Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FG syndrome (OMIM 305450) is an X-linked condition comprising mental retardation, congenital hypotonia, constipation or anal malformations, and a distinctive appearance with disproportionately large head, tall and broad forehead, cowlicks and telecanthus. In a first linkage analysis carried out on 10 families, we demonstrated heterogeneity and assigned one gene [FGS1] to region Xq12-q21.31 [Briault et al., 1997: Am J Med Genet 73:87-90] corroborated by Graham et al. [1998: Am J Med Genet 80:145-156]. Heterogeneity was supported by the study of one family with apparent FG syndrome co-segregating with an inversion of X chromosome [inv(X)(q11q28)] ([FGS2], OMIM 300321) [Briault et al., 1999: Am J Med Genet 86:112-114 and Briault et al., 2000: Am J Med Genet 95:178-181]. We present the results of a new linkage analysis carried out on two families with FG syndrome. The two earlier known loci for FG syndrome, FGS1 and FGS2 (Xq11 or Xq28) were excluded by multipoint analysis of both families. Linkage was found, however, with locus DXS1060 suggesting that a third FG locus might be located at Xp22.3. In this region, two potential candidate genes, VCX-A and PRKX, were excluded by sequence analysis of the coding region in patients of the two reported FG families. The search for new candidate genes is in progress.
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PMID:FG syndrome: linkage analysis in two families supporting a new gene localization at Xp22.3 [FGS3]. 1223 12

FG syndrome (FGS, MIM 305450) is a rare X-linked recessive disorder comprising mental retardation and multiple malformations. Various families have been described to date, increasing our knowledge of the phenotype variability and making the clinical diagnosis complex, especially in sporadic patients. The first locus for FG syndrome (FGS1) was linked to chromosome region Xq12-q21.31, but other families have been excluded from this locus. The genetic heterogeneity of FG syndrome has been confirmed by analysis of an X chromosome inversion [inv(X)(q11q28)] in an affected boy and in his mentally retarded maternal uncle, suggesting that an additional locus for FG syndrome (FGS2, MIM 300321) is located at either Xq11 or Xq28. Recently, a third locus (FGS3) has been mapped to Xp22.3. We have identified and clinically characterized an Italian FG family, including 31 members with three affected males in two generations and two obligate carriers. We have excluded linkage to known FGS loci, whereas an extensive study of the whole X chromosome has yielded a maximum LOD score (Z(max)) of 2.66 (recombination fraction=0) for markers between DXS8113 and sWXD805. This new locus for FG syndrome corresponds to a region of approximately 4.6 Mb on the X chromosome.
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PMID:Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. 1252 52

We describe two brothers with a unique pattern of malformations that includes coloboma (iris, optic nerve), high forehead, severe retrognathia, mental retardation, and agenesis of the corpus callosum (ACC). Both boys have low-set cupped ears with sensorineural hearing loss, normal phallus, pectus excavatum, scoliosis, and short stature. One brother had choanal atresia and cardiac defects consisting of ventricular septal defect (VSD) and patent ductus arteriosus (PDA) which resolved spontaneously. Differential diagnosis between a number of clinical entities was considered, however, because ACC and the distinctive facial features were reminiscent of FG syndrome, DNA was analyzed for markers linked to the FGS1 locus at Xq13-q21. Notably, the brothers were concordant for markers spanning this presumed FG region, and in both we have identified adjacent alterations (-57delT and T-55A) in the Alpha 4 gene located within this interval. Alpha 4 is a regulatory subunit of the major cellular phosphatase, PP2A, that has recently been shown to interact with MID1, the product of the gene mutated in X-linked Opitz GBBB syndrome. The double nucleotide change identified in this family was not observed in 410 control chromosomes, suggesting that it may be a pathogenetic change. Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome.
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PMID:A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13. 1455 45

Opitz-Kaveggia syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. We report here that the original family for whom the condition is named and five other families have a recurrent mutation (2881C>T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.
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PMID:A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. 1733 63

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.
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PMID:The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. 1736 3

FG syndrome was originally described as a rare syndromic cause of X-linked mental retardation associated with congenital heart disease, anal atresia, inguinal hernia, cryptorchidism, and other anomalies. However, recent reports have highlighted the more common milder presentation which has for cardinal features developmental delay, particularly in speech, neonatal hypotonia, relative macrocephaly, dysmorphic facial features, severe constipation, and few if any congenital malformations. Thus far, five separate loci have been identified on the X chromosome but attempts at finding the responsible gene have not yet been successful. Given that one putative FG locus (FGS2) is situated at Xq28, which is the location of the Filamin A gene (FLNA), and that a Filamin A mutation was reported in a boy with facial dysmorphism and constipation, it was hypothesized that Filamin A mutations could be one cause of FG syndrome. Indeed, a previously unreported FLNA missense mutation (P1291L) was detected in our patient with FG syndrome, thus supporting this hypothesis and indicating that FG syndrome could now be added to the list of Filamin A-related disorders. Filamin A studies in other children with FG syndrome would help to confirm this association.
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PMID:Filamin A mutation is one cause of FG syndrome. 1763 75

Mediator occupies a central role in RNA polymerase II transcription as a sensor, integrator, and processor of regulatory signals that converge on protein-coding gene promoters. Compared to its role in gene activation, little is known regarding the molecular mechanisms and biological implications of Mediator as a transducer of repressive signals. Here we describe a protein interaction network required for extraneuronal gene silencing comprising Mediator, G9a histone methyltransferase, and the RE1 silencing transcription factor (REST; also known as neuron restrictive silencer factor, NRSF). We show that the MED12 interface in Mediator links REST with G9a-dependent histone H3K9 dimethylation to suppress neuronal genes in nonneuronal cells. Notably, missense mutations in MED12 causing the X-linked mental retardation (XLMR) disorders FG syndrome and Lujan syndrome disrupt its REST corepressor function. These findings implicate Mediator in epigenetic restriction of neuronal gene expression to the nervous system and suggest a pathologic basis for MED12-associated XLMR involving impaired REST-dependent neuronal gene regulation.
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PMID:Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation. 1869 61

