This was a prospective study including 261 patients with multiple congenital malformations with or without mental retar- dation (MCA/MR). Clinical geneticists evaluated all patients prior to referral to the study. Common aneuploidies, such as trisomies 21, 13, 18 and Turner syndrome, were not included. The ﬁrst 209 patients were assessed for the presence of prenatal growth retar- dation, postnatal growth abnormalities, facial and non-facial dys- morphisms, congenital abnormalities and familial occurrence of mentalretardation and were given a de Vries score (a check list for subtelomeric imbalances) . The de Vries score was used as an abnormality evaluation, not as criteria for inclusion or exclusion in molecular screening. The presence and severity of mental retar- dation could not be determined for all cases because many patients were neonates or younger than three years old at the time of referral.
SUMO-binding proteins interact with SUMO modified proteins to mediate a wide range of functional consequences. Here, we report the identification of a new SUMO-binding protein, ZNF261. Four human proteins including ZNF261, ZNF198, ZNF262, and ZNF258 contain a stretch of tandem zinc fingers called myeloproliferative and mentalretardation (MYM)-type zinc fingers. We demonstrated that MYM-type zinc fingers from ZNF261 and ZNF198 are necessary and sufficient for SUMO- binding and that individual MYM-type zinc fingers function as SUMO-interacting motifs (SIMs). Our binding studies revealed that the MYM-type zinc fingers from ZNF261 and ZNF198 interact with the same surface on SUMO-2 recognized by the archetypal consensus SIM. We also present evidence that MYM-type zinc fingers in ZNF261 contain zinc, but that zinc is not required for SUMO-binding. Immunofluorescence microscopy studies using truncated fragments of ZNF198 revealed that MYM-type zinc fingers of ZNF198 are necessary for localization to PML-nuclear bodies (PML-NBs). In summary, our studies have identified and characterized the SUMO-binding activity of the MYM-type zinc fingers in ZNF261 and ZNF198.
Background: BC RNAs and the fragile X mentalretardation protein (FMRP) are translational repressors that have been implicated in the control of local protein synthesis at the synapse. Work with BC1 and Fmr1 animal models has revealed that phenotypical consequences resulting from the absence of either BC1 RNA or FMRP are remarkably similar. To establish functional interactions between BC1 RNA and FMRP is important for our understanding of how local protein synthesis regulates neuronal excitability.
The RNA-binding protein Fragile X MentalRetardation (FMRP) is an evolutionarily conserved protein that is particularly abundant in the brain due to its high expression in neurons [1,2,3]. The absence of FMRP causes the development of Fragile X syndrome, the most frequent form of hereditary mental re- tardation [4,5]. FMRP is considered to be a nucleocytoplasmic shuttling protein [6,7,8,9]. In the cytoplasm, the major fraction of FMRP is associated with mRNP complexes bound to polyribo- somes [10,11,12], in support of a translational role for FMRP [5,13,14,15]. In neurons, FMRP may also act as a translational repressor by trapping mRNAs into neuronal RNA granules which are then transported out of the soma in a repressed state until they reach their destination in the neurites . It was previously suggested that mammalian FMRP might also promote translation repression of its mRNA targets under stress conditions by trapping them into stress granules (SG) . SG are cytoplasmic bodies whose formation during stress correlates with the inhibition of translation initiation and might constitute the actual sites where stalled translation initiation complexes accumulate [17,18]. The formation of SG, which occurs under stress conditions, requires
Marfanoid features associated with mentalretardation are often a diagnostic challenge for general neurologists, since sev- eral genetic and inborn metabolic diseases present this clinical spectrum. Some of these diseases have typical clinical markers that may aid diagnosis. For instance, Lujan-Fryns syndrome is a recessive X-linked condition characterized by mental retar- dation, marfanoid habitus, and facial dysmorphisms 1,2 .
The fragile X syndrome is the most common X- linked mentalretardation disorder affecting ~1 in 4,000 males and ~1 in 8,000-9,000 females (Crawford et al., 2001). The Fragile-X MentalRetardation 1 gene (FMR1) was cloned in 1991 (Oberlé et al., 1991; Verkerk et al., 1991; Yu et al., 1991), and the vast majority of fragile-X cases are due to expansions of the polymorphic CGG trinucleotide repeat in the 5’-untranslated region of the gene. In the general population, CGG-repeat size varies from 6 to 55. In affected individuals the repeat greatly ex- ceeds 200 and transcription silencing of FMR1 gene occurs (Pieretti et al., 1991), thus characterizing the full mutation. Alleles with repeats in the ~55-200 range, which are tran- scribed, but unstable, may expand to full mutations upon maternal transmission. These are known as premutations. Indeed the boundary between common and premutation al-
(typical species, hand with enlarged thumb, anal sounds in the speech attempt) and genetically (karyotype). Even with this early diagnosis and the beginning of treatment, clinical repercussions are still present: deficit in school learning, showing that currently he can count from 1 to 20 and write his name, but the school grades are maximum. This is justified by the presence of mild mentalretardation and the anatomical differences in the hands due to the syndrome, writing becomes more difficult. It is worth mentioning that he studies in a school for children with some special need, but that aims at social inclusion.
