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PubMed2002

Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: is there a need for routine screening?

Mutations in the methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome, a severe neurodevelopmental disorder occurring predominantly in females. Male patients with Rett syndrome are extremely rare, as the Rett-causing mutations in the MECP2 gene are usually lethal in hemizygous males. However, different mutations in the same gene were reported to cause mental retardation, both in sporadic non-syndromic males as well as in syndromic families with disease manifestation in carrier females. The majority of the reported MECP2 mutations in mentally retarded patients cause amino acid substitutions and, especially in isolated cases, discrimination between a disease-causing mutation and a rare polymorphism is not obvious and the significance of each individual variation should be verified. We mapped a new non-syndromic X-linked family (MRX79) to the chromosomal region Xq27.3-Xq28 and identified an A140V mutation in the MEPC2 gene in all patients with the disease haplotype. In addition to data published by others, this suggests that A140V is a recurrent mutation (and not a polymorphism) found in patients with X-linked mental retardation.

Alanine↗

PubMed2003

RettBASE: The IRSA MECP2 variation database-a new mutation database in evolution.

Rett syndrome (RTT) is a neurodevelopmental disorder affecting primarily females, with an incidence of around 1 in 15,000 females. In 1999, mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) were first reported in RTT subjects, and since that time there have been a number of publications describing cohorts of patients and their mutations. In addition, MECP2 mutations have been reported in patients who do not fit the diagnostic criteria for Rett syndrome. We have developed a new locus-specific database, RettBASE (http://mecp2.chw.edu.au/), loosely based on the PAHdb website. The aim is to obtain data relating to all known instances of MECP2 variations, including published ta and data directly submitted by one of various means (either by using an online submission form, or by sending the same form in Adobe portable document format (pdf) or Microsoft Word format by email or fax to the database curators). The database has a range of query capabilities, allowing for simple or complex interrogation of the database. To address the issue of patient confidentiality, we have incorporated an Excel spreadsheet algorithm that allows the generation of a unique number based on the subject's name and date of birth. We believe this database will prove to be a useful resource, allowing the development of accurate prevalence data for disease-causing mutations, providing a catalog of polymorphisms, and potentially allowing more accurate phenotype-genotype correlations to be drawn.

Chromosomal Proteins, Non-Histone↗

PubMed2003

Mutations and polymorphisms in the human methyl CpG-binding protein MECP2.

Rett syndrome (RTT or RS) is a neurodevelopmental disorder and one of the most frequent genetic diseases in girls. Mutations of the MECP2 gene have been found in a variety of different RTT phenotypes. The MECP2 gene (Xq28) has been described in 1992. Up to now, 218 different mutations have been reported in a total group, of more than 2,100 patients. Mutations in the MECP2 gene are responsible for up to 75% of the classical RTT cases. The mutations, are distributed along the whole gene and are comprised of all types of mutations. Several polymorphisms and benign genetic variants have also been described. Apart from spared reported familial cases, almost all cases are sporadic. RTT syndrome has been considered to be a lethal trait in males. Studying the parental origin of the mutations, however, we and others have found a very high prevalence of de novo mutations on the paternal chromosome. In this work we summarize the mutational reports published until now. One of our aims was to check the mutations' descriptions for consistency and particularly to rename them according to the recommended mutation nomenclature. The increasing number of investigations on the functions of the MeCP2 can help to gain more information about the neuropathogenetic mechanisms causing RTT. Hum Mutat 22:107-115, 2003.

Chromosomal Proteins, Non-Histone↗

PubMed2001

DHPLC analysis of the MECP2 gene in Italian Rett patients.

Rett Syndrome (RTT) is an X-linked dominant neurodevelopmental disorder, which almost exclusively affects girls, with an estimated prevalence of one in 10,000-15,000 female births. Mutations in the methyl CpG binding protein 2 gene (MECP2) have been identified in roughly 75% of classical Rett girls. The vast majority of Rett cases (99%) are sporadic in origin, and are due to de novo mutations. We collected DNA samples from 50 Italian classical Rett girls, and screened the MECP2 coding region for mutations by denaturing high-performance liquid chromatography (DHPLC) and subsequent direct sequencing. DHPLC is a recently developed method for mutation screening which identifies heteroduplexes formed in DNA samples containing mismatches between wild type and mutant DNA strands, combining high sensitivity, reduced cost per run, and high throughput. In our series, 19 different de novo MECP2 mutations, eight of which were previously unreported, were found in 35 out of 50 Rett girls (70%). Seven recurrent mutations were characterized in a total of 22 unrelated cases. Initial DHPLC screening allowed the identification of 17 out of 19 different mutations (90%); after optimal conditions were established, this figure increased to 100%, with all recurrent MECP2 mutations generating a characteristic chromatographic profile. Detailed clinical data were available for 27 out of 35 mutation carrying Rett girls. Milder disease was detectable in patients carrying nonsense mutation as compared to patients carrying missense mutations, although this difference was not statistically significant (P = 0.077).

