Cause Of X-linked Mental Retardation Research Articles

Targeted Deep Resequencing IdentifiesMID2Mutation for X-Linked Intellectual Disability with Varied Disease Severity in a Large Kindred from India

We report a novel missense mutation (c.1040G>A, p.Arg347Gln) in MID2, which encodes ubiquitin ligase E3, as the likely cause of X-linked mental retardation in a large kindred. The mutation was observed in all affected and obligate carriers but not in any unaffected males of the family or in population controls (n=200). When transiently expressed in HEK293T cell line, the mutation was found to abolish the function of the COS domain in the protein. The GFP-tagged mutant protein accumulated in the cytoplasm instead of binding to the cytoskeleton resulting in its altered subcellular localization. Screening of coding exons of this gene in additional 480 unrelated individuals with idiopathic intellectual disability identified another novel variation p.Asn343Ser. This study highlights the growing role of the ubiquitin pathway in intellectual disability and also, the difference in MID2 determined phenotype observed in this study compared with that of its paralogue MID1 reported in literature.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.

Lack of Cul4b, an E3 Ubiquitin Ligase Component, Leads to Embryonic Lethality and Abnormal Placental Development

Cullin-RING ligases (CRLs) complexes participate in the regulation of diverse cellular processes, including cell cycle progression, transcription, signal transduction and development. Serving as the scaffold protein, cullins are crucial for the assembly of ligase complexes, which recognize and target various substrates for proteosomal degradation. Mutations in human CUL4B, one of the eight members in cullin family, are one of the major causes of X-linked mental retardation. We here report the generation and characterization of Cul4b knockout mice, in which exons 3 to 5 were deleted. In contrast to the survival to adulthood of human hemizygous males with CUL4B null mutation, Cul4b null mouse embryos show severe developmental arrest and usually die before embryonic day 9.5 (E9.5). Accumulation of cyclin E, a CRL (CUL4B) substrate, was observed in Cul4b null embryos. Cul4b heterozygotes were recovered at a reduced ratio and exhibited a severe developmental delay. The placentas in Cul4b heterozygotes were disorganized and were impaired in vascularization, which may contribute to the developmental delay. As in human CUL4B heterozygotes, Cul4b null cells were selected against in Cul4b heterozygotes, leading to various degrees of skewed X-inactivation in different tissues. Together, our results showed that CUL4B is indispensable for embryonic development in the mouse.

The fragile X syndrome: 13 years of experience

The fragile X syndrome: 13 years of experience Fragile X syndrome (FXS; MIM #300624; FRAXA, Xq27.3) is well known and a common cause of X-linked mental retardation. The syndrome is caused by dynamic mutation of FMR1 gene CpG island CGG repeats. Clinically FXS patients demonstrate delayed developmental milestones, particularly speech, attention-deficit/hyperactivity disorder, autistic features, and psychomotor development delay. Dysmorphic face and macroorchidism are important features in the postpubertal age. We present our 13-year experience with FXS patients who were confirmed by molecular diagnostic. Phenotype-genotype evaluation was made for 12 male FXS patients. Genotype-phenotype analysis did not reveal significant correlation between clinical symptoms observed in FXS patients and genotypes obtained from leucocytes DNA analysis. The prevalence of the fragile X syndrome in the Latvian male population was estimated to be 1/6428 (95% CI 5538-7552) or 15.55/100 000 males (95% CI 13.24 - 18.05). The prevalence of the fragile X syndrome among mentally retarded male patients was estimated to be 2.67%. The low number of diagnosed patients with fragile X syndrome demonstrated in our study led to the conclusion that fragile X syndrome is generally clinically unrecognised.

CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

Response to creatine analogs in fibroblasts and patients with creatine transporter deficiency

Creatine transporter (CRTR) deficiency is one of the most frequent causes of X-linked mental retardation. The lack of an effective treatment for this disease, in contrast to creatine (Cr) biosynthesis disorders that respond to Cr monohydrate (CM), led us to analyze the efficacy of a lipophilic molecule derived from Cr, creatine ethyl ester (CEE), in fibroblasts and patients with CRTR deficiency. CM and CEE uptake studies were performed in six controls and four fibroblast cell lines from patients. We found a significant increase in Cr uptake after 72h of incubation with CEE (500μmol/L) in patients and control fibroblasts compared to incubation with CM. Subsequently, we assayed the clinical effect of CEE administration in four patients with CRTR deficiency. After 1year of treatment, a lack of significant improvement in neuropsychological assessment or changes in Cr level in brain 1H MRS was observed, and CEE was discontinued. In conclusion, this 12-month trial with CEE did not increase the brain concentration of Cr. Our in vitro data lend support to the idea of a certain passive transport of CEE in both pathological and control cells, although more lipophilic molecules or other cell systems that mimic the BBB should be used for a better approach to the in vivo system.

Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia

Background:Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively...

A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features

PAK3-related mental retardation represents a rare cause of X-linked mental retardation associated with behavioural symptoms. So far, four families carrying PAK3 mutations have been reported, and in most cases PAK3 dysfunction resulted from missense mutations thought to affect either the catalytic or the N-terminal regulatory domain activity. Here, we report on a Tunisian family of X-linked moderate mental retardation with behavioural symptoms, common dysmorphic features, oro-motor impairment and secondary microcephaly. Linkage analysis showed that affected male subjects and obligate carrier female subjects share a common haplotype in the Xp21.31 - Xq23 region that contains the PAK3 gene. Direct sequencing of PAK3 coding exons and flanking intronic sequences allowed us to identify the first splice mutation in PAK3 gene located at the 5' end of intron 6 (c.276+4A>G), which results in a complete switch-off of the genuine donor splice site and an activation of a cryptic donor splice site (GTAAG) located four nucleotides downstream to the genuine one. RT-PCR experiments using the RNA from the patient's lymphoblasts showed that PAK3 transcripts contain four additional nucleotides that lead to a disruption of reading frame with a premature stop codon at position 128. Together with previously reported observations, our data further confirm that PAK3 mutations result in a specific form of X-linked mental retardation with fairly constant clinical features.

Characterization of novel isoforms and evaluation of SNF2L/SMARCA1 as a candidate gene for X-linked mental retardation in 12 families linked to Xq25-26

BackgroundMutations in genes whose products modify chromatin structure have been recognized as a cause of X-linked mental retardation (XLMR). These genes encode proteins that regulate DNA methylation (MeCP2), modify histones (RSK2 and JARID1C), and remodel nucleosomes through ATP hydrolysis (ATRX). Thus, genes encoding other chromatin modifying proteins should also be considered as disease candidate genes. In this work, we have characterized the SNF2L gene, encoding an ATP-dependent chromatin remodeling protein of the ISWI family, and sequenced the gene in patients from 12 XLMR families linked to Xq25-26.MethodsWe used an in silico and RT-PCR approach to fully characterize specific SNF2L isoforms. Mutation screening was performed in 12 patients from individual families with syndromic or non-syndromic XLMR. We sequenced each of the 25 exons encompassing the entire coding region, complete 5' and 3' untranslated regions, and consensus splice-sites.ResultsThe SNF2L gene spans 77 kb and is encoded by 25 exons that undergo alternate splicing to generate several distinct transcripts. Specific isoforms are generated through the alternate use of exons 1 and 13, and by the use of alternate donor splice sites within exon 24. Alternate splicing within exon 24 removes a NLS sequence and alters the subcellular distribution of the SNF2L protein. We identified 3 single nucleotide polymorphisms but no mutations in our 12 patients.ConclusionOur results demonstrate that there are numerous splice variants of SNF2L that are expressed in multiple cell types and which alter subcellular localization and function. SNF2L mutations are not a cause of XLMR in our cohort of patients, although we cannot exclude the possibility that regulatory mutations might exist. Nonetheless, SNF2L remains a candidate for XLMR localized to Xq25-26, including the Shashi XLMR syndrome.

Filamin A mutation is one cause of FG syndrome

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.

Mutation screening of the Aristaless-related homeobox ( ARX) gene in Thai pediatric patients with delayed development: First report from Thailand

Mutations in the Aristaless-related homeobox gene, ARX, have been a cause of X-linked mental retardation (XLMR) and are responsible for a vast phenotypic spectrum including syndromic and non-syndromic forms of mental retardation. Since the gene was initially identified, it has been generally screened in several patients with XLMR. This study is the first report of ARX mutational screening in Thai pediatric patients with delayed development. Two hundred and fifty-one patients participated in this study. Two hundred and three of the 251 patients were initially referred for molecular diagnosis of the Fragile XA syndrome and had negative test results. The remaining 48 patients were specifically recruited for the ARX mutational analysis and had previously reported phenotypes of the ARX mutations. Screening for the c.428_451 dup mutation was performed in all samples. Screening for other point mutations in all coding exons was performed in all 48 patients recruited for the ARX mutational analysis and in 29 patients initially referred for diagnosis of the Fragile XA syndrome who had two or more affected males in the family suggesting an X-linked inheritance pattern. Two patients were found to have the c.428_451 dup mutation. Considering genotype-phenotype correlation, we suggest screening of the most common mutation, the c.428_451 dup mutation by PCR, in patients with infantile spasm syndrome, Partington syndrome and non-syndromic X-linked mental retardation. Screening in patients who have negative Fragile XA test results should be considered when no other known causes of mental retardation are identified especially in families with suggestive X-linked inheritance pattern.

