RESUMEN
Aging is a multifactorial process that affects the entire organism by cumulative alterations. Visual function impairments that go along with aging are commonly observed, causing lower visual acuity, lower contrast sensitivity, and impaired dark adaptation. Electroretinogram analysis revealed that the amplitudes of rod- and cone-mediated responses are reduced in aged mice and humans. Reports suggested that age-related changes observed in both rod and cone photoreceptor functionality were linked to oxidative stress regulation or free radical production homeostasis. Interestingly, several recent reports linked the fragile X mental retardation protein (FMRP) cellular activity with oxidative stress regulation in several tissue including brain tissue where FMRP participates to the response to stress via protein translation in neurite or is involved in free radical production and abnormal glutathione homeostasis. Based on these recent literatures, we raised the question about the effect of FMRP absence in the aging retina of Fmr1-/y compared to their WT littermates. Indeed, up to now, only young or adult mice (<6 months) were investigated and have shown a specific retinal phenotype. Herein, we demonstrated that Fmr1-/y mice do not present the aging effect on retinal function observed in WT littermates since ERG a- and b-waves amplitudes as well as oscillatory potentials amplitudes were not collapsed with age (12/18 months old). Absence of FMRP and its consequences seem to protect the retina against aging effect, rising a pivotal role of FMRP in retinal aging process.
Asunto(s)
Electrorretinografía , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Retina , Animales , Ratones , Envejecimiento/fisiología , Sensibilidad de Contraste , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Retina/patología , Células Fotorreceptoras Retinianas Conos/metabolismoRESUMEN
Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.
Asunto(s)
Trastorno Autístico/genética , Codón sin Sentido/genética , Discapacidad Intelectual/genética , Neuronas/metabolismo , Proteínas de Unión al ARN/genética , Adulto , Sustitución de Aminoácidos/genética , Animales , Trastorno Autístico/complicaciones , Línea Celular , Espinas Dendríticas/metabolismo , Regulación hacia Abajo , Femenino , Hipocampo/metabolismo , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Ratones , Persona de Mediana Edad , Linaje , Estabilidad del ARN , Proteínas de Unión al ARN/metabolismoRESUMEN
Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.
Asunto(s)
Trastorno Autístico/genética , Transmisión Sináptica , Síndrome de Asperger/genética , Síndrome de Asperger/fisiopatología , Astrocitos/patología , Astrocitos/fisiología , Trastorno Autístico/epidemiología , Trastorno Autístico/fisiopatología , Proteínas Portadoras/genética , Moléculas de Adhesión Celular Neuronal , Niño , Trastornos Generalizados del Desarrollo Infantil/epidemiología , Trastornos Generalizados del Desarrollo Infantil/genética , Comorbilidad , Epilepsia/epidemiología , Epilepsia/genética , Ácido Glutámico/fisiología , Humanos , Incidencia , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Receptores de Glutamato/genética , Receptores de Glutamato/fisiología , Transmisión Sináptica/genética , Transmisión Sináptica/fisiologíaRESUMEN
Truncating mutations were found in the PHF8 gene (encoding the PHD finger protein 8) in two unrelated families with X linked mental retardation (XLMR) associated with cleft lip/palate (MIM 300263). Expression studies showed that this gene is ubiquitously transcribed, with strong expression of the mouse orthologue Phf8 in embryonic and adult brain structures. The coded PHF8 protein harbours two functional domains, a PHD finger and a JmjC (Jumonji-like C terminus) domain, implicating it in transcriptional regulation and chromatin remodelling. The association of XLMR and cleft lip/palate in these patients with mutations in PHF8 suggests an important function of PHF8 in midline formation and in the development of cognitive abilities, and links this gene to XLMR associated with cleft lip/palate. Further studies will explore the specific mechanisms whereby PHF8 alterations lead to mental retardation and midline defects.
