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PubMed2006

Tourette's syndrome (TS): cognitive performance in adults with uncomplicated TS.

Tourette's syndrome (TS) is a neurodevelopmental disorder associated with frontostriatal dysfunction. The extent of any cognitive impairment associated with uncomplicated TS is unclear, as comorbid psychiatric symptomatology is thought to contribute to cognitive deficits. Previous studies have found evidence of mild performance deficits, most commonly on tasks that involve inhibitory processes. The present study evaluated this in carefully screened adult participants with TS. The findings showed the TS group to perform more poorly on one test involving behavioral inhibition (sentence completion), but did not provide strong support for an interpretation based solely on inhibitory deficits, and there was no evidence of impairment on another behavioral inhibition task (flanker test). There were also no differences between the groups on tasks involving working memory (n-back), task switching, or object alternation learning. The findings provide further evidence that uncomplicated TS is associated with only mild, circumscribed impairment. The nature of any impairment is discussed.

Adult↗

PubMed1999

Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.

Amino Acid Sequence↗

PubMed2001

A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome.

Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000-15,000 births. Affected females develop normally for 6-18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 3-12), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

Animals↗

PubMed2006

Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome.

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1 per 10,000-15,000 female births worldwide. The disease-causing gene has been identified as MECP2 (methyl-CpG-binding protein 2). In this study, we performed diagnostic mutational analysis of the MECP2 gene in RTT patients. Four exons and a putative promoter of the MECP2 gene were analyzed from the peripheral blood of 43 Korean patients with Rett syndrome by PCR-RFLP and direct sequencing. Mutations were detected in the MECP2 gene in approximately 60.5% of patients (26 cases/43 cases). The mutations consisted of 14 different types, including 9 missense mutations, 4 nonsense mutations and 1 frameshift mutation. Of these, three mutations (G161E, T311M, p385fsX409) were newly identified and were determined to be disease-causing mutations by PCR- RFLP and direct sequencing analysis. Most of the mutations were located within MBD (42.3%) and TRD (50%). T158M, R270X, and R306C mutations were identified at a high frequency. Additionally, an intronic SNP (IVS3+23C>G) was newly identified in three of the patients. IVS3+23C>G may be a disease-related and Korea-specific SNP for RTT. L100V and A201V are apparently disease-causing mutations in Korean RTT, contrary to previous studies. Disease-causing mutations and polymorphisms are important tools for diagnosing RTT in Koreans. The experimental procedures used in this study should be considered for clinical molecular biologic diagnosis.

Base Sequence↗

PubMed1992

Isolation and characterization of a candidate gene for Norrie disease.

Previous analysis has refined the location of the gene for Norrie disease, a severe, X-linked, recessive neurodevelopmental disorder, to a yeast artificial chromosome subfragment of 160 kilobases (kb). This fragment was used to screen cDNA libraries from human fetal and adult retina. As a result, we have identified an evolutionarily conserved cDNA, which is expressed in fetal and adult brain and encodes a predicted protein of 133 amino acids. The cDNA detects genomic sequences which span a maximum of 50 kb, and which are partly deleted in several typical Norrie disease patients. An EcoRI polymorphism with a calculated heterozygosity value of 43% was observed. The locus identified is a strong candidate for the Norrie disease gene.

Amino Acid Sequence↗

PubMed2004

Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.

Mutations in MECP2 are associated with Rett syndrome, an X-linked neurodevelopmental disorder. To identify genes targeted by Mecp2, we sequenced 100 in vivo Mecp2-binding sites in mouse brain. Several sequences mapped to an imprinted gene cluster on chromosome 6, including Dlx5 and Dlx6, whose transcription was roughly two times greater in brains of Mecp2-null mice compared with those of wild-type mice. The maternally expressed gene DLX5 showed a loss of imprinting in lymphoblastoid cells from individuals with Rett syndrome. Because Dlx5 regulates production of enzymes that synthesize gamma-aminobutyric acid (GABA), loss of imprinting of Dlx5 may alter GABAergic neuron activity in individuals with Rett syndrome. In mouse brain, Dlx5 imprinting was relaxed, yet Mecp2-mediated silent-chromatin structure existed at the Dlx5-Dlx6 locus in brains of wild-type, but not Mecp2-null, mice. Mecp2 targeted histone deacetylase 1 to a sharply defined, approximately 1-kb region at the Dlx5-Dlx6 locus and promoted repressive histone methylation at Lys9 at this site. Chromatin immunoprecipitation-combined loop assays showed that Mecp2 mediated the silent chromatin-derived 11-kb chromatin loop at the Dlx5-Dlx6 locus. This loop was absent in chromatin of brains of Mecp2-null mice, and Dlx5-Dlx6 interacted with far distant sequences, forming distinct active chromatin-associated loops. These results show that formation of a silent-chromatin loop is a new mechanism underlying gene regulation by Mecp2.

