Form Of X-linked Mental Retardation Research Articles

Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation.

We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.

Animal models of mental retardation: from gene to cognitive function

About 2–3% of all children are affected by mental retardation, and genetic conditions rank among the leading causes of mental retardation. Alterations in the information encoded by genes that regulate critical steps of brain development can disrupt the normal course of development, and have profound consequences on mental processes. Genetically modified mouse models have helped to elucidate the contribution of specific gene alterations and gene–environment interactions to the phenotype of several forms of mental retardation. Mouse models of several neurodevelopmental pathologies, such as Down and Rett syndromes and X-linked forms of mental retardation, have been developed. Because behavior is the ultimate output of brain, behavioral phenotyping of these models provides functional information that may not be detectable using molecular, cellular or histological evaluations. In particular, the study of ontogeny of behavior is recommended in mouse models of disorders having a developmental onset. Identifying the role of specific genes in neuropathologies provides a framework in which to understand key stages of human brain development, and provides a target for potential therapeutic intervention.

Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity.

The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short- and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.

Syndromic form of X-linked mental retardation with marked hypotonia in early life, severe mental handicap, and difficult adult behavior maps to Xp22.

An X-linked recessive syndromic form of mental retardation is described in a family in which 10 males in four generations were affected. The main manifestations were severe to profound intellectual disability, muscular hypotonia in childhood, delayed walking, and difficult, aggressive behavior. There was a moderate reduction both in occipitofrontal circumference (OFC) and height and a similar facial appearance, triangular in shape with a high forehead, prominent ears, and a small pointed chin. Linkage analysis located the gene at Xp22 with maximum lod scores of 4.8 at theta = 0.0 for markers mapping between the closest recombination points at DXS7104 and DXS418. The physical length of this region is approximately 6 Mb. Mutations in the GRPR gene and M6b genes were excluded by sequence analysis. Nearby genes in which mutations are known to be associated with mental retardation (RPS6KA3, STK9, and VCXA, B and C), were excluded by position.

Paternally Transmitted FMR1 Alleles Are Less Stable than Maternally Transmitted Alleles in the Common and Intermediate Size Range

Fragile X syndrome, a form of X-linked mental retardation, results from the hyperexpansion of a CGG trinucleotide repeat located in the 5' untranslated region of the fragile X mental retardation (FMR1) gene. Relatively little is known about the initial mutation that causes a stable allele to become unstable and, eventually, to expand to the full mutation. In the present study, we have examined 1,452 parent-child transmissions of alleles of common (< or =39 repeats) or intermediate (40-59 repeats) sizes to study the initial mutation events. Of these, 201 have been sequenced and haplotyped. Using logistic regression analysis, we found that parental origin of transmission, repeat size (for unsequenced alleles), and number of the 3' CGGs (for sequenced alleles) were significant risk factors for repeat instability. Interestingly, transmission of the repeat through males was less stable than that through females, at the common- and intermediate-size level. This pattern differs from that seen for premutation-size alleles: paternally transmitted alleles are far more stable than maternally transmitted alleles. This difference that depends on repeat size suggests either a different mutational mechanism of instability or an increase in selection against sperm as their repeat size increases.

Unusual Splice-Site Mutations in the RSK2 Gene and Suggestion of Genetic Heterogeneity in Coffin-Lowry Syndrome

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation that is characterized, in male patients, by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological hand aspects exhibited by patients are essential clues for the diagnosis. CLS is caused by mutations in a gene that is located in Xp22.2 and that encodes RSK2, a growth-factor-regulated protein kinase. RSK2 mutations are extremely heterogeneous and lead to premature termination of translation and/or loss of phosphotransferase activity. Surprisingly, among a series of 250 patients screened by single-strand conformation polymorphism (SSCP) analysis, in whom a clinical diagnosis of CLS was made, no mutations were detected in 66% (165) of the patients. To determine what proportion of these latter patients have a RSK2 mutation that has not been detected and what proportion have different disorders that are phenotypically similar to CLS, we have, in the present article, investigated, by western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed us to identify seven novel RSK2 mutations: two changes in the coding sequence of RSK2, one intragenic deletion, and four unusual intronic nucleotide substitutions that do not affect the consensus GT or AG splice sites. We have also determined the nucleotide sequence of the promoter region of the RSK2 gene, and we have screened it for mutations. No disease-causing nucleotide change was identified, suggesting that mutations affecting the promoter region are unlikely to account for a large number of patients with CLS. Finally, our results provide evidence that some patients have a disease that is phenotypically very similar to CLS, which is not caused by RSK2 defects. This suggests that there are defects in either additional genes or combinations of genes that may result in a CLS-like phenotype.