Asunto(s)
Cromosomas Humanos X , Labio Leporino/genética , Fisura del Paladar/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Factores de Transcripción/genética , Animales , Histona Demetilasas , Humanos , Ratones , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Transcripción GenéticaRESUMEN
Finding the diagnosis in children with mental retardation and a normal karyotype, whether or not associated with dysmorphic features, is important for defining an eventual syndrome and for genetic counselling of the families. Telomeric re-arrangements may be a common and underestimated-to-date cause of non-syndromic mental retardation. Using a FISH-based approach combining subtelomeric probes, we report the detection of 4 cases of cryptic translocations t(2;10)(p25.3;q26.3), t(4;17)(p16.2;q25), t(4;20)(p16.2;q13) and t(5;7)(p15.3;q36) associated with MR and dysmorphic features. We discuss the usefulness of subtelomeric FISH in children with unexplained delayed psychomotor development, when the genetic cause remains unknown and the karyotype is normal.
Asunto(s)
Discapacidad Intelectual/genética , Translocación Genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Preescolar , Citogenética , Femenino , Asesoramiento Genético , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Discapacidad Intelectual/diagnóstico , Masculino , Linaje , Fenotipo , Embarazo , Telómero/genéticaRESUMEN
BACKGROUND: Pseudoxanthoma elasticum (PXE) is normally associated with mutations in the ABCC6 gene. A PXE phenotype without mutations in ABCC6 has been described in Greek and Italian patients presenting with beta thalassemia. We attempted to determine the incidence of beta thalassemia in a cohort of French patients with PXE. PATIENTS AND METHODS: Fifty patients with PXE were included in the study. Laboratory examinations comprised hemoglobin electrophoresis, ABCC6 gene study and in some studies: mutation analysis, beta-globin gene. RESULTS: No cases of beta thalassemia were diagnosed in this cohort of French patients with PXE. However, 20% of the latter exhibited a significant but isolated (i.e. without microcytic anemia) increase of hemoglobin A2 (HbA2). Statistical comparisons showed no difference in terms of geographical origin or severity of PXE between patients with high levels of HbA2 and those with normal levels of HbA2 other than the extent of cutaneous involvement. Study of the beta-globin gene displayed mutations only in the two patients with the highest recorded levels of HbA2. ABCC6 + beta-globin digenism was ruled out of the pathogenesis of PXE. DISCUSSION: The PXE phenotype seen in some patients with beta thalassemia appears to be associated with epigenetic modification of ABCC6 transcription and depends specifically on the beta globin locus. Isolated increase in HbA2 is probably a laboratory marker for PXE. Here again, a functional epigenetic reaction between ABCC6 and the beta-globin locus was suspected. However, these reciprocal interactions are clearly unequal since the change in ABCC6 transcription occurring during the course of beta thalassaemia is responsible for a PXE phenotype while increased HbA2 during the course of PXE has no clinical consequences.
Asunto(s)
Hemoglobina A2/análisis , Seudoxantoma Elástico/sangre , Adolescente , Adulto , Anciano , Estudios de Cohortes , Epigénesis Genética/genética , Volumen de Eritrocitos , Femenino , Globinas/análisis , Globinas/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/análisis , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación/genética , Fenotipo , Seudoxantoma Elástico/clasificación , Seudoxantoma Elástico/genética , Transcripción Genética/genética , Talasemia beta/sangreRESUMEN
UNLABELLED: Mutations in LMNA gene encoding two ubiquitously expressed nuclear proteins, lamins A and C, give rise to up to 7 different pathologies affecting specific tissues. Three of these disorders affect cardiac and/or skeletal muscles with atrio-ventricular conduction disturbances, dilated cardiomyopathy and sudden cardiac death as common features. RESULTS: A new LMNA mutation (1621C>T, R541C) was found in two members of a French family with a history of ventricular rhythm disturbances and an uncommon form of systolic left ventricle dysfunction. The two patients: the proband and his daughter, were affected and exhibited an atypical form of dilated cardiomyopathy with an unexplained left ventricle aneurysm revealed by ventricular rhythm disturbances without atrio-ventricular block. CONCLUSION: This finding reinforces the highly variable phenotypic expression of LMNA mutation and emphasizes the fact that LMNA mutations can be associated with different cardiac phenotypes.
