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1.
Mol Psychiatry ; 24(11): 1748-1768, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-29728705

RESUMEN

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.


Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Adolescente , Adulto , Animales , Niño , Preescolar , Trastorno de la Conducta/genética , Femenino , Genes Ligados a X , Células HEK293 , Humanos , Recién Nacido , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Ratones , Persona de Mediana Edad , Mutación , Linaje , Factores de Transcripción/genética , Ubiquitinación , Inactivación del Cromosoma X , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
2.
Biol Sex Differ ; 9(1): 10, 2018 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-29463315

RESUMEN

BACKGROUND: Sexual dimorphism in DNA methylation levels is a recurrent epigenetic feature in different human cell types and has been implicated in predisposition to disease, such as psychiatric and autoimmune disorders. To elucidate the genetic origins of sex-specific DNA methylation, we examined DNA methylation levels in fibroblast cell lines and blood cells from individuals with different combinations of sex chromosome complements and sex phenotypes focusing on a single autosomal region--the differentially methylated region (DMR) in the promoter of the zona pellucida binding protein 2 (ZPBP2) as a reporter. RESULTS: Our data show that the presence of the sex determining region Y (SRY) was associated with lower methylation levels, whereas higher X chromosome dosage in the absence of SRY led to an increase in DNA methylation levels at the ZPBP2 DMR. We mapped the X-linked modifier of DNA methylation to the long arm of chromosome X (Xq13-q21) and tested the impact of mutations in the ATRX and RLIM genes, located in this region, on methylation levels. Neither ATRX nor RLIM mutations influenced ZPBP2 methylation in female carriers. CONCLUSIONS: We conclude that sex-specific methylation differences at the autosomal locus result from interaction between a Y-linked factor SRY and at least one X-linked factor that acts in a dose-dependent manner.


Asunto(s)
Cromosomas Humanos X , Cromosomas Humanos Y , Metilación de ADN , Proteínas del Huevo/genética , Genes sry , Proteínas de la Membrana/genética , Caracteres Sexuales , Línea Celular , Femenino , Humanos , Masculino
3.
Am J Med Genet A ; 138A(3): 272-7, 2005 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16158429

RESUMEN

The Simpson-Golabi-Behmel syndrome (SGBS) (OMIM 312870) is an overgrowth/multiple congenital anomalies syndrome caused by a semi-dominant X-linked gene encoding glypican 3 (GPC3). It shows great clinical variability, ranging from mild forms in carrier females to lethal forms with failure to thrive in males. The most consistent findings in SGBS are pre- and postnatal macrosomia, characteristic facial anomalies and abnormalities affecting the internal organs, skeleton, and on some occasions, mental retardation of variable degree. SGBS is also associated with an increased risk of developing embryonal tumors, mostly Wilms and liver tumors. We describe two molecularly-confirmed families with SGBS. All patients had typical manifestations of SGBS including some female relatives who had minor manifestations of the disorder. Some patients had novel findings such as a deep V-shaped sella turcica and six lumbar vertebrae. Molecular studies in affected patients showed a deletion of exon 6 in family 1 and an intronic mutation in family 2.


Asunto(s)
Anomalías Múltiples/genética , Facies , Macrosomía Fetal/genética , Glipicanos/genética , Anomalías Múltiples/fisiopatología , Adulto , Secuencia de Bases , Análisis Citogenético , Femenino , Macrosomía Fetal/fisiopatología , Humanos , Lactante , Masculino , Mutación , Linaje , Eliminación de Secuencia , Síndrome
4.
Brain Dev ; 26(3): 209-12, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15030912

RESUMEN

We report another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome) characterized by mental retardation and characteristic facies: narrow forehead, synophris, hypertelorism, broad nasal bridge, long philtrum, micrognathia, triangular-shaped mouth and low posterior hairline, and also brachycephaly, calcified clinoid ligaments, and upper rib deformities. Although the severity of mental retardation within the syndrome varies, the reported case shows not only a severe degree, but also cerebral malformations not reported in any of the previous cases of cerebro-facio-thoracic syndrome. These include cortical-subcortical atrophy with hypoplasia of the corpus callosum, and of the cerebellar vermis. We also discuss the inheritance pattern and differential diagnosis, comparing this phenotype to other similar dysmorphic syndromes.


Asunto(s)
Encéfalo/anomalías , Cara/anomalías , Tórax/anomalías , Adulto , Encéfalo/patología , Cerebelo/anomalías , Aberraciones Cromosómicas , Consanguinidad , Femenino , Genes Recesivos , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Embarazo , Radiografía Torácica , Violación , Síndrome , Tomografía Computarizada por Rayos X
5.
Am J Med Genet A ; 120A(2): 222-8, 2003 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-12833403

RESUMEN

Opitz (or G/BBB) syndrome is a pleiotropic genetic disorder characterized by hypertelorism, hypospadias, and additional midline defects. This syndrome is heterogeneous with an X-linked (XLOS) and an autosomal dominant (ADOS) form. The gene implicated in the XLOS form, MID1, encodes a protein containing a RING-Bbox-Coiled-coil motif belonging to the tripartite motif (TRIM) family. To further clarify the molecular basis of XLOS, we have undertaken mutation analysis of the MID1 gene in patients with Opitz syndrome (OS). We found novel mutations in 11 of 63 male individuals referred to us as sporadic or familial X-linked OS cases. The mutations are scattered throughout the gene, although more are represented in the 3' region. By reviewing all the MID1-mutated OS patients so far described, we confirmed that hypertelorism and hypospadias are the most frequent manifestations, being present in almost every XLOS individual. However, it is clear that laryngo-tracheo-esophageal (LTE) defects are also common anomalies, being manifested by all MID1-mutated male patients. Congenital heart and anal abnormalities are less frequent than reported in literature. In addition, we can include limb defects in the OS clinical synopsis as we found a MID1-mutated patient showing syndactyly. The low frequency of mutations in MID1 and the high variability of the phenotype suggest the involvement of other genes in the OS phenotype.


Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos X/genética , Mutación , Región de Flanqueo 3' , Anomalías Múltiples/patología , Análisis Mutacional de ADN , Ligamiento Genético , Humanos , Hipertelorismo/genética , Hipertelorismo/patología , Hipospadias/genética , Hipospadias/patología , Laringe/anomalías , Masculino , Linaje , Síndrome
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