RESUMO
Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.
Assuntos
Catarata/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Nucleares/genética , Adulto , Sequência de Bases , Catarata/congênito , Catarata/metabolismo , Criança , Pré-Escolar , Feminino , Dosagem de Genes , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Recém-Nascido , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Linhagem , Adulto JovemRESUMO
Neonatal herpetic infection is uncommon, with an estimated incidence of 1 in 3000 to 20,000 births. Ocular involvement most commonly consists of blepharoconjunctivitis or keratitis. We present a further manifestation of congenital herpes simplex virus (HSV) 2 infection.
Assuntos
Infecções Oculares Virais/virologia , Herpes Genital/transmissão , Herpesvirus Humano 2/isolamento & purificação , Macula Lutea/patologia , Doenças Retinianas/virologia , DNA Viral/análise , Diagnóstico Diferencial , Infecções Oculares Virais/congênito , Infecções Oculares Virais/diagnóstico , Feminino , Seguimentos , Herpes Genital/virologia , Herpesvirus Humano 2/genética , Humanos , Recém-Nascido , Macula Lutea/virologia , Doenças Retinianas/congênito , Doenças Retinianas/diagnósticoRESUMO
Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.