Asunto(s)
Aneurisma Cardíaco/genética , Ventrículos Cardíacos/patología , Lamina Tipo A/genética , Adulto , Cardiomiopatía Dilatada , Análisis Mutacional de ADN , Femenino , Aneurisma Cardíaco/patología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/genéticaRESUMEN
It has been demonstrated in several X-linked disorders, both with and without mental retardation, that the X-inactivation process plays a significant role in the expression of X-linked diseases in females. Moreover, in some disorders extremely skewed inactivation of the X chromosome is constant in carriers, and this is thought to result from a proliferation or a survival advantage for cells expressing the normal allele at this locus over cells expressing the mutated allele. X-linked mental retardation (XLMR) is heterogeneous, and cloning and characterization of the mutated genes are in progress. XLMR can be expressed in carrier females but often with milder manifestations. We report the systematic study of the X-inactivation profile of obligate carriers and other females in 19 multiplex XLMR pedigrees, using leucocyte-extracted DNA. Extremely skewed profiles were observed in carriers in three of 19 families.
Asunto(s)
Compensación de Dosificación (Genética) , Discapacidad Intelectual/genética , Cromosoma X/genética , Salud de la Familia , Femenino , Ligamiento Genético , Haplotipos , Heterocigoto , Humanos , Masculino , Repeticiones de Microsatélite , LinajeRESUMEN
FG syndrome is an X-linked incomplete recessive condition comprising mental retardation, congenital hypotonia, macrocephaly, a distinctive facial appearance, and constipation or anal malformations. Here, we report on a chromosome X inversion [inv(X)(q12q28)] in a boy with FG syndrome and in his mentally retarded maternal uncle, and we discuss the possible involvement of this paracentric inversion in the FG syndrome.
Asunto(s)
Anomalías Múltiples/genética , Inversión Cromosómica , Cromosoma X/genética , Adulto , Preescolar , Salud de la Familia , Femenino , Humanos , Lactante , Discapacidad Intelectual/genética , Cariotipificación , Masculino , Linaje , SíndromeRESUMEN
Linkage analysis was performed in a family with non-specific X-linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non-specific X-linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping.
Asunto(s)
Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Cromosoma X , Adulto , Mapeo Cromosómico , Facies , Femenino , Francia , Tamización de Portadores Genéticos , Ligamiento Genético , Humanos , Recién Nacido , Discapacidad Intelectual/fisiopatología , Masculino , Pruebas Neuropsicológicas , LinajeRESUMEN
Linkage analysis was performed in three generations of a French family segregating a syndromal form of X-linked mental retardation. All affected males had neonatal hypotonia, seizures, muscular hypodevelopment, and severe mental deficiency. A peak lod score of 2.90 at a recombination fraction of theta = 0 was detected for DXS 1052 and DXS 451 (Xp22.13). Recombination between the disease locus and the polymorphic markers in DXS7163 and DXS1238 suggested a gene mapping to the Xp22.13-Xp21.2 region. Three candidate genes in this region were investigated: the cDNA for kinase Rsk-2 involved in Coffin-Lowry syndrome, the brain-specific exon of a transcript in the DMD locus (DP140 isoform of dystrophin), and exon 18 of the glycerol kinase gene, which is specific to fetal brain transcripts. All three sequences were normal.