A clinical study of Brazilian patients with neurofibromatosis type 1 (NF1) was performed in a multidisciplinary Neurofibromatosis Pro- gram called CEPAN (Center of Research and Service in Neurofibro- matosis). Among 55 patients (60% females, 40% males) who met the NIH criteria for the diagnosis of NF1, 98% had more than six café-au- lait patches, 94.5% had axillary freckling, 45% had inguinal freckling, and 87.5% had Lisch nodules. Cutaneous neurofibromas were ob- served in 96%, and 40% presented plexiform neurofibromas. A posi- tive family history of NF1 was found in 60%, and mentalretardation occurred in 35%. Some degree of scoliosis was noted in 49%, 51% had macrocephaly, 40% had short stature, 76% had learning difficulties, and 2% had optic gliomas. Unexpectedly high frequencies of plexi- form neurofibromas, mentalretardation, learning difficulties, and scoliosis were observed, probably reflecting the detailed clinical analysis methods adopted by the Neurofibromatosis Program. These same patients were screened for mutations in the GAP-related do- main/GRD (exons 20-27a) by single-strand conformation polymor- phism. Four different mutations (Q1189X, 3525-3526delAA, E1356G, c.4111-1G>A) and four polymorphisms (c.3315-27G>A, V1146I, V1317A, c.4514+11C>G) were identified. These data were recently published.
Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mentalretardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.
We investigated the chromosomal constitution of patients with mentalretardation and/or congenital malformations in order to determine genetic causes for such disturbances. The GTG and CBG banding patterns were studied using phytohemagglutinin M-stimulated lympho- cytes cultured from peripheral blood. Among 98 individuals with mentalretardation and/or congenital malformations who were analyzed there were 12 cases of Down’s syndrome, two of Edward’s syndrome, one of Patau’s syndrome, five of Turner’s syndrome, two of Klinefelter’s syndrome, one of “cri-du-chat” syndrome, one case of a balanced translocation between chromosomes 13 and 14, one case of a derivative chromosome and one of a marker chromosome. We found abnormal chromosomes in 26% of the patients, 82% of which were numerical abnormalities, with the remaining 18% being structural variants. We conclude that patients with mentalretardation and/or congenital malformations should be routinely karyotyped.
One of the consequences of human brain ex- posure to MeHg is cognitive damages, which can cause loss of intelligence and mentalretardation. According to the American Association of Men- tal Retardation, this diagnosis is configured when the individual has a low IQ and adaptive injury. There are different levels of mentalretardation and it is estimated that 85% of cases are of mild type (MMR), which has an idiopathic nature in most cases. The MMR is considered one of the most common psychiatric disorders in children and adolescents, with prevalence ranging from 1 to 3% in the population 15 .
Retardation X-related). ATRX is localized on the X chromosome in position Xq13.1–q21.1. Individuals with mutations in this gene present several phenotypic charateristics that may include mentalretardation, craniofacial and urogenital deformities, psychomotor failure and alpha-thalassemia . Since its description, there have been important advances in the characterization of the molecular functions of the protein encoded by this gene. In humans, there are mainly two isoforms named hATRX (289 kDa) and hATRXt (t, from truncated, 200 kDa) that are encoded by this gene . Both proteins contain an amino-terminal domain which is composed of PHD and GATA-like zinc fingers, named ADD after the three proteins that contain this domain (ATRX, DNMT3b and DNMT3L). It was recently demonstrated through different in vitro and in vivo approaches that this domain recognizes the combination of K9me3 and unmethylated K4 residues of the histone H3 tail . This domain directs the protein mainly to pericentric heterochromatin . Mutations described in patients afflicted with the syndrome mainly affect the important amino acids that form the "pocket" of the ADD domain for the histone H3 tail recognition. The hATRX protein additionally has a helicase/ATPase domain, which classifies it as a member of the SNF2 subfamily of chromatin remodelers . The hATRX SNF2 domain has in vitro ATPase activity, which can be stimulated both by DNA and nucleosomes . About 50% of the mutations described in patients fall in the ADD domain, whereas the other 50% affect the SNF2 helicase/ATPAse and other protein domains . hATRX, as many chromatin remodelers, has been identified as a component of a complex that includes the histone variant H3.3 chaperone DAXX (Death domain Associated protein). This particular histone variant is incorporated at different chromatin regions, such as promoters, enhancers and heterochromatic regions, and it has been proposed to have dual functions in promoting both an active chromatin state and the maintenance of hetero- chromatin . hATRX ATPase activity is important for incorporation of the histone variant H3.3 by the chaperone DAXX into specific regions of the chromosomes, such as telomeres and pericentric heterochromatin .
