RESUMEN
Previous studies provide evidence for a genetic component for susceptibility to bipolar affective disorder (BPAD) in the old-order Amish population. El-Mallakh and Wyatt [1995: Biol Psychiatry 37:235-244] have suggested that the Na(+),K(+)-ATPase may be a candidate gene for BPAD. This study examines the relationship between BPAD in the old-order Amish cohort and the Na(+),K(+)-ATPase alpha1 and beta3 subunit genes (ATP1A3, ATP1B3). A total of 166 sibling pairs were analyzed for linkage via nonparametric methods. Suggestive levels of statistical significance were not reached in any stratification model for affective illness. Overall, the results do not support linkage of bipolar disorder to the Na(+),K(+)-ATPase alpha subunit gene (ATP1A3) and beta subunit gene (ATP1B3) in these old-order Amish families and they show that these Na(+),K(+)-ATPase subunit genes are not major effect genes (>or=fourfold increased genetic risk of disease) for BPAD in the old-order Amish pedigrees. We cannot exclude other genetic variants of the Na(+),K(+)-ATPase hypothesis for BPAD, whereby other loci may modifying Na(+),K(+)-ATPase activity.
Asunto(s)
Trastorno Bipolar/genética , Ligamiento Genético , ATPasa Intercambiadora de Sodio-Potasio/genética , Trastorno Bipolar/epidemiología , Trastorno Bipolar/etnología , Estudios de Casos y Controles , Estudios de Cohortes , Etnicidad/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Núcleo Familiar , Subunidades de Proteína , Estadísticas no ParamétricasRESUMEN
Childhood-onset schizophrenia (COS) is defined by the development of first psychotic symptoms by age 12. While recruiting patients with COS refractory to conventional treatments for a trial of atypical antipsychotic drugs, we discovered a unique case who has a familial t(1;7)(p22;q21) reciprocal translocation and onset of psychosis at age 9. The patient also has symptoms of autistic disorder, which are usually transient before the first psychotic episode among 40-50% of the childhood schizophrenics but has persisted in him even after the remission of psychosis. Cosegregating with the translocation, among the carriers in the family available for the study, are other significant psychopathologies, including alcohol/drug abuse, severe impulsivity, and paranoid personality and language delay. This case may provide a model for understanding the genetic basis of schizophrenia or autism. Here we report the progress toward characterization of genomic organization across the translocation breakpoint at 7q21. The polymorphic markers, D7S630/D7S492 and D7S2410/D7S646, immediately flanking the breakpoint, may be useful for further confirming the genetic linkage for schizophrenia or autism in this region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:749-753, 2000. Published 2000 Wiley-Liss, Inc.
Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 7/genética , Esquizofrenia/genética , Translocación Genética , Trastorno Autístico/patología , Niño , Rotura Cromosómica/genética , Cromosomas Bacterianos , Mapeo Contig , ADN/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Esquizofrenia/patologíaRESUMEN
We determined the genomic organization of the human OPA-containing gene (HOPA) and characterized its developmental expression. The gene encoding HOPA, which contains a rare polymorphism tightly associated with non-specific mental retardation, is 25 kb in length and consists of 44 exons. A promoter scan analysis demonstrates two possible transcription initiation sites without TATA boxes upstream from the putative translation initiation start site. Several informative polymorphisms are evident in the sequence including a large pentanucleotide repeat. Northern blot analysis of the gene transcript and its murine orthologue, MOPA-1, demonstrates that only one transcript is expressed throughout the soma and the CNS, and that the transcript is highly expressed during early fetal development. We conclude that the delineation of the function of the HOPA gene locus merits further study.
Asunto(s)
Cromosoma X , Northern Blotting , Encéfalo/metabolismo , Cósmidos , ADN Complementario/análisis , Embrión de Mamíferos/metabolismo , Genotipo , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Polimorfismo Genético , Análisis de Secuencia de ADN , Síndrome , Distribución TisularRESUMEN
Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5. 22 x 10(-4); SIBPAL Pempirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3.29, P = 2.57 x 10(-3); SIBPAL Pempirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 4 , Etnicidad/genética , Salud Mental , Adulto , Trastorno Bipolar/epidemiología , Cristianismo , Mapeo Cromosómico , ADN/sangre , Ligamiento Genético , Marcadores Genéticos , Genotipo , Humanos , Persona de Mediana Edad , Pennsylvania/epidemiología , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
We have systematically isolated and characterized DNA containing large CTG (n > 7) repeats from a human cosmid genomic DNA library. Using a CTG10 probe, more than 100 cosmid clones were identified, and 30 of these have been extensively characterized. The sequenced cosmids contain repeats that are between three and 19 perfect units (average 10 perfect repeats). The cosmids map to at least 12 different chromosomes. Sequence analysis of flanking regions suggests that more than one third of the repeats occur in exons, and many share strong sequence identity with databank sequences, including the gene involved in dentatorubral pallidoluysian atrophy (DRPLA). Genotyping of human DNA samples demonstrates that more than half of the repeats are polymorphic. This and similar collections of clones containing trinucleotide repeats should aid in the identification of genes that may contain expansions of trinucleotide repeats involved in human disease.
