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C Beldjord

Publications and source records attributed to C Beldjord.

At least 19 recordsLinked to original sources
PubMed2005

Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation.

We describe two brothers with mental retardation (MR) due to a c.428_451dup24 in the ARX gene. The mother did not apparently carry the mutation, as determined by dHPLC and by fragment size analysis. Using semiquantitative fluorescent PCR, we show however that 4% of her lymphocytes and 24% of her fibroblasts harbored the duplication. We thus show that the mother displays somatic mosaicism for the duplication thereby highlighting the need to reconsider the molecular screening in sporadic cases of MR.

Amino Acid Sequence↗
PubMed2005

Screening of ARX in mental retardation families: Consequences for the strategy of molecular diagnosis.

Mutations in the human ARX gene have been shown to cause nonsyndromic X-linked mental retardation (MRX) as well as syndromic forms such as X-linked lissencephaly with abnormal genitalia (XLAG), Partington syndrome and X-linked infantile spasm. The most common causative mutation, a duplication of 24 bp, was found in families with a variety of phenotypes, but not in the more severe XLAG phenotypes. The aim of the study was to access the frequency of ARX mutations in families with established or putative X-linked mental retardation (XLMR) collected by the European XLMR Consortium. We screened the entire coding region of ARX for mutations in 197 novel XLMR families by denaturing high-performance liquid chromatography, and we identified eight mutations (six c.428_451dup24, one insertion and one novel missense mutation p.P38S). To better define the prevalence of ARX mutations, we included previously reported results of 157 XLMR families. Together, these data showed the relatively high rate (9.5%) of ARX mutations in X-linked MR families and an expectedly low rate in families with affected brother pairs (2.2%). This study confirms that the frequency of ARX mutations is high in XLMR, and the analysis of ARX in MRX should not be limited to duplication.

Amino Acid Sequence↗
PubMed2005

Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.

BACKGROUND: Mutations of oligophrenin 1, one of the first genes identified in nonspecific X-linked mental retardation (MRX), have been described in patients with moderate to severe cognitive impairment and predominant cerebellar hypoplasia, in the vermis. OBJECTIVE: To further delineate the phenotypic and mutational spectrum of the syndrome, by screening oligophrenin 1 in two cohorts of male patients with mental retardation (MR) with or without known posterior fossa anomalies. METHODS: Clinical examination, cognitive testing, MRI studies, and mutational analysis (denaturing gradient gel electrophoresis and direct sequencing) on blood lymphocytes were performed in 213 unrelated affected individuals: 196 patients classified as MRX and 17 patients with MR and previously detected cerebellar anomalies. RESULTS: Four novel oligophrenin 1 mutations were identified. In the MRX group, two nonsense mutations were detected. In the MR group, two mutations were found: a deletion of exons 16 to 17 and a splice site mutation. All patients shared characteristic clinical, radiologic, and distinctive features with a degree of intrafamilial variability in motor and cognitive deficits. CONCLUSIONS: Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group.

Adolescent↗
PubMed2003

Familial bilateral medial parietooccipital band heterotopia not related to DCX or LIS1 gene defects.

A father and his daughter displayed strictly similar focal brain dysplasia at MR examination, characterized by regional medial posterior laminar sub-cortical grey matter heterotopia. To our knowledge, no family presenting such anomalies has yet been described. LIS1 and DCX gene defects were excluded. Collecting patients with such inherited dysplasia should improve our knowledge of the genetic basis of cortical malformations.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

DHPLC-based method for DNA methylation analysis of differential methylated regions from imprinted genes.

The bisulfite genomic sequencing method is one of the most widely used techniques for methylation analysis in heterogeneous unbiased PCR, amplifying for both methylated and unmethylated alleles simultaneously. However, it requires labor-intensive and time-consuming cloning and sequencing steps. In the current study, we used a denaturing high-performance liquid chromatography (DHPLC) procedure in a complementary way with the bisulfite genomic sequencing to analyze the methylation of differentially methylated regions (DMRs) of imprinted genes. We showed reliable and reproducible results in distinguishing overall methylation profiles of DMRs regions of human SNRPN, H19, MEST/PEG1, LIT1, IGF2, TSSC5, WT1 antisense, and mouse H19, Mest/Peg1, Igf2R imprinted genes. These DHPLC profiles were in accordance with bisulfite genomic sequencing data and may serve as a type of "fingerprint," revealing the overall methylation status of DMRs associated with sample heterogeneity. We conclude that DHPLC analysis could be used to increase the throughput efficiency of methylation pattern analysis of imprinted genes after the bisulfite conversion of genomic DNA and unbiased PCR amplification.

Animals↗
PubMed2002

So-called 'cryptogenic' partial seizures resulting from a subtle cortical dysgenesis due to a doublecortin gene mutation.

We report the case of a female suffering from resistant partial seizures, which were related to 'cryptogenic' epilepsy, as the cerebral cortex was considered normal on the initial MRI images. As her son is mentally retarded and has a pachygyria, the doublecortin gene, usually involved in band heterotopia or lissencephaly, was screened for mutations. A missense mutation was identified, shared by both the son and his mother, and a subtle discontinuous subcortical heterotopia was subsequently detected on the mother's MRI. The pathophysiology of epilepsy in this woman is discussed in the light of the role of doublecortin, not only in neuronal migration, but also in axonal growth and dendritic connectivity.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2001

Five novel frameshift mutations in exon 3 and 4 of the MECP2 gene identified in Rett patients: Consequences for the molecular diagnosis strategy.

Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in 70-85% of RTT cases. We report here five novel frameshift mutations (named 345delC, 895del202, 989ins18del8, 996insAG and 1124del53) in exon 3 and 4 of the MECP2 gene. To avoid the missing of few small deletions in RTT patients using classical mutation screening approaches, we suggest that screening of the mutations in the MECP2 gene in RTT girls should include at least a large PCR to amplify exon 4 entirely.

