deformity, and a cut off appearance of the distal phalanges of the toes is described in a family with double translocation t (7; 12), t (2; 6) heterozygosity. A bracydactyly E was also found. These disorders seemed unrelated to the chromosomal aberration.
Assuntos
Anormalidades Múltiplas/genética , Dedos/anormalidades , Dedos do Pé/anormalidades , Adolescente , Feminino , Heterozigoto , Humanos , Masculino , Translocação GenéticaRESUMO
The authors present 11 patients with Peters' anomaly, short stature, brachymorphy, mental retardation, abnormal ears and cheilo(gnatho)palatoschisis. The condition can be relatively mild, but also even lethal in the fetal period.