Chromatography, High Pressure Liquid↗

PubMed2001

Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation.

Rett syndrome is an X-linked dominant neurodevelopmental disorder that affects females almost exclusively. The recent identification of mutations of the methyl-CpG-binding protein 2 gene (MECP2) in patients with RTT, encouraged us to analyze the gene in 37 Japanese patients divided into classical RTT (14 cases), variant RTT (13 cases), and mentally retarded patients with Rett-like features (10 cases). Mutations in MECP2 were identified from most of the patients with classical and variant RTT (25 of 27 cases). Six reported common mutations were detected in 17 cases, and rare single nucleotide substitutions were found in 3 patients. In addition, one insertion mutation (1189insA) and four deletion mutations including one double deletion mutant (451delG, 100del4, 1124del53 and 881del289 plus 1187del8) were newly identified. In the 10 mentally retarded patients with Rett-like features, however, no mutation was detected in the coding region of MECP2. The finding of MECP2 mutations in 92.5% of patients with RTT indicates that RTT fulfilling the diagnostic criteria are due to genetic alteration.

Amino Acid Substitution↗

PubMed2004

Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

Base Sequence↗

PubMed2005

The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype.

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.

Amino Acid Sequence↗

PubMed2005

Functional domains of necdin for protein-protein interaction, nuclear matrix targeting, and cell growth suppression.

Necdin is a growth suppressor expressed predominantly in postmitotic neurons. The necdin gene is involved in the etiology of the genomic imprinting-associated neurodevelopmental disorder Prader-Willi syndrome and belongs to the MAGE gene family. All the MAGE family proteins contain a large homology domain termed the MAGE homology domain (MHD). We here characterize the regions of necdin required for the protein-protein interaction, nuclear matrix targeting, and cell growth suppression. The region including entire MHD (amino acids 116-280) of necdin was required for its interaction with p53, while the regions amino acids 144-184 and 191-222 within the MHD were required for both the nuclear matrix targeting and the cell growth suppression of osteosarcoma SAOS-2 cells. The amino-terminal proline-rich acidic region (amino acids 60-100) was also necessary for cell growth suppression. Tetracycline-regulatable overexpression of necdin induced growth arrest of SAOS-2 cells in a reversible manner, and the necdin-overexpressing cells showed a large, flattened morphology with double nuclei. In contrast, a necdin mutant lacking amino acids 191-222 did not induce such changes. These findings suggest that different functions of necdin are mediated via its distinct domains.

Cell Division↗

PubMed2007

Rett syndrome: an overlooked diagnosis in women with stereotypic hand movements, psychomotor retardation, Parkinsonism, and dystonia?

Rett syndrome is an X-linked neurodevelopmental disorder resulting in profound psychomotor retardation. It is usually diagnosed by a pediatrician or pediatric neurologist. Adult neurologists may, therefore, overlook the possibility of Rett syndrome in women with psychomotor retardation of unknown etiology. We report the case of a woman diagnosed with Rett syndrome at age 49 years. This report emphasizes the diagnostic value of movement disorders, including hand stereotypies, Parkinsonism, and dystonia, in adults with Rett syndrome.

Dystonia↗

PubMed2026

Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis.

BACKGROUND: Biallelic variants in VPS41, encoding a subunit of the HOPS complex, cause autosomal recessive spinocerebellar ataxia 29 (SCAR29), a rare neurodevelopmental disorder with an incompletely defined phenotypic and molecular spectrum. METHODS: We investigated a 24-year-old man with cerebellar ataxia, hypotonia, and intellectual disability. Exome sequencing identified four candidate VPS41 variants. Because maternal DNA was unavailable, long-read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses. RESULTS: In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan-neck deformities and pes cavus. Long-read genome sequencing demonstrated that two VPS41 variants were in trans. RNA analysis revealed distinct splicing consequences: one allele produced an out-of-frame transcript predicted to undergo nonsense-mediated decay, whereas the other generated an in-frame exon-skipped transcript. These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification. CONCLUSION: Our findings expand the phenotypic spectrum of VPS41-related disease and highlight the value of long-read allelic resolution in clarifying pathogenic mechanisms in rare genetic disorders.