Chromosomal Proteins, Non-Histone↗
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↗
PubMed2001

No mutations in the coding region of the Rett syndrome gene MECP2 in 59 autistic patients.

Autistic disorder is a pervasive developmental disorder considered to have a multigenic origin. Mental retardation is present in 75% of autistic patients. Autistic features are found in Rett syndrome, a neurological disorder affecting girls and associated with severe mental retardation. Recently, the gene responsible for the Rett syndrome, methyl CpG-binding protein (MECP2) gene, was identified on the X chromosome by a candidate gene strategy. Mutations in this gene were also observed in some mentally retarded males. In this study we tested MECP2 as a candidate gene in autistic disorder by a DGGE analysis of its coding region and intron-exon boundaries. Among 59 autistic patients, 42 males and 17 females, mentally retarded or not, no mutations or polymorphisms were present in the MECP2 gene. Taking into account the size of our sample, we conclude that MECP2 coding sequence mutations are not an important factor (less than 5% of cases) in the aetiology of autistic disorder.

Autistic Disorder↗
PubMed2000

Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation.

X-linked mental retardation is a very common condition that affects approximately 1 in 600 males. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Recently, a study using the candidate gene approach demonstrated the presence of mutations in PAK3 (p21-activating kinase) associated with nonspecific mental retardation. PAK3 is a member of the larger family of PAK genes. PAK proteins have been implicated as critical downstream effectors that link Rho-GTPases to the actin cytoskeleton and to MAP kinase cascades, including the c-Jun amino-terminal kinase (JNK) and p38. We screened 12 MRX pedigrees that map to a large region overlying Xq21-q24. Mutation screening of the whole coding region of the PAK3 gene was performed by using a combination of denaturing gradient gel electrophoresis and direct sequencing. We have identified a novel missense mutation in exon 2 of PAK3 gene (R67C) in MRX47. This confirms the involvement of PAK3 in MRX following the report of a nonsense mutation recently reported in MRX30. In the MRX47 family, all affected males show moderate to severe mental retardation. No seizures, statural growth deficiency, or minor facial or other abnormal physical features were observed. This mutation R67C is located in a conserved polybasic domain (AA 66-68) of the protein that is predicted to play a major role in the GTPases binding and stimulation of Pak activity.

Amino Acid Sequence↗
PubMed2000

MECP2 mutations account for most cases of typical forms of Rett syndrome.

Rett syndrome (RTT) is a severe progressive neurological disorder that affects almost exclusively females, with an estimated prevalence of approximately one in 10 000-15 000 female births. Most cases are sporadic, but several reports about familial recurrence support X-linked dominant inheritance with male lethality. The gene responsible for this disorder, MECP2, was recently identified by candidate gene strategy. Mutations were detected in <25% of RTT cases in this first report. To characterize the spectrum of mutations in the MECP2 gene in RTT patients, we selected 46 typical RTT patients and performed mutation screening by denaturing gradient gel electrophoresis combined with direct sequencing. We identified 30 mutations, accounting for 65% of RTT patients. They include 12 novel mutations (11 located in exon 3 and one in exon 2). Mutations, such as R270X and frameshift deletions in a (CCACC) (n) rich region, have been found with multiple recurrences. Most of the mutations were de novo, except in one family where the non-affected transmitter mother exhibited a bias of X inactivation. Although this study showed that MECP2 mutations account for most cases of typical forms of RTT (65%) and mutations in non-coding regions cannot be excluded for the remaining cases, an alternative hypothesis that takes into account the homogeneous phenotype and exclusive involvement of females, could be the implication in RTT of a putative second X-linked gene.

Base Sequence↗
PubMed2000

A novel, rapid, and accurate method for detecting microdeletion involving the DAZ gene in infertile men.

OBJECTIVE: To report on a novel, accurate method for detecting microdeletion involving the DAZ gene in infertile men. DESIGN: Retrospective clinical study. SETTING: University Infertility Center of Cochin Hospital, Paris, France. PATIENT(S): Infertile patients (n = 25) consulting our infertility department during 1998. The patient cohort included subjects with nonobstructive azoospermia and oligoasthenospermia. INTERVENTION(S): Blood samples were collected from each subject. MAIN OUTCOME MEASURE(S): DNA analysis using polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). RESULT(S): We used a new molecular genetic strategy to rapidly identify deletions of the Y chromosome that include the DAZ locus. The experiment consists of amplifying simultaneously exon 4 of the DAZ and DAZLA genes with the use of specific primers that are complementary to intronic sequences of these genes. DGGE was used to separate the two PCR products, with good resolution. In infertile men with a microdeletion of the DAZ gene, this method allows amplification of an internal control when a deletion of that portion of the Yq chromosome is observed on a single amplification. CONCLUSION(S): This PCR-DGGE method for detection of DAZ gene deletion is simple and fast and does not require the use of radioactive elements. Compared with the classic PCR approach, this new method allows the amplification of the DAZLA copy to be used as an effective internal control in infertile men with microdeletion of the DAZ locus. This procedure could be particularly useful in screening for the DAZ locus in the diagnostic workup of nonobstructive azoospermia and severe oligoasthenoteratozoospermia.

Adult↗
PubMed2000

A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation.

X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous. They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features. At least five MRX genes have been identified by positional cloning, but each accounts for only 0.5%-1.0% of MRX cases. Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families. RNA in situ hybridization showed that TM4SF2 is highly expressed in the central nervous system, including the cerebral cortex and hippocampus. TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes including beta-1 integrins. We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth.

Amino Acid Sequence↗