Annotation. Purpose: to study the rehabilitation program recovery of motor function of children with mentalretardation. Material-methods: the study involved 19 students from primary diagnosis - mentalretardation. Age of children was 8 - 9 years and 9 - 10 years. Motor speed detection reaction carried out using a falling line setting (in cm.) Determination of speed integral motor actions performed with running 30 meters to go. From cross-country test also used the shuttle run 4x9 meters. Results: a program of exercise for children with mentalretardation. Exercises aimed at correcting the basic movements, flexibility correction, correction and development of coordination abilities, adjustment and development of physical fitness, correction and prevention of secondary fractures. Conclusions: it was found that the rehabilitation program for development and correction of motor function of children with mentalretardation is an effective and affordable to adjust coordination abilities and flexibility.
Fragile X syndrome (FXS) is the most common cause of heritable mentalretardation. Expansion of trinucleotide CGG repeats in the Fmr1 gene results in hypermethylation and loss-of- function of the gene . Fmr1 encodes Fragile X mentalretardation protein (FMRP), an mRNA-binding protein that regulates local mRNA translation. FMRP is expressed in layer IV of sensory cortex, with peak expression in the critical period of cortical plasticity, during which pronounced synaptogenesis and dendritic rearrangement occur, suggesting its role in developmen- tal plasticity [2,3]. Lack of FMRP exaggerates mGluR-stimulated protein synthesis and has been hypothesized to underlie many of the abnormal phenotypes of FXS [4,5].
According with Lorna Wing, the degree of autism varies with the deficits observed over time at social in- teraction, verbal and non-verbal communication and the use of imagination, being called the “Triade of Social Impediments” . Deviations of these disturbances re- sult from their very heterogeneous and mostly unknown aetiology . So, description of autistic spectrum goes far from strict definitions, including individuals with low cognitive potential that reveal deficit on reciprocal ver- bal communication and repetitive behaviours together with mentalretardation and those having high cognitive potential that even having deficit in social interaction with repetitive and stereotyped behaviours, do not show retardation in speech development (like in the As-
In our patient, besides an apparently balanced recip- rocal 11p;13q translocation, several 11p cosmids showed an associated deletion extending over approximately 7.5 Mb which included the ~800 kb of the WAGR contiguous gene region. The FISH results were compatible with a proximal breakpoint in the der(11) distal to the EXT2 locus and re- cently mapped to an approximately 20 cM region of 11p → p13 (Bartsch et al., 1996). The distal breakpoint map- ped between CO8160 and F1238 and was therefore distal to D11S302 (239FB) probes. Using Northern blot analy- sis, Schwartz et al. (1995) showed that this gene is promi- nently expressed in fetal brain cortex. Consequently, it has been proposed as a possible candidate gene for the mentalretardation phenotype associated with WAGR. The deletion observed in our patient extends telomerically to F1238 (in- terval XV, Fantes et al., 1995b) and may have also included the BDNF (brain-derived neurotrophic locus), which has also been implicated in the mentalretardation phenotype (Hanson et al., 1993; Fantes et al., 1995b). Our patient, however,
After several decades of halting progress, the entire field of autism genetics is moving forward at a remarkable pace. Over just the past couple of years, a specific genetic mutation in NLGN4 has been identified as being responsible for rare ca- ses of mentalretardation and/or pervasive developmental disabilities, EN2 has emerged as a strong candidate for association with the autism phenotype, and a linkage region on chromosome 17q has been confirmed in independent samples using rigorous statistical criteria. These are just a handful of the exciting recent findings in the field that offer avenues for real progress. Of course, the identification of risk alleles or rare causative mutations is just one important step in unraveling the biology of ASDs, and effort that will require the combined contributions of a variety of fields including geneticists, clinical researchers, developmental neurobiologists and neuroimagers. Though the final goal of leveraging an understanding of pathophysiology to develop new treatments and to reveal strategies for prevention is still over the horizon, we have clearly now have started to take the necessary first steps in that direction.
In the item on the causes of mentalretardation, I understand the author to mean to highlight exposure to teratogens 6 during the prenatal period and not toxins as one cause, is this correct? Still on this item, we have emphasis given to cases of lead poisoning, pointing out that there are no reports of the prevalence of this cause in Brazil, which leads us to believe that this is not such an important cause as to merit prominence, whereas the use of teratogens is an important cause and was not highlighted, in common with the sequelae of prematurity and postnatal asphyxia by varying causes, such as pneumonia, meningitis, post-heart surgery, brain damage from sickle-cell anemia, untreated hypoglycemia, which are the most common causes for treatment in the routine of a pediatrician. 3
What would be the importance of confirming something that the common sense suggests? In other words, would not an as- sociation between MR and school dropout be expected? In this sense, some points must be highlighted. Firstly, all students with probable MR in both groups were attending regular pub- lic state schools and their teachers never suspected of their hav- ing MR. Although being aware that probable cases of MR might include false positives, our findings suggest that teachers are not always prepared to suspect of the disease in our schools. Such a diagnosis, the more difficult the milder the MR, is usu- ally thought of especially when there are phenotypic alterations which are characteristic of syndromes such as the Down Syn- drome that are normally associated to more important levels of MR. Therefore, a special attention is needed to not create a perverse mechanism in the school: children with unrecognized mild mentalretardation are kept in regular schools which are not prepared to give them the appropriate pedagogical work, and, consequently, they repeat the grade year after year until dropping out of school.