An Integrated, Functionally Annotated Gene Map of the DXS8026–ELK1 Interval on Human Xp11.3–Xp11.23: Potential Hotspot for Neurogenetic Disorders

Human chromosome Xp11.3–Xp11.23 encompasses the map location for a growing number of diseases with a genetic basis or genetic component. These include several eye disorders, syndromic and nonsyndromic forms of X-linked mental retardation (XLMR), X-linked neuromuscular diseases and susceptibility loci for schizophrenia, type 1 diabetes, and Graves' disease. We have constructed an ∼2.7-Mb high-resolution physical map extending from DXS8026 to ELK1, corresponding to a genetic distance of ∼5.5 cM. A combination of chromosome walking and sequence-tagged site (STS)-content mapping resulted in an integrated framework and transcript map, precisely positioning 10 polymorphic microsatellites (one of which is novel), 16 ESTs, and 12 known genes (RP2, PCTK1, UHX1, UBE1, RBM10, ZNF157, SYN1, ARAF1, TIMP1, PFC, ELK1, UXT). The composite map is currently anchored with 89 STSs to give an average resolution of ∼1 STS every 30 kb. By a combination of EST database searches and in silico detection of UniGene clusters within genomic sequence generated from this template map, we have mapped several novel genes within this interval: a Na+/H+ exchanger (SLC9A7), at least two zincfinger transcription factors (KIAA0215 and Hs.68318), carbohydrate sulfotransferase-7 (CHST7), regucalcin (RGN), inactivation-escape-1 (INE1), the human ortholog of mouse neuronal protein 15.6, and four putative novel genes. Further genomic analysis enabled annotation of the sequence interval with 20 predicted pseudogenes and 21 UniGene clusters of unknown function. The combined PAC/BAC transcript map and YAC scaffold presented here clarifies previously conflicting data for markers and genes within the Xp11.3–Xp11.23 interval and provides a powerful integrated resource for functional characterization of this clonally unstable, yet gene-rich and clinically significant region of proximal Xp.

A syndromic form of X-linked mental retardation: the Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS, OMIM 303600) is an X-linked inherited disorder characterised in male patients by growth and psychomotor retardation, hypotonia and progressive skeletal changes. Typically, male patients are of short stature and exhibit a characteristic coarse face with a prominent forehead, orbital hypertelorism, downslanting palpebral fissures, thick lips, a thick nasal septum with anteverted nares, and irregular or missing teeth. Their large and soft hands with lax skin and tapering fingers, are usually a strong diagnostic feature. Some patients present with additional complications including, sensorineural deafness, seizures, drop episodes and cardiac disease. There is some variability in the mental development of affected males, but most of the males who receive appropriate care appear to be moderately affected. A majority of carrier females have only minimal findings (mild facial coarsening, tapering fingers and obesity). Early diagnosis of CLS is essential for proper management, including survey of some specific complications already mentioned, and for genetic counselling. Establishing the diagnosis in very young children is often much more difficult than in older patients since physical characteristics are milder and not specific. Loss of function mutations in the gene encoding the growth-factor induced protein kinase ribosomal S6 kinase are responsible for CLS. A mutation has been detected in about 50% of patients with clinical features suggestive of CLS, and over 80 different mutations have so far been identified. They are distributed throughout the gene, the vast majority being unique to single families and a high proportion appear to be de novo events. Some missense mutations are associated with milder phenotypes. In one family, a missense mutation was associated solely with mild mental retardation and no other clinical feature. Coffin-Lowry syndrome is a well characterised entity and a detailed clinical examination usually allows diagnosis. However, recognising it in very young children is often difficult since physical characteristics are mild and not specific. In addition, most cases are sporadic. Screening for ribosomal S6 kinase mutations is essential in most cases to confirm the diagnosis as well as for genetic counselling.