Animals↗

PubMed2002

Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice.

Williams syndrome is a neurodevelopmental disorder caused by the hemizygous deletion of 1.6 Mb on human chromosome 7q11.23. This region comprises the gene CYLN2, encoding CLIP-115, a microtubule-binding protein of 115 kD. Using a gene-targeting approach, we provide evidence that mice with haploinsufficiency for Cyln2 have features reminiscent of Williams syndrome, including mild growth deficiency, brain abnormalities, hippocampal dysfunction and particular deficits in motor coordination. Absence of CLIP-115 also leads to increased levels of CLIP-170 (a closely related cytoplasmic linker protein) and dynactin at the tips of growing microtubules. This protein redistribution may affect dynein motor regulation and, together with the loss of CLIP-115-specific functions, underlie neurological alterations in Williams syndrome.

Animals↗

PubMed2006

Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized.

The discovery that Rett syndrome is caused by mutations that affect the methyl-CpG-binding protein MeCP2 provided a major breakthrough in understanding this severe neurodevelopmental disorder. Animal models and expression studies have contributed to defining the role of MeCP2 in development, highlighting its contribution to postnatal neuronal morphogenesis and function. Furthermore, in vitro assays and microrray studies have delineated the potential molecular mechanisms of MeCP2 function, and have indicated a role in the transcriptional silencing of specific target genes. As well as unravelling the mechanisms that underlie Rett syndrome, these studies provide more general insights into how DNA-methylation patterns are recognized and translated into biological outcomes.

DNA Methylation↗

PubMed2026

Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are essential for neuronal development, synaptic organization and signaling. Defects in GPI-anchor biosynthesis or remodeling cause rare neurodevelopmental disorders, including post-GPI attachment to proteins 1 (PGAP1) deficiency. PGAP1 encodes an inositol deacylase required for GPI-anchor remodeling and appropriate trafficking and membrane localization of GPI-APs. Loss of PGAP1 function disrupts GPI-AP processing, but the clinical spectrum remains incompletely defined because reported cohorts are small. We report 15 individuals with biallelic PGAP1 variants from 11 unrelated families identified through international collaboration. Clinical information was collected using a standardized phenotyping questionnaire and review of available clinical records. The most frequently recorded features were developmental delay or intellectual disability, motor developmental delay, speech impairment, facial dysmorphism, hypotonia and seizures. Independent walking was clearly recorded in a minority of individuals, while feeding, ophthalmological, musculoskeletal and neuroimaging findings were recorded in subsets of the cohort. Clinical investigations were performed as part of routine care and were not uniform across sites. Accordingly, source-dependent assessments including MRI, EEG, EMG/NCS, formal ophthalmology, hearing assessment, systemic imaging, IQ/DQ testing, MRC scoring and anthropometric Z-scores are reported descriptively or using available-data denominators. Spasticity, hypertonia or possible peripheral nerve involvement was recorded in some clinical summaries; however, electrophysiological confirmation was not uniformly available, and confirmed peripheral neuropathy was not analyzed as a cohort-level prevalence outcome. Functional studies in selected patient-derived cells or model systems demonstrated PI-PLC resistance of GPI-APs, supporting impaired GPI-anchor remodeling. These findings expand the genotypic and recorded phenotypic spectrum of PGAP1 deficiency.

Journal Article↗

PubMed2023

Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex.

Throughout bacteria, archaea and eukarya, certain tRNA transcripts contain introns. Pre-tRNAs with introns require splicing to form the mature anticodon stem loop. In eukaryotes, tRNA splicing is initiated by the heterotetrameric tRNA splicing endonuclease (TSEN) complex. All TSEN subunits are essential, and mutations within the complex are associated with a family of neurodevelopmental disorders known as pontocerebellar hypoplasia (PCH). Here, we report cryo-electron microscopy structures of the human TSEN-pre-tRNA complex. These structures reveal the overall architecture of the complex and the extensive tRNA binding interfaces. The structures share homology with archaeal TSENs but contain additional features important for pre-tRNA recognition. The TSEN54 subunit functions as a pivotal scaffold for the pre-tRNA and the two endonuclease subunits. Finally, the TSEN structures enable visualization of the molecular environments of PCH-causing missense mutations, providing insight into the mechanism of pre-tRNA splicing and PCH.