ELEVATED SERUM T3 IS A MARKER FOR X-LINKED MENTAL RETARDATION/”CEREBRAL PALSY” SYNDROME CAUSED BY MUTATION IN MONOCARBOXYLATE TRANSPORTER-8

Objectives: Monocarboxylate transporter-8 (MCT-8) is a transporter of the thyroid hormones T3 and T4, and it was recently shown that mutation of this gene causes an X-linked mental retardation / “cerebral palsy” (MR/CP) syndrome with severe motor compromise and abnormal thyroid hormones profile, with inappropriate elevated T3 and normal or elevated TSH. This condition is allelic to Allan-Herndon-Dudley syndrome, one of the recognized causes of X-linked mental retardation but its clinical features are closer to what is seen in severe dystonic cerebral palsy. The purpose of this presentation is to report clinical and laboratorial features of a family with MCT-8 mutation.

Mutations in exon 1 of MECP2B are not a common cause of X-linked mental retardation in males

Mutations in exon 1 of MECP 2 B are not a common cause of X-linked mental retardation in males

TM4SF10 gene sequencing in XLMR patients identifies common polymorphisms but no disease-associated mutation.

BackgroundThe TM4SF10 gene encodes a putative four-transmembrane domains protein of unknown function termed Brain Cell Membrane Protein 1 (BCMP1), and is abundantly expressed in the brain. This gene is located on the short arm of human chromosome X at p21.1. The hypothesis that mutations in the TM4SF10 gene are associated with impaired brain function was investigated by sequencing the gene in individuals with hereditary X-linked mental retardation (XLMR).MethodsThe coding region (543 bp) of TM4SF10, including intronic junctions, and the long 3' untranslated region (3 233 bp), that has been conserved during evolution, were sequenced in 16 male XLMR patients from 14 unrelated families with definite, or suggestive, linkage to the TM4SF10 gene locus, and in 5 normal males.ResultsFive sequence changes were identified but none was found to be associated with the disease. Two of these changes correspond to previously known SNPs, while three other were novel SNPs in the TM4SF10 gene.ConclusionWe have investigated the majority of the known MRX families linked to the TM4SF10 gene region. In the absence of mutations detected, our study indicates that alterations of TM4SF10 are not a frequent cause of XLMR.

Monogenic causes of X-linked mental retardation.

Mutations in X-linked genes are likely to account for the observation that more males than females are affected by mental retardation. Causative mutations have recently been identified in both syndromic X-linked mental retardation (XLMR) and in the genetically heterogeneous 'nonspecific' forms of XLMR, for which cognitive impairment is the only defining clinical feature. Proteins that function in chromatin remodelling are affected in three important syndromic forms of XLMR. In nonspecific forms of the disorder, defects have been found in signal-transduction pathways that are believed to function during neuronal maturation. These findings provide important insights into the molecular and cellular defects that underlie mental retardation.

Breakthroughs in molecular and cellular mechanisms underlying X-linked mental retardation.

Although genetic causes of X-linked mental retardation (XLMR) are heterogeneous and complex, recent concerted actions between physicians and biologists have allowed some major difficulties to be overcome and led to the identification of an increasing number of genes involved in these conditions. Indeed, over the past 2 years significant progress has been made in understanding the molecular basis underlying not only XLMR, where there are distinguishing phenotypic or genetic markers (syndromal forms of XLMR), but also non-specific (or idiopathic) mental retardation (MRX). Recent breakthroughs have shown that genes responsible for these latter conditions encode for proteins involved in signalling pathways which regulate cytoskeleton organization, synaptic vesicle transport and, maybe, other cellular functions. Also, they suggest a provacative picture that conceptualizes MRX as disorders resulting from a dysfunctioning of genes required for processes such as the remodelling, establishment and stabilization of connections between neuronal cells. Such processes are crucial for the development of intellectual and cognitive functions. As these functions begin to evolve mainly in post-natal stages through contact with diverse stimuli and environments, a potential therapeutic approach would be the development of drugs that target cellular signalling pathways shown to be implicated in MRX.

Fragile X syndrome. I. An overview on its genetic mechanism

A large body of literature has accumulated within the last decade concerning the fragile X syndrome, the most common cause of X-linked mental retardation. The first article of this review summarizes the peculiar genetic mechanisms and molecular biology properties (eg, unstable DNA triplet repeats), which have been characterized since the detection of the FMR-1 gene in 1991. However, the most important question concerning the function of the FMR-1 gene is still an unresolved issue and is in need of future research. The second article of this review addresses the clinical picture, neuropsychological functioning and psychopathological characteristics of pre- and full mutation carriers.