X-linked Coffin-Lowry syndrome (CLS, MIM 303600, RPS6KA3 gene, protein product known under various names: pp90rsk2, RSK2, ISPK, MAPKAP1)

The Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation characterised in male patients by psychomotor and growth retardation, and various skeletal anomalies. CLS is caused by mutations in a gene located in Xp22.2 and encoding RSK2, a growth-factor regulated protein kinase. Mutations are extremely heterogeneous and lead to premature termination of translation and/or to loss of phosphotransferase activity. No correlation between the type and location of mutation and the clinical phenotype is evident. However, in one family (MRX19), a missense mutation was associated solely with mild mental retardation and no other clinical feature. Screening for RSK2 mutations is essential in most cases to confirm the diagnosis as well as for genetic counseling.

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.

IL1RAPL2 maps to Xq22 and is specifically expressed in the central nervous system

We report the identification and characterization of a homologue of the IL1RAPL transcript which is responsible for a form of X-linked mental retardation (MRX34). This new transcript was cloned by analysis of genomic sequences from the Xq22 region and was named IL1RAPL2 (Interleukin 1 Receptor Accessory Protein-Like-2). The two X-linked genes share the same domains, the same exon–intron organization and a high degree of similarity at the protein level (70.4% similarity). RNA in situ expression studies on mouse embryo tissue section at different developmental stages show that Il1rapl2 is specifically expressed in the nervous system from embryonic day 12.5. The homologies together with the pattern of expression render ILRAPL2 a candidate gene for disorders displaying involvement of the CNS, including the MRX loci for which the gene has not been identified yet.

Linkage mapping of a nonspecific form of X-linked mental retardation (MRX53) in a large Pakistani family.

Nonspecific X-linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X-linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2-26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081.

SES17.02 Behavioural phenotypes in different forms of X-linked mental retardation

SES17.02 Behavioural phenotypes in different forms of X-linked mental retardation

Apparently Unstable Normal FMR1 Alleles in Nine Developmentally Delayed Patients: Implications for Molecular Diagnosis of the Fragile X Syndrome

The Fragile X syndrome is a common form of X-linked mental retardation, affecting approximately 1 in 4,000 males. Since the discovery of the FMR1 gene responsible for the syndrome, molecular, rather than cytogenetic, diagnosis of Fragile X syndrome has become the gold standard. Numerous molecular diagnostic centers worldwide use PCR and Southern blotting to characterize the size of the CGG repeats within the gene, expansion of which has been shown to be associated with the vast majority of cases of Fragile X syndrome. Instability of this repeat through successive generations has been demonstrated in many patients and has been associated with numerous factors, including repeat length and molecular structure of the repeat. Nine males with normal-size alleles that exhibit repeat length instability by the presence of a second normal length distinct band by repeated PCR analysis from peripheral lymphocytes are reported. Many hypotheses addressing the reason for this apparent instability were tested without elucidating the underlying molecular causes, including cytogenetic analysis, sequence analysis of the repeat locus, and analysis of flanking dinucleotide repeat loci. All patients exhibited a normal complement of sex chromosomes by cytogenetic and molecular analysis. These results from the widely used PCR analysis illustrate an interesting molecular phenomenon and raise many questions relating to the factors and mechanisms involved in trinucleotide instability as well as having implications for the diagnostic testing of the Fragile X syndrome.

Novel syndromic form of X-linked complicated spastic paraplegia.

This study presents a family with a syndromic form of X-linked mental retardation in which four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia. Multipoint linkage analysis with 24 highly polymorphic markers indicated two possible candidate regions: Xp21.1-Xq21.3 (flanking markers DXS1214 and DXS990) and Xq23-Xq27.1 (flanking markers DXS8020 and DXS984). The two known loci for X-linked mental retardation and spastic paraplegia are excluded: proteolipid protein in Xp21 and L1 cell adhesion molecule in Xq28. Therefore, the syndrome in this family appears to represent a previously undescribed X-linked spastic paraplegia-mental retardation syndrome.

Linkage mapping of a new syndromic form of X-linked mental retardation, MRXS7, associated with obesity.

A new syndromic form of X-linked mental retardation associated to obesity, MRXS7, has been localised to Xp11.3-Xq23 in a large Pakistani family. The ten affected males show clinical manifestations of mental retardation, obesity and hypogonadism. The family was genotyped by a set of microsatellite markers spaced at approximately 10 cM intervals on the X chromosome. Linkage to five adjacent microsatellite markers, mapping in the pericentromeric area, was established and a maximum two-point lod score of 3.86 was reached at zero recombination with marker DXS1106. Reduced recombination events around the centromere prevented precise mapping of the gene.

Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function

Fragile X syndrome is an X-linked form of mental retardation resulting from the absence of expression of the fragile X mental retardation 1 gene. The encoded protein is a ribosome-associated, RNA-binding protein thought to play a role in translational regulation of selective messenger RNA transcripts. A knockout mouse has been described that exhibits subtle deficits in spatial learning but normal early-phase long-term potentiation. We expanded these studies by examination of late-phase hippocampal long-term potentiation, the protein synthesis-dependent form of long-term potentiation, in the Fmr1 knockout mice. Here, late-phase long-term potentiation was normal, suggesting either that absence of fragile X mental retardation protein has no influence on long-term potentiation or that any influence is too subtle to be detected by this technique. Alternatively, the hippocampus may not be the primary site affected by the absence of this protein. Accordingly, we examined spatial learning in the knockout mice using the hippocampus-dependent Morris water maze. Contrary to earlier reports, near-normal performance was observed. Since the knockout line used in this study has been back-crossed to C57BL/6 for more than 15 generations, whereas the line used in the earlier studies contained a substantial strain 129 contribution, we examined F1 siblings of knockout and 129 crosses. Here, significant but subtle increased swim latencies in reversal trials were observed, in agreement with the previous studies. These data suggest strain differences between C57BL/6 and 129 that influence the Fmr1 knockout phenotype. In order to investigate a paradigm less dependent on hippocampal function, the knockout mice were examined using the conditional fear paradigm. Here, the knockout animals displayed significantly less freezing behavior than their wild-type littermates following both contextual and conditional fear stimuli. These data suggest that amygdala disturbances may also be involved in fragile X syndrome.

A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation.

We demonstrate here the importance of interleukin signalling pathways in cognitive function and the normal physiology of the CNS. Thorough investigation of an MRX critical region in Xp22.1-21.3 enabled us to identify a new gene expressed in brain that is responsible for a non-specific form of X-linked mental retardation. This gene encodes a 696 amino acid protein that has homology to IL-1 receptor accessory proteins. Non-overlapping deletions and a nonsense mutation in this gene were identified in patients with cognitive impairment only. Its high level of expression in post-natal brain structures involved in the hippocampal memory system suggests a specialized role for this new gene in the physiological processes underlying memory and learning abilities.

Methanol/acetone treatment helps the amplification of FMR1 CGG repeat fragment in dried blood spots from Guthrie cards

The fragile X syndrome is a cause of intellectual disability resulting from an absence of the protein FMR1. It has a prevalence in white populations of 1/4000 in men and 1/8000 in women. 1 Turner G Webb T Wake S Robinson H Prevalence of fragile X syndrome. Am J Med Genet. 1996; 64: 196-197 Crossref PubMed Scopus (594) Google Scholar The associated cytogenetic finding is almost always the demonstration of a fragile site at Xq27·3 2 Brookwell R Daniel A Turner G Fishburn J The fragile X(q27) form of X-linked mental retardation: FUdR as an inducing agent for fra(X)(q27) expression in lymphocytes, fibroblasts, and amniocytes. Am J Med Genet. 1982; 13: 139-148 Crossref PubMed Scopus (38) Google Scholar —the associated molecular finding is usually an expanded CGG repeat identifiable by Southern blot or PCR techniques. 3 Verkerk AJ Pieretti M Sutcliffe JS et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991; 65: 905-914 Summary Full Text PDF PubMed Scopus (2864) Google Scholar To facilitate the identification of fragile X syndrome, we developed a method to treat Guthrie blood-spot samples and improve the PCR amplification of CGG repeat fragment in FMR1 gene.

Evidence for a new X-linked mental retardation gene in Xp21-Xp22: clinical and molecular data in one family.

Linkage analysis was performed in three generations of a French family segregating a syndromal form of X-linked mental retardation. All affected males had neonatal hypotonia, seizures, muscular hypodevelopment, and severe mental deficiency. A peak lod score of 2.90 at a recombination fraction of theta = 0 was detected for DXS 1052 and DXS 451 (Xp22.13). Recombination between the disease locus and the polymorphic markers in DXS7163 and DXS1238 suggested a gene mapping to the Xp22.13-Xp21.2 region. Three candidate genes in this region were investigated: the cDNA for kinase Rsk-2 involved in Coffin-Lowry syndrome, the brain-specific exon of a transcript in the DMD locus (DP140 isoform of dystrophin), and exon 18 of the glycerol kinase gene, which is specific to fetal brain transcripts. All three sequences were normal.