Opitz and Kaveggia [Opitz and Kaveggia (1974); Z Kinderheilk 117:1-18] reported on a family of five affected males with distinctive facial appearance, mental retardation, macrocephaly, imperforate anus and hypotonia. Risheg et al. [Risheg et al. (2007); Nat Genet 39:451-453] identified an identical mutation (p.R961W) in MED12 in six families with Opitz-Kaveggia syndrome, including a surviving affected man from the family reported in 1974. The previously defined behavior phenotype of hyperactivity, affability, and excessive talkativeness is very frequent in young boys with this mutation, along with socially oriented, attention-seeking behaviors. We present case studies of two older males with FG syndrome and the p.R961W mutation to illustrate how their behavior changes with age. We also characterize the behavior of eight additional individuals with FG syndrome and this recurrent mutation in MED12 using the Vineland Adaptive Behavior Scales 2nd edition, the Reiss Profile of Fundamental Goals and Motivation Sensitivities, and the Achenbach Child Behavior Checklist. Males with this MED12 mutation had deficits in communication skills compared to their socialization and daily living skills. In addition, they were at increased risk for maladaptive behavior, with a propensity towards aggression, anxiety, and inattention. Based on the behavior phenotype in 10 males with this recurrent MED12 mutation, we offer specific recommendations and interventional strategies. Our findings reinforce the importance of testing for the p.R961W MED12 mutation in males who are suspected of having developmental and behavioral problems with a clinical phenotype that is consistent with FG syndrome.
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PMID:Behavior of 10 patients with FG syndrome (Opitz-Kaveggia syndrome) and the p.R961W mutation in the MED12 gene. 1897 76

Rarely in the history of medicine has an X-linked mental retardation syndrome so thoroughly entered every branch of medicine, at least of pediatrics, but also of internal medicine, on account of its protean manifestations. In such countries as Zambia, malaria, tuberculosis, HIV, and other infections diseases, and many environmental and nutritional disorders still top the list of childhood morbidity and mortality. However, in the more developed nations of the Old and New Worlds, prematurity, birth defects, and genetic conditions constitute the major burden of infant mortality adn chronic childhood handicaps. One of the most pervasive of these is the group of FG syndromes seen in every pediatric clinic and mental health service. Thus, in our experience FGS emerges as the most common yet the least known developmental disabilities condition in our society. FGS imposes a tremendous burden of morbidity, and to some extent also of mortality, on society and families. After successful neonatal adaptation, such recurring problems as otitis, reactive airway disease, and constipation can be routinely treated symptomatically. However, the neurodevelopmental burden represents the greatest challenge that FGS presents for families and to society. Under the best of circumstances, motor and speech development catch up. However, virtually all FGS children, boys and girls, have difficulties in psychologic development, school performance, and ultimate emotional adaptation to adult life and social integration. The many such cases added to those with outright psychiatric disturbances are overwhelming social, psychologic, and psychiatric services and, above all, public and private school systems, which are understaffed, under-funded, beyond formulating individual educational plans, and helpless to deal with the enormous burden of special service needs of these children. It's time that handicapped children receive care according to needs and not according to diagnosis. However, the near absence of information on FGS available to these professionals is a handicap in arriving at a specific diagnosis (allowing state and federal support for special services) and in understanding the prognosis, natural history, and such complications as "autism," seizures, and tethered cord that affect the child's success at home, in school, and out in society. The FGS parent support group has been of enormous help in informing families about all of these "issues," and to this day remains the greatest repository of knowledge on FGS. As they say in baseball, it is time at long last for the professionals "to step up to the plate."
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PMID:The FG syndromes (Online Mendelian Inheritance in Man 305450): perspective in 2008. 1904 30

First described in 1974, FG syndrome (FGS) is an X-linked multiple congenital anomaly/mental retardation (MCA/MR) disorder, characterized by high clinical variability and genetic heterogeneity. Five loci (FGS1-5) have so far been linked to this phenotype on the X chromosome, but only one gene, MED12, has been identified to date. Mutations in this gene account for a restricted number of FGS patients with a more distinctive phenotype, referred to as the Opitz-Kaveggia phenotype. We report here that a p.R28L (c.83G-->T) missense mutation in CASK causes FGS phenotype in an Italian family previously mapped to Xp11.4-p11.3 (FGS4). The identified missense mutation cosegregates with the phenotype in this family and is absent in 1000 control X chromosomes of the same ethnic origin. An extensive analysis of CASK protein functions as well as structural and dynamic studies performed by molecular dynamics (MD) simulation did not reveal significant alterations induced by the p.R28L substitution. However, we observed a partial skipping of the exon 2 of CASK, presumably a consequence of improper recognition of exonic splicing enhancers (ESEs) induced by the c.83G-->T transversion. CASK is a multidomain scaffold protein highly expressed in the central nervous system (CNS) with specific localization to the synapses, where it forms large signaling complexes regulating neurotransmission. We suggest that the observed phenotype is most likely a consequence of an altered CASK expression profile during embryogenesis, brain development, and differentiation.
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PMID:A missense mutation in CASK causes FG syndrome in an Italian family. 1920 May 22


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