Humans↗

PubMed2002

Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype.

Rett syndrome is a neurodevelopmental disorder of early postnatal brain growth in girls. Patients show a normal neonatal period with subsequent developmental regression and a loss of acquired skills (communication and motor skills), deceleration of head growth, and development of typical hand stereotypies. Recent studies have shown that mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2) cause most typical cases of Rett syndrome. The MeCP2 gene encodes a protein that binds methylated cytosine residues of CpG dinucleotides and mediates, with histone deacetylases and transcriptional repressors, the transcription "silencing" of other genes. Girls with Rett syndrome exhibit mosaic expression for the MeCP2 defect at the cellular level, with most patients showing random X-inactivation and approximately equal numbers of cells expressing the normal MeCP2 gene and the mutated MeCP2 gene. In rare cases, females with a MeCP2 mutation escape phenotypic expression of the disorder because of nonrandom X-inactivation and the preferential inactivation of the mutated MeCP2 allele. Nonrandom patterns of X-inactivation may also contribute to the clinical variability often seen in girls with Rett syndrome. The spectrum of clinical phenotype caused by MeCP2 mutations is wide, including milder "preserved speech" variants, the severe congenital Rett variant, and a subset of X-linked recessive mental retardation in boys. Studies have shown that atypical and classical Rett syndrome can caused by the same MeCP2 mutations, indicating clinical phenotype is variable even among girls with the same MeCP2 mutation. The relationship between type of MeCP2 mutation, X-inactivation status, and clinical phenotype of Rett syndrome is complex and likely involves other environmental and polygenic modifiers.

Chromosomal Proteins, Non-Histone↗

PubMed2005

Applications of gene targeting technology to mental retardation and developmental disability research.

The human and mouse genome projects elucidated the sequence and position map of innumerous genes expressed in the central nervous system (CNS), advancing our ability to manipulate these sequences and create models to investigate regulation of gene expression and function. In this article, we reviewed gene targeting methodologies with emphasis on applications to CNS development and neurodevelopmental disorders.

Alleles↗

PubMed2005

Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism.

Schizophrenia and autism are neurodevelopmental disorders with genetic and environmental etiologies. Prenatal viral infection has been associated with both disorders. We investigated the effects of prenatal viral infection on gene regulation in offspring of Balb-c mice using microarray technology. The results showed significant upregulation of 21 genes and downregulation of 18 genes in the affected neonatal brain homogenates spanning gene families affecting cell structure and function, namely, cytosolic chaperone system, HSC70, Bicaudal D, aquaporin 4, carbonic anhydrase 3, glycine receptor, norepinephrine transporter, and myelin basic protein. We also verified the results using QPCR measurements of selected mRNA species. These results show for the first time that prenatal human influenza viral infection on day 9 of pregnancy leads to alterations in a subset of genes in brains of exposed offspring, potentially leading to permanent changes in brain structure and function.

Animals↗

PubMed2000

The Williams syndrome cognitive profile.

Williams syndrome is a rare neurodevelopmental disorder caused by a hemizygous deletion of approximately 1.5 megabases on chromosome 7q11.23. In this article, we outline a Williams Syndrome Cognitive Profile (WSCP) that operationalizes the cognitive characteristics of the syndrome using measures of absolute and relative performance on subtests of the Differential Abilities Scales (Elliot, 1990a). Testing confirmed excellent sensitivity and specificity scores for the WSCP. Seventy-four of 84 individuals with Williams syndrome fit the WSCP while only 4 participants in a contrast group met all of the WSCP criteria. It was also found that the WSCP does not vary greatly with chronological age or overall level of cognitive ability for individuals with Williams syndrome. Possible applications for the WSCP include psychoeducational evaluation and empirical research such as the search for genotype/phenotype relations in this genetically based syndrome.

Adolescent↗

PubMed2002

Neuromotor speech deficits in children and adults with spina bifida and hydrocephalus.

