RESUMEN
The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function.
Asunto(s)
Genes Ligados a X , Discapacidad Intelectual/genética , Antígenos Nucleares/genética , Proteínas de Ciclo Celular , Cromosomas Humanos X , Duplicación de Gen , Pruebas Genéticas/métodos , Humanos , Proteína 2 de Unión a Metil-CpG , Proteína Proteolipídica de la Mielina/genética , Monoéster Fosfórico Hidrolasas/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
X-Linked intellectual disability (XLID) accounts for 5%-10% of intellectual disability in males. Over 150 syndromes, the most common of which is the fragile X syndrome, have been described. A large number of families with nonsyndromal XLID, 95 of which have been regionally mapped, have been described as well. Mutations in 102 X-linked genes have been associated with 81 of these XLID syndromes and with 35 of the regionally mapped families with nonsyndromal XLID. Identification of these genes has enabled considerable reclassification and better understanding of the biological basis of XLID. At the same time, it has improved the clinical diagnosis of XLID and allowed for carrier detection and prevention strategies through gamete donation, prenatal diagnosis, and genetic counseling. Progress in delineating XLID has far outpaced the efforts to understand the genetic basis for autosomal intellectual disability. In large measure, this has been because of the relative ease of identifying families with XLID and finding the responsible mutations, as well as the determined and interactive efforts of a small group of researchers worldwide.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Mapeo Cromosómico/historia , Mapeo Cromosómico/métodos , Femenino , Síndrome del Cromosoma X Frágil/historia , Síndrome del Cromosoma X Frágil/psicología , Genes Ligados a X/genética , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/historia , Masculino , MutaciónRESUMEN
A novel missense mutation in the mediator of RNA polymerase II transcription subunit 12 (MED12) gene has been found in the original family with Lujan syndrome and in a second family (K9359) that was initially considered to have Opitz-Kaveggia (FG) syndrome. A different missense mutation in the MED12 gene has been reported previously in the original family with FG syndrome and in five other families with compatible clinical findings. Neither sequence alteration has been found in over 1400 control X chromosomes. Lujan (Lujan-Fryns) syndrome is characterised by tall stature with asthenic habitus, macrocephaly, a tall narrow face, maxillary hypoplasia, a high narrow palate with dental crowding, a small or receding chin, long hands with hyperextensible digits, hypernasal speech, hypotonia, mild-to-moderate mental retardation, behavioural aberrations and dysgenesis of the corpus callosum. Although Lujan syndrome has not been previously considered to be in the differential diagnosis of FG syndrome, there are some overlapping clinical manifestations. Specifically, these are dysgenesis of the corpus callosum, macrocephaly/relative macrocephaly, a tall forehead, hypotonia, mental retardation and behavioural disturbances. Thus, it seems that these two X-linked mental retardation syndromes are allelic, with mutations in the MED12 gene.
Asunto(s)
Anomalías Múltiples/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación Missense/genética , Fenotipo , Receptores de Hormona Tiroidea/genética , Anomalías Múltiples/patología , Humanos , Masculino , Complejo Mediador , Discapacidad Intelectual Ligada al Cromosoma X/patología , LinajeRESUMEN
Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.
Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Transportadores de Ácidos Monocarboxílicos/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Cromosomas Humanos X , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Mutación , Paraplejía/genética , Linaje , SimportadoresRESUMEN
The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.
Asunto(s)
Epilepsia/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Receptores de Superficie Celular/genética , ATPasas de Translocación de Protón Vacuolares/genética , Empalme Alternativo , Secuencia de Aminoácidos , Elementos de Facilitación Genéticos , Epilepsia/metabolismo , Exones , Femenino , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/metabolismo , Datos de Secuencia Molecular , Mutación , Linaje , Receptores de Superficie Celular/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiología , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.