Asunto(s)
Cósmidos/genética , Repeticiones de Trinucleótidos/genética , Animales , Mapeo Cromosómico , Clonación Molecular , Cósmidos/aislamiento & purificación , Biblioteca de Genes , Humanos , Hibridación Fluorescente in Situ , Ratones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Análisis de Secuencia de ADNRESUMEN
Mental retardation is a prominent feature of many neurodevelopmental syndromes. In an attempt to identify genetic components of these illnesses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<< 1% in non-iII males) having an increased prevalence in non-Fragile X males with mental retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-Fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher prevalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multivariate analysis was conducted in an effort to identify other phenotypic components in affected individuals, and the findings suggested an increased incidence of histories of hypothyroidism (P < 0.001) and treatment with antidepressants (P < 0.001). We conclude that the presence of this 12-bp variant confers significant susceptibility for mental retardation.
Asunto(s)
Elementos Transponibles de ADN , Variación Genética , Discapacidad Intelectual/genética , Polimorfismo Genético , Cromosoma X , Alelos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , California/epidemiología , Mapeo Cromosómico , Secuencia Conservada , Cósmidos , Europa (Continente)/epidemiología , Exones , Femenino , Finlandia/epidemiología , Síndrome del Cromosoma X Frágil/genética , Biblioteca de Genes , Humanos , Hipotiroidismo/epidemiología , Hipotiroidismo/genética , Hibridación Fluorescente in Situ , Masculino , Ratones , Datos de Secuencia Molecular , Prevalencia , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Repeticiones de TrinucleótidosRESUMEN
The complete spectrum of clinical phenotypes resulting from glucocerebrosidase deficiency continues to evolve. While most patients with Gaucher disease have residual glucocerebrosidase activity, we describe a fetus with severe prenatal lethal type 2 (acute neuronopathic) Gaucher disease lacking glucocerebrosidase activity. This 22-week fetus was the result of a first cousin marriage and had hydrops, external abnormalities, hepatosplenomegaly, and Gaucher cells in several organs. Fetal fibroblast DNA was screened for common Gaucher mutations, none of which was detected. Southern blot analysis using the restriction enzymes SstII and SspI ruled out a fusion gene, deletion, or duplication of either allele, and quantitative studies of SspI digested genomic DNA indicated that both alleles were present. Northern blot analysis of total RNA from fetal fibroblasts demonstrated no detectable transcription, although RT-PCR successfully amplified several exons, suggesting the presence of a very unstable mRNA. Direct PCR sequencing of all exons demonstrated a homozygous frameshift mutation (deletion of a C) on codon 139 in exon 5, thereby introducing a premature termination codon in exon 6. The absence of glucocerebrosidase protein was confirmed by Western analysis. This unique case confirms the essential role of glucocerebrosidase in human development and, like the null allele Gaucher mouse, demonstrates the lethality of a homozygous null mutation. The presence of this novel mutation and the resulting unstable mRNA accounts for the severity of the phenotype observed in this fetus, and contributes to the understanding of genotype/phenotype correlation in Gaucher disease.
Asunto(s)
Muerte Fetal , Enfermedad de Gaucher/enzimología , Eliminación de Gen , Glucosilceramidasa/genética , Homocigoto , Southern Blotting , Western Blotting , Exones , Femenino , Mutación del Sistema de Lectura , Enfermedad de Gaucher/embriología , Enfermedad de Gaucher/genética , Enfermedad de Gaucher/mortalidad , Glucosilceramidasa/metabolismo , Humanos , Masculino , Linaje , Reacción en Cadena de la Polimerasa , EmbarazoRESUMEN
Exposure of cultured cerebellar granule neurons to subtoxic concentrations of N-methyl-D-aspartate (NMDA) has been shown previously to result in a neuroprotective state, as measured by subsequent exposure to toxic concentrations of glutamate. In the present study, we have further characterized the excitoprotective actions of NMDA in these neurons. NMDA-induced excitoprotection was concentration dependent (EC50 approximately 30 microM) and time dependent, with maximal protection observed following 16 h of preexposure to NMDA. NMDA-induced excitoprotection did not require continuous exposure to NMDA, as a 4-h preincubation was sufficient to induce full excitoprotection when measured 8 h later. Maximal protection was manifest as a "right shift" in the concentration-response relationship for glutamate toxicity of approximately three orders of magnitude (EC50 approximately 30 microM in untreated neurons compared with > or = 50 mM in NMDA-treated neurons). After removal of NMDA, complete reversal of the excitoprotective state was observed by 48 h (t1/2 approximately 24 h). The ability of NMDA to induce excitoprotection was observed in neurons maintained for up to 14 days in vitro (DIV) [postnatal day (PND) 22], but was absent at 21 and 32 DIV (PND 29-40), despite little to no difference in the toxicity of glutamate at any DIV examined. Preexposure of cerebellar granule neurons to a maximally excitoprotective concentration of NMDA (50 microM) failed to alter the density of NMDA receptors measured by the specific binding of [3H]MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)