Humans↗

PubMed2005

Intrinsic sensory deprivation induced by neonatal capsaicin treatment induces changes in rat brain and behaviour of possible relevance to schizophrenia.

Schizophrenia is considered to be a neurodevelopmental disorder with origins in the prenatal or neonatal period. Brains from subjects with schizophrenia have enlarged ventricles, reduced cortical thickness (CT) and increased neuronal density in the prefrontal cortex compared with those from normal subjects. Subjects with schizophrenia have reduced pain sensitivity and niacin skin flare responses, suggesting that capsaicin-sensitive primary afferent neurons might be abnormal in schizophrenia. This study tested the hypothesis that intrinsic somatosensory deprivation, induced by neonatal capsaicin treatment, causes changes in the brains of rats similar to those found in schizophrenia. Wistar rats were treated with capsaicin, 50 mg kg(-1) subcutaneously, or vehicle (control) at 24-36 h of life. At 5-7 weeks behavioural observations were made, and brains removed, fixed and sectioned. The mean body weight of capsaicin-treated rats was not significantly different from control, but the mean brain weight of male, but not female, rats, was significantly lower than control. Capsaicin-treated rats were hyperactive compared with controls. The hyperactivity was abolished by haloperidol. Coronal brain sections of capsaicin-treated rats had smaller cross-sectional areas, reduced CT, larger ventricles and aqueduct, smaller hippocampal area and reduced corpus callosum thickness, than brain sections from control rats. Neuronal density was increased in several cortical areas and the caudate putamen, but not in the visual cortex. It is concluded that neonatal capsaicin treatment of rats produces brain changes that are similar to those found in brains of subjects with schizophrenia.

Animals↗

PubMedDate not supplied

Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the absence of a maternal contribution to chromosome 15q11-q13. There are four classes of AS according to molecular or cytogenetic status: maternal microdeletion of 15q11-q13 (approximately 70% of AS patients); uniparental disomy (UPD); defects in a putative imprinting centre (IM); the fourth includes 20-30% of AS individuals with biparental inheritance and a normal pattern of allelic methylation in 15q11-q13. Mutations of UBE3A have recently been identified as causing AS in the latter group. Few studies have investigated the phenotypic differences between these classes. We compared 20 non-deletion to 20 age-matched deletion patients and found significant phenotypic differences between the two groups. The more severe phenotype in the deletion group may suggest a contiguous gene syndrome.

Adolescent↗

PubMed2000

WBSCR14, a putative transcription factor gene deleted in Williams-Beuren syndrome: complete characterisation of the human gene and the mouse ortholog.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting several systems caused by a heterozygous deletion in the chromosomal region 7q11.23. A common interval that includes up to 17 genes reported so far is deleted in the great majority of patients. Elastin haploinsufficiency is responsible for the cardiovascular features, but the specific contribution of other deleted genes to the WBS phenotype remains unknown. We have fully characterised a gene commonly deleted in WBS, WBSCR14, previously reported in a truncated form as WS-bHLH. The WBSCR14 cDNA encodes an 852amino acid protein with a basic helix-loop-helix-leucine-zipper motif (bHLHZip) and a bipartite nuclear localisation signal (BNLS), suggesting a function as a transcription factor. WBSCR14 is expressed as a 4.2kb transcript predominantly in adult liver and at late stages of foetal development. The WBSCR14 locus encompasses 33 kb of genomic DNA with 17 exons. Two intragenic polymorphic dinucleotide repeats have been identified and used to verify hemizygosity in WBS patients. We have also cloned the mouse ortholog and mapped its locus to mouse chromosome 5, in a region of conserved synteny with human 7q11.23. Given that other bHLHZip proteins are dosage sensitive and based on the putative function of WBSCR14 as a transcription factor, hemizygosity at this locus could be involved in some features of WBS.

Adult↗

PubMed2001

MECP2 mutations in Danish patients with Rett syndrome: high frequency of mutations but no consistent correlations with clinical severity or with the X chromosome inactivation pattern.