Asunto(s)
Empalme Alternativo/genética , ADN Helicasas/genética , Exones/genética , Mutación del Sistema de Lectura/genética , Genes Recesivos/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteínas Nucleares/genética , Secuencia de Aminoácidos , Cromosomas Humanos X/genética , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Sitios de Empalme de ARN/genética , Proteína Nuclear Ligada al Cromosoma XAsunto(s)
Proteínas Portadoras , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Mutación/genética , Proteínas Nucleares/genética , Anomalías Múltiples/genética , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas de Unión al ADN , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Microcefalia/complicaciones , Datos de Secuencia Molecular , Proteínas Nucleares/química , Linaje , SíndromeRESUMEN
Polyamines (putrescine, spermidine, spermine) are ubiquitous, simple molecules that interact with a variety of other molecules in the cell, including nucleic acids, phospholipids and proteins. Various studies indicate that polyamines are essential for normal cell growth and differentiation. Furthermore, these molecules, especially spermine, have been shown to modulate ion channel activities of certain cells. Nonetheless, little is known about the specific cellular functions of these compounds, and extensive laboratory investigations have failed to identify a heritable condition in humans in which polyamine synthesis is perturbed. We report the first polyamine deficiency syndrome caused by a defect in spermine synthase (SMS). The defect results from a splice mutation, and is associated with the Snyder-Robinson syndrome (SRS, OMIM_309583), an X-linked mental retardation disorder. The affected males have mild-to-moderate mental retardation (MR), hypotonia, cerebellar circuitry dysfunction, facial asymmetry, thin habitus, osteoporosis, kyphoscoliosis, decreased activity of SMS, correspondingly low levels of intracellular spermine in lymphocytes and fibroblasts, and elevated spermidine/spermine ratios. The clinical features observed in SRS are consistent with cerebellar dysfunction and a defective functioning of red nucleus neurons, which, at least in rats, contain high levels of spermine. Additionally, the presence of MR reflects a role for spermine in cognitive function, possibly by spermine's ability to function as an 'intrinsic gateway' molecule for inward rectifier K(+) channels.
Asunto(s)
Poliaminas Biogénicas/metabolismo , Cromosomas Humanos X , Ligamiento Genético , Espermina Sintasa/genética , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Linaje , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Mental retardation (MR) affects an estimated 2-3% of the population. A considerable fraction of mental retardation is due to X-linked genes. Of these genes, about 136 are responsible for syndromic X-linked MR (XLMR). One such XLMR syndrome, Stocco dos Santos, was first described in 1991. This family was re-visited, which allowed further delineation of the clinical phenotype. Additionally, linkage analysis was conducted, which resulted in the localization of this XLMR syndrome to the pericentric region, Xp11.3 to Xq21.1, with a maximum LOD score of 3.14 at loci AR and DXS983.
Asunto(s)
Cromosomas Humanos X , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mapeo Cromosómico , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Escala de Lod , Masculino , Linaje , Fenotipo , SíndromeRESUMEN
This report describes a family with mental retardation in two brothers. The pedigree is consistent with either X-linked mental retardation or autosomal recessive inheritance. The clinical features consist of coarse face, prominent lower lip, large testes, and obesity. This same constellation of findings was observed in a family with X-linked mental retardation (XLMR) reported by Shashi et al. [2000: Am J Hum Genet 66:469-479]. Furthermore, haplotype analysis was consistent with localization of the Shashi XLMR syndrome in Xq26-q27. Thus, the family likely represents a second occurrence of the Shashi XLMR syndrome.
Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/genética , Adulto , Femenino , Marcadores Genéticos , Humanos , Masculino , LinajeRESUMEN
Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, approximately 50% demonstrate markedly skewed X inactivation (i.e., patterns > or =80:20), compared with only approximately 10% of female control subjects (P<.001). Thus, skewed X inactivation is a relatively common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns > or =80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome.
Asunto(s)
Compensación de Dosificación (Genética) , Ligamiento Genético , Discapacidad Intelectual/genética , Estudios de Casos y Controles , Femenino , Heterocigoto , Humanos , Masculino , Mutación , Linaje , Receptores Androgénicos/genéticaRESUMEN
A family with X-linked mental retardation characterized by severe mental retardation, speech and behavioral abnormalities, and seizures in affected male patients has been found to have a G1141C transversion in the creatine-transporter gene SLC6A8. This mutation results in a glycine being replaced by an arginine (G381R) and alternative splicing, since the G-->C transversion occurs at the -1 position of the 5' splice junction of intron 7. Two female relatives who are heterozygous for the SLC6A8 mutation also exhibit mild mental retardation with behavior and learning problems. Male patients with the mutation have highly elevated creatine in their urine and have decreased creatine uptake in fibroblasts, which reflects the deficiency in creatine transport. The ability to measure elevated creatine in urine makes it possible to diagnose SLC6A8 deficiency in male patients with mental retardation of unknown etiology.