Asunto(s)
Ligamiento Genético , Discapacidad Intelectual/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa , Cromosoma X/genética , Adulto , Niño , Mapeo Cromosómico , Citogenética , Distrofina/genética , Cara/anomalías , Femenino , Glicerol Quinasa/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/patología , Escala de Lod , Masculino , Hipotonía Muscular/congénito , Hipotonía Muscular/genética , Linaje , Proteínas Quinasas/genética , Convulsiones/genética , SíndromeRESUMEN
FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Inversión Cromosómica , Cromosoma X , Canal Anal/anomalías , Encéfalo/anomalías , Cromosomas Artificiales de Levadura/genética , Cósmidos/genética , Electroforesis en Gel de Campo Pulsado , Facies , Salud de la Familia , Ligamiento Genético , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Masculino , Modelos Genéticos , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , SíndromeRESUMEN
FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.
Asunto(s)
Anomalías Múltiples/genética , Cromosoma X , Mapeo Cromosómico , Cara/anomalías , Femenino , Heterogeneidad Genética , Humanos , Discapacidad Intelectual/genética , Masculino , Hipotonía Muscular/congénito , Hipotonía Muscular/genética , Linaje , SíndromeRESUMEN
We report two cases of t(8;9) with probable breakpoints in 8q12 and 9p21 in malignant lymphoma. In a review of the literature, we found two cases of acute lymphocytic leukemia and one case of malignant lymphoma which probably share the same breakpoints.
Asunto(s)
Cromosomas Humanos Par 8 , Cromosomas Humanos Par 9 , Linfoma/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética , Anciano , Niño , Femenino , Marcadores Genéticos , Humanos , Cariotipificación , Masculino , Persona de Mediana EdadRESUMEN
We report three cases of chromosome 13 rearrangements as additional abnormalities in two patients with Burkitt lymphoma (BL) and one with type 3 acute lymphoblastic leukemia (ALL). Involvement of chromosome 13 has been reported most often as 13q+, without identification of the supplementary chromosomal material; in our three cases with 13q+, we identified two duplications: dup(13)(q13q22) and dup(13)(q21q22).
Asunto(s)
Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 13 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Anciano , Niño , Preescolar , Femenino , Humanos , Cariotipificación , MasculinoRESUMEN
We report a female with a de novo 46,X,der(X)t(X;Y) (p22;q12) translocation who presented with short stature, mild clinical features of Turner syndrome and a Madelung deformity. It appears that some particular radiological and/or clinical skeletal features are common in females carrying X-Y translocation. Based on the corresponding papers and on clinical findings of our patient we discuss the significance of Madelung deformity encountered in X-Y translocations, dyschondrosteosis and Turner syndrome.
Asunto(s)
Estatura , Huesos/anomalías , Translocación Genética , Síndrome de Turner , Cromosoma X , Cromosoma Y , Adulto , Femenino , HumanosAsunto(s)
Análisis Mutacional de ADN/métodos , Trastornos del Desarrollo Sexual , Proteínas del Grupo de Alta Movilidad/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Osteocondrodisplasias/genética , Eliminación de Secuencia , Factores de Transcripción/genética , Región de Flanqueo 5' , Animales , Secuencia de Bases , Huesos/diagnóstico por imagen , Preescolar , Cromosomas Humanos X , Cromosomas Humanos Y , Secuencia Conservada , Femenino , Peces/genética , Humanos , Lactante , Masculino , Ratones , Datos de Secuencia Molecular , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/diagnóstico por imagen , Linaje , Radiografía , Secuencias Reguladoras de Ácidos Nucleicos , Reproducibilidad de los Resultados , Factor de Transcripción SOX9 , SíndromeAsunto(s)
Cromosomas Humanos X/genética , Hibridación de Ácido Nucleico/métodos , Aberraciones Cromosómicas Sexuales , Cromosomas Artificiales Bacterianos/genética , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Cariotipificación , Masculino , Reproducibilidad de los ResultadosRESUMEN
Risk for leukemic conditions increases in individuals with Down syndrome. We report a third trimester antenatal diagnosis of leukemia in a Down syndrome fetus. The third trimester ultrasound examination revealed a hepatosplenomegaly, which may suggest a myelopoiesis disorder. A review of the literature of eight cases described antenatally and 14 cases in the immediate neonatal period is presented.