Rett syndrome (RTT) is a neurodevelopmental disorder, which almost exclusively affects girls, who, after an initial period of apparently normal development, display gradual loss of speech and purposeful hand use, gait abnormalities and stereotypical hand movements. In the year 2000, mutations in the gene for the methyl CpG binding protein 2, MECP2, have been identified in 35-80% of the patients in three different studies. We have identified 15 different MECP2 mutations in 26 of 30 Danish RTT patients. The mutations included five novel mutations (one point mutation, three smaller deletions involving identical regions in the gene, and one duplication). In contrast to the point mutations and the duplication, which all affect the methyl binding domain or the transcriptional repressing domain, the three overlapping deletions are clustered in the 3' end of the gene. We found no consistent correlation between the type of mutation and the clinical presentation of the patient or the X-inactivation pattern in peripheral blood. Our high mutation detection rate, compared to two of the previous studies, underscores the importance of the inclusion criteria of the patients and supports that MECP2 is the most important, if not the only, gene responsible for RTT.

Base Sequence↗

PubMed2001

A Rett syndrome patient with a ring X chromosome: further evidence for skewing of X inactivation and heterogeneity in the aetiology of the disease.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, characterised by regression of development in young females. Recently, mutations in the MECP2 gene were found to be present in 80% of sporadic cases, but in much lower frequency (< 30%) among familial cases. Several reports claim that the pattern of X chromosome inactivation (XCI) relates to the penetrance of RTT; in some cases skewed XCI is seen in Rett patients, and in others it is observed among normal carriers. We present here a case of RTT with a 46,X,r(X) in which complete skewed inactivation of the ring was demonstrated. Further, no mutations were found in the MECP2 gene present on the intact X. Our data, in conjunction with two previously published cases of X chromosome abnormalities in RTT, indicate that X chromosome rearrangements are sporadically associated with RTT in conjunction with extreme skewing of X inactivation. Based on our case and reported data, we discuss the evidence for a second X-linked locus for RTT associated with lower penetrance, and a different pattern of XCI, than for MECP2. This would result in a larger proportion of phenotypically normal carrier women transmitting the mutation for this putative second locus, and account for the minority of sporadic and majority of familial cases that are negative for MECP2 mutations.

Dosage Compensation, Genetic↗

PubMed2001

Parental origin of de novo MECP2 mutations in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females as sporadic cases. Recently, DNA mutations in the MECP2 gene have been detected in approximately 70% of patients with RTT. To explain the sex-limited expression of RTT, it has been suggested that de novo X-linked mutations occur exclusively in male germ cells resulting therefore only in affected daughters. To test this hypothesis, we have analysed 19 families with RTT syndrome due to MECP2 molecular defects. In seven informative families we have found by DHPLC a nucleotide variant which could be used to differentiate between the maternal and the paternal allele. In each subject investigated from these families, we have amplified specifically each allele and sequenced allele-specific PCR products to identify the allele bearing the mutation as well as the parental origin of each X chromosome. This approach allowed us to determine the parental origin of de novo mutations in all informative families. In five cases, the de novo MECP2 mutations have a paternal origin and in the two other cases a maternal origin. In all transitions at CpG, the de novo mutation observed was of paternal origin. The high frequency of male germ-line transmission of the mutation (71% of RTT informative cases) is consistent with a predominant occurrence of the disease in females.

Base Sequence↗

PubMed2002

Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy.

Rett syndrome is a severe neurodevelopmental disorder that arises from mutations in the X-linked MECP2 gene. It is almost exclusively seen in girls due to the predominant occurrence of the mutations on the paternal X-chromosome, and also the early postnatal lethal effect of the disease causing mutations in hemizygous boys. We identified a boy with features of classic Rett syndrome who is mosaic for the truncating MECP2 mutation R270X. Chromosome analysis showed normal karyotype. These results indicate that a MECP2 mutation associated with Rett syndrome in females could lead to a similar phenotype in males as a result of somatic mosaicism.

Child↗

PubMed2002

MECP2 gene mutation analysis in Chinese patients with Rett syndrome.

Rett syndrome (RTT) is a progressive neurodevelopmental disorder that affects almost exclusively girls. Mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2) have been found to be a cause. In order to study the spectrum of MECP2 mutations in Chinese patients, we employed PCR and sequencing of the coding region of MECP2 gene in 31 Chinese cases of classical sporadic RTT. Mutations in MECP2 were found in about 55%. Twelve different mutations in exon 3 were identified in 17 of these 31 patients; two of these are novel. A novel missense variant was detected in the C-terminal region in a patient and her father who was normal. In addition, there was a single nucleotide variant in the 3'UTR.

Amino Acid Substitution↗