Acquired cerebellar lesions are associated with motor speech deficits. Spina bifida with hydrocephalus (SBH) is a neurodevelopmental disorder that involves significant dysmorphology of the cerebellum. Videotaped narratives produced by 40 children and adults with SBH and their 40 age-matched controls were coded for three motor speech deficits: dysfluency, ataxic dysarthria (articulatory inaccuracy, prosodic excess, and phonatory-prosodic insufficiency) (Brown, Darley, & Aronson, 1970; Darley, Aronson, & Brown, 1969a), and speech rate. Individuals with SBH had more motor speech deficits than controls. Dysfluency was related to an interaction between chronological age and SBH. Speech rate was related independently to chronological age and SBH. Ataxic dysarthria was related to the biology of SBH, and was associated with both physical phenotype (level of spinal cord lesion) and medical history (number of shunt revisions). The data show that developmental as well as acquired lesions of the cerebellum disrupt motor speech, and add to the developmental role of the cerebellum in the automatization of motor skills, including speech.

Adult↗

PubMed1993

Norrie disease gene: characterization of deletions and possible function.

Positional cloning experiments have resulted recently in the isolation of a candidate gene for Norrie disease (pseudoglioma; NDP), a severe X-linked neurodevelopmental disorder. Here we report the isolation and analysis of human genomic DNA clones encompassing the NDP gene. The gene spans 28 kb and consists of 3 exons, the first of which is entirely contained within the 5' untranslated region. Detailed analysis of genomic deletions in Norrie patients shows that they are heterogeneous, both in size and in position. By PCR analysis, we found that expression of the NDP gene was not confined to the eye or to the brain. An extensive DNA and protein sequence comparison between the human NDP gene and related genes from the database revealed homology with cysteine-rich protein-binding domains of immediate--early genes implicated in the regulation of cell proliferation. We propose that NDP is a molecule related in function to these genes and may be involved in a pathway that regulates neural cell differentiation and proliferation.

Amino Acid Sequence↗

PubMed1998

Genes for the CPE receptor (CPETR1) and the human homolog of RVP1 (CPETR2) are localized within the Williams-Beuren syndrome deletion.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting multiple systems. Haploinsufficiency of genes deleted in chromosomal region 7q11.23 is the likely cause for this syndrome. We now report the localization of the genes for the CPE-R (Clostridium perfringens enterotoxin receptor, CPETR1) and the human homolog of RVP1 (rat ventral prostate 1 protein, CPETR2), both previously mapped to 7q11, to the WBS critical region. A single nucleotide polymorphism (SNP) present in CPETR1 has been identified and was used to determine parental origin of the deleted allele in five informative families. The mouse homologs Cpetr1 and Cpetr2 were identified and mapped to the conserved syntenic region on mouse chromosome 5. Northern blot analysis of CPETR1 demonstrates tissue specificity, with expression in kidney, lung, thyroid, and gastrointestinal tissues. In mouse, Cpetr1 is expressed in the early embryo, appears to be developmentally upregulated during gestation, and is present in adult tissues. Our results suggest a role for CPE-R in internal organ development and function during pre- and postnatal life.

5' Untranslated Regions↗

PubMed2002

A developmental fMRI study of the Stroop color-word task.

We used fMRI to investigate developmental changes in brain activation during a Stroop color-word interference task. A positive correlation was observed between age and Stroop-related activation (n = 30) in the left lateral prefrontal cortex, the left anterior cingulate, and the left parietal and parieto-occipital cortices. No regions showed a negative correlation between activation and age. We further investigated age-related differences by stratifying the sample into three age groups: children (ages 7-11), adolescents (ages 12-16), and young adults (ages 18-22). Young adult subjects (n = 11) displayed significant activation in the inferior and middle frontal gyri bilaterally, the left anterior cingulate, and bilateral inferior and superior parietal lobules. Between-group comparisons revealed that young adults had significantly greater activation than adolescent subjects (n = 11) in the left middle frontal gyrus and that young adults showed significantly greater activation than children (n = 8) in the anterior cingulate and left parietal and parieto-occipital regions, as well as in the left middle frontal gyrus. Compared to children, both adult and adolescent subjects exhibited significantly greater activation in the parietal cortex. Adult and adolescent groups, however, did not differ in activation for this region. Together, these data suggest that Stroop task-related functional development of the parietal lobe occurs by adolescence. In contrast, prefrontal cortex function contributing to the Stroop interference task continues to develop into adulthood. This neuromaturational process may depend on increased ability to recruit focal neural resources with age. Findings from this study, the first developmental fMRI investigation of the Stroop interference task, provide a template with which normal development and neurodevelopmental disorders of prefrontal cortex function can be assessed.

Adolescent↗