RESUMEN
In a monozygotic twin couple with mental retardation (MR), we identified a maternally inherited inversion and a paternally inherited translocation: 46,XY,inv(10)(p11.2q21.2)mat,t(9;18)(p22;q21.1)pat. The maternally inherited inv(10) was a benign variant without any apparent phenotypical implications. The translocation breakpoint at 9p was within a cluster of interferon α genes and the 18q21 breakpoint truncated ZBTB7C (zinc finger and BTB containing 7C gene). In addition, analyses with array-CGH revealed a 931 kb maternally inherited deletion on chromosome 8q22 as well as an 875 kb maternally inherited duplication on 5p14. The deletion encompasses the RIM2 (Rab3A-interacting molecule 2), FZD6 (Frizzled homolog 6) and BAALC (Brain and Acute Leukemia Gene, Cytoplasmic) genes and the duplication includes the 5' end of the CDH9 (cadherin 9) gene. Exome sequencing did not reveal any additional mutations that could explain the MR phenotype. The protein products of the above mentioned genes are involved in different aspects of brain development and/or maintenance of the neurons which suggest that accumulation of genetic defects segregating from both parents might be the basis of MR in the twins. This hypothesis was further supported by protein interaction analysis.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Discapacidad Intelectual/genética , Gemelos Monocigóticos/genética , Animales , Niño , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Duplicación Cromosómica , Exones/genética , Regulación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Fenotipo , Mapeo de Interacción de Proteínas , Proteínas/genética , ARN Mensajero/genética , Translocación GenéticaRESUMEN
Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with unknown aetiology. Even though ASDs are suggested to be among the most heritable complex disorders, only a few reproducible mutations leading to susceptibility for ASD have been identified. In an attempt to identify ASD susceptibility genes through chromosome rearrangements, we investigated a female patient with childhood autism and high-grade myopia, and an apparently balanced de novo translocation, t(5;18)(q34;q12.2). Further analyses revealed a 3.2 Mb deletion encompassing 17 genes at the 18q break point and an additional deletion of 1.27 Mb containing two genes on chromosome 4q35. Q-PCR analysis of 14 of the 17 genes deleted on chromosome 18 showed that 11 of these genes were expressed in the brain, suggesting that haploinsufficiency of one or more genes may have contributed to the childhood autism phenotype of the patient. Identification of multiple genetic changes in this patient with childhood autism agrees with the most frequently suggested genetic model of ASDs as complex, polygenic disorders.
Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 18 , Miopía/genética , Eliminación de Secuencia , Adulto , Trastorno Autístico/complicaciones , Niño , Femenino , Humanos , Hibridación in Situ , Miopía/complicaciones , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
In the human embryo, from approximately 6 weeks gestational age (GA), dopaminergic (DA) neurons can be found in the ventral mesencephalon (VM). More specifically, the post-mitotic neurons are located in the ventral part of the tegmentum (VT), whereas no mature DA neurons are found in the neighboring dorsal part. We used Affymetrix HG-U133 GeneChip technology to compare genome-wide expression profiles of ventral and dorsal tegmentum from 8 weeks GA human embryos, in order to identify genes involved in specification, differentiation, and survival of mesencephalic DA (mDA) neurons. Known mDA marker genes including ALDH1A1, DAT1, VMAT2, TH, CALB1, NURR1, FOXA1, GIRK2, PITX3, RET, and DRD2 topped the list of 96 genes from HG-U133A with higher expression in VT, validating the experimental set-up. In addition, 28 probes from HG-U133B were identified whereof most are annotated to UniGene clusters with no gene associated or to genes of unknown function. Of these, the fifteen most regulated transcripts, representing changes down to 56% could be verified by quantitative real-time PCR (Q-PCR) on a developmental series of subdissected human embryonic and fetal brain material, resulting in not only a regional but also a temporal expression profile. This revealed a distinct DA-associated profile for in particular a putative transcription factor (FLJ45455) and the uncharacterized transmembrane proteins KIAA1145 and SLC10A4. The data presented here may help to device cell replacement and regenerative therapies for Parkinson's disease (PD).
Asunto(s)
Regulación del Desarrollo de la Expresión Génica/genética , Mesencéfalo/metabolismo , Neuronas/metabolismo , Factores de Transcripción/metabolismo , Análisis por Conglomerados , Dopamina/metabolismo , Embrión de Mamíferos , Feto , Edad Gestacional , Humanos , Mesencéfalo/citología , Mesencéfalo/embriología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factores de Transcripción/genéticaRESUMEN
Sonic hedgehog (SHH) is involved in the induction and differentiation of nigrostriatale dopaminergic neurons. We have investigated the promoter, two putative enhancer elements and the coding region of SHH for mutations in patients with Parkinson's disease (PD). None of the identified sequence variations were present at a significantly different frequency in PD patients compared to healthy individuals, suggesting that they are not involved in the pathogenesis of PD.