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1.
Am J Med Genet B Neuropsychiatr Genet ; 165B(4): 303-13, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24700553

RESUMEN

Genome-wide single nucleotide polymorphism (SNP) data from 936 bipolar disorder (BD) individuals and 940 psychiatrically healthy comparison individuals of North European descent were analyzed for copy number variation (CNV). Using multiple CNV calling algorithms, and validating using in vitro molecular analyses, we identified CNVs implicating several candidate genes that encode synaptic proteins, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5, as well as the neuronal splicing regulator RBFOX1 (A2BP1), and neuronal cell adhesion molecule CHL1. We have also identified recurrent CNVs on 15q13.3 and 16p11.2-regions previously reported as risk loci for neuropsychiatric disorders. In addition, we performed CNV analysis of individuals from 215 BD trios and identified de novo CNVs involving the NRXN1 and DRD5 genes. Our study provides further evidence of the occasional involvement of genomic mutations in the etiology of BD, however, there is no evidence of an increased burden of CNVs in BD. Further, the identification of CNVs at multiple members of the neurexin gene family in BD individuals, supports the role of synaptic disruption in the etiology of BD.


Asunto(s)
Trastorno Bipolar/genética , Variaciones en el Número de Copia de ADN/genética , Sinapsis/genética , Proteínas de Unión al Calcio , Canadá , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/genética , Humanos , Proteínas del Tejido Nervioso/genética , Moléculas de Adhesión de Célula Nerviosa , Reproducibilidad de los Resultados , Reino Unido , Adulto Joven
2.
Am J Hum Genet ; 85(6): 909-15, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20004765

RESUMEN

Mental retardation/intellectual disability is a devastating neurodevelopmental disorder with serious impact on affected individuals and their families, as well as on health and social services. It occurs with a prevalence of approximately 2%, is an etiologically heterogeneous condition, and is frequently the result of genetic aberrations. Autosomal-recessive forms of nonsyndromic MR (NS-ARMR) are believed to be common, yet only five genes have been identified. We have used homozygosity mapping to search for the gene responsible for NS-ARMR in a large Pakistani pedigree. Using Affymetrix 5.0 single nucleotide polymorphism (SNP) microarrays, we identified a 3.2 Mb region on 8q24 with a continuous run of 606 homozygous SNPs shared among all affected members of the family. Additional genotype data from microsatellite markers verified this, allowing us to calculate a two-point LOD score of 5.18. Within this region, we identified a truncating homozygous mutation, R475X, in exon 7 of the gene TRAPPC9. In a second large NS-ARMR/ID family, previously linked to 8q24 in a study of Iranian families, we identified a 4 bp deletion within exon 14 of TRAPPC9, also segregating with the phenotype and truncating the protein. This gene encodes NIK- and IKK-beta-binding protein (NIBP), which is involved in the NF-kappaB signaling pathway and directly interacts with IKK-beta and MAP3K14. Brain magnetic resonance imaging of affected individuals indicates the presence of mild cerebral white matter hypoplasia. Microcephaly is present in some but not all affected individuals. Thus, to our knowledge, this is the sixth gene for NS-ARMR to be discovered.


Asunto(s)
Proteínas Portadoras/genética , Quinasa I-kappa B/metabolismo , Discapacidad Intelectual/genética , Mutación , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Proteínas/genética , Adolescente , Adulto , Encéfalo/metabolismo , Niño , Preescolar , Femenino , Genes Recesivos , Humanos , Péptidos y Proteínas de Señalización Intercelular , Escala de Lod , Espectroscopía de Resonancia Magnética , Masculino , Repeticiones de Microsatélite , Linaje , Fenotipo , Unión Proteica , Quinasa de Factor Nuclear kappa B
3.
PLoS One ; 9(4): e91742, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24699272

RESUMEN

Mutations in MECP2 are responsible for the majority of Rett syndrome cases. MECP2 is a regulator of transcription, and has two isoforms, MECP2_e1 and MECP2_e2. There is accumulating evidence that MECP2_e1 is the etiologically relevant variant for Rett. In this study we aim to detect genes that are differentially transcribed in neuronal cells over-expressing either of these two MECP2 isoforms. The human neuroblastoma cell line SK-N-SH was stably infected by lentiviral vectors over-expressing MECP2_e1, MECP2_e2, or eGFP, and were then differentiated into neurons. The same lentiviral constructs were also used to infect mouse Mecp2 knockout (Mecp2(tm1.1Bird)) fibroblasts. RNA from these cells was used for microarray gene expression analysis. For the human neuronal cells, ∼ 800 genes showed >three-fold change in expression level with the MECP2_e1 construct, and ∼ 230 with MECP2_e2 (unpaired t-test, uncorrected p value <0.05). We used quantitative RT-PCR to verify microarray results for 41 of these genes. We found significant up-regulation of several genes resulting from over-expression of MECP2_e1 including SRPX2, NAV3, NPY1R, SYN3, and SEMA3D. DOCK8 was shown via microarray and qRT-PCR to be upregulated in both SK-N-SH cells and mouse fibroblasts. Both isoforms up-regulated GABRA2, KCNA1, FOXG1 and FOXP2. Down-regulation of expression in the presence of MECP2_e1 was seen with UNC5C and RPH3A. Understanding the biology of these differentially transcribed genes and their role in neurodevelopment may help us to understand the relative functions of the two MECP2 isoforms, and ultimately develop a better understanding of RTT etiology and determine the clinical relevance of isoform-specific mutations.


Asunto(s)
Biomarcadores/metabolismo , Diferenciación Celular , Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Proteína 2 de Unión a Metil-CpG/fisiología , Neuroblastoma/genética , Neuronas/metabolismo , Animales , Células Cultivadas , Fibroblastos/citología , Humanos , Ratones , Ratones Noqueados , Neuroblastoma/patología , Neuronas/citología , Análisis de Secuencia por Matrices de Oligonucleótidos , Isoformas de Proteínas , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
J Neurodev Disord ; 2(4): 182-209, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21124998

RESUMEN

Intellectual disability (ID), also referred to as mental retardation (MR), is frequently the result of genetic mutation. Where ID is present together with additional clinical symptoms or physical anomalies, there is often sufficient information available for the diagnosing physician to identify a known syndrome, which may then educe the identification of the causative defect. However, where co-morbid features are absent, narrowing down a specific gene can only be done by 'brute force' using the latest molecular genetic techniques. Here we attempt to provide a systematic review of genetic causes of cases of ID where no other symptoms or co-morbid features are present, or non-syndromic ID. We attempt to summarize commonalities between the genes and the molecular pathways of their encoded proteins. Since ID is a common feature of autism, and conversely autistic features are frequently present in individuals with ID, we also look at possible overlaps in genetic etiology with non-syndromic ID.

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