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C Beldjord

Publications and source records attributed to C Beldjord.

At least 37 records · Page 2Linked to original sources
PubMed1999

Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental retardation gene (MRX54).

Nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. A large genetic interval of assignment obtained on individual families by linkage analysis, genetic, heterogeneity, and phenotypic variability usually are major obstacles to fine-map and identify the related disease genes. Here we report on a large Tunisian family (MRX54) with an MRX condition. X-linked recessive inheritance is strongly suggested by the segregation of MR through seven unaffected carrier females to 14 affected males in two generations. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp21.3-22.1 (maximum LOD score Zmax = 3.56, recombination fraction 0 = 0 at DXS1202), which was confirmed by multipoint linkage analyses. Recombinant events observed with the flanking markers DXS989 and DXS1218 delineate a refined locus of approximately 2.7 cM in accordance with the physical distance between these two markers. The small interval of assignment observed in this family overlaps not only with nine large MRX loci previously reported in Xp21.3-22.1 but also with two inherited microdeletions in Xp21.3-22.1 involved in nonspecific MR. Although the involvement of several genes located in the Xp21.3-22.1 region cannot be ruled out, data reported in this study could be used as a starting point for the search of such gene(s).

Adolescent↗
PubMed1999

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.

Amino Acid Sequence↗
PubMed1999

Follow up of precocious pseudopuberty associated with isolated ovarian follicular cysts.

The clinical outcomes of seven girls presenting with pseudosexual precocity caused by isolated autonomous ovarian follicular cysts are presented. Six of the seven girls, aged 11 months to 6.9 years, had a unilateral ovarian cyst detected by ultrasound at the first acute episode. Plasma oestradiol was raised in only five of the cases, but all had a low response to luteinising hormone releasing hormone stimulation. Follow up lasted for up to eight years with recurrent episodes of variable frequency and severity in all seven patients. Evidence of McCune-Albright syndrome appeared later in only three patients. It could not be predicted from the initial symptoms or the clinical course. Mutations of the G(s)alpha protein leading to activation were investigated in the lymphocytes and ovarian and bone tissues of four patients. Only one patient showed a mutation in bone tissue. Close follow up with repeated searches for skeletal lesions remains necessary since the distribution of somatic mutations cannot be assessed by molecular studies. Most patients with recurrent ovarian cysts require a conservative approach.

Child↗
PubMed1998

Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas.

Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-beta-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the beta-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the beta-catenin gene similar to those found in colon cancers and melanomas. These alterations in the beta-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of beta-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of beta-catenin in the nucleus. Thus alterations in the beta-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-beta-catenin pathway is a major event in the development of HCC in humans and mice.

Animals↗
PubMed1998

Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation.

Primary or nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment. Although it is present in approximately 0.15-0.3% of males, most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown. Here we report the characterization of a new gene on the long arm of the X-chromosome (position Xq12) and the identification in unrelated individuals of different mutations that are predicted to cause a loss of function. This gene is highly expressed in fetal brain and encodes a protein of relative molecular mass 91K, named oligophrenin-1, which contains a domain typical of a Rho-GTPase-activating protein (rhoGAP). By enhancing their GTPase activity, GAP proteins inactivate small Rho and Ras proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. Such activation is known to affect cell migration and outgrowth of axons and dendrites in vivo. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.

Amino Acid Sequence↗
PubMed1998

A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome.

X-SCLH/LIS syndrome is a neuronal migration disorder with disruption of the six-layered neocortex. It consists of subcortical laminar heterotopia (SCLH, band heterotopia, or double cortex) in females and lissencephaly (LIS) in males, leading to epilepsy and cognitive impairment. We report the characterization of a novel CNS gene encoding a 40 kDa predicted protein that we named Doublecortin and the identification of mutations in four unrelated X-SCLH/LIS cases. The predicted protein shares significant homology with the N-terminal segment of a protein containing a protein kinase domain at its C-terminal part. This novel gene is highly expressed during brain development, mainly in fetal neurons including precursors. The complete disorganization observed in lissencephaly and heterotopia thus seems to reflect a failure of early events associated with neuron dispersion.

Adolescent↗
PubMed1998

Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours.

OBJECTIVE: The molecular mechanisms underlying ACTH-secreting tumour formation remain unknown. Transmembrane signalling pathways play an important role in several endocrine disorders including pituitary tumours. To investigate the role of the pituitary vasopressin (V3) receptor (R) in ACTH-secreting tumours we have qualitatively and quantitatively analysed its mRNA. DESIGN: RT-PCR, denaturing gradient gel electrophoresis and S1 nuclease protection experiments were used to analyse V3 mRNA structure in ACTH-secreting tumours. We also developed a competitive RT-PCR system to compare the levels of expression of POMC, V3 and CRH-R genes. This system used as competitor a single mutant template (termed multi-mutant) containing primers for the three genes flanking an unrelated core sequence allowing multiple quantifications from the same cDNA preparations. We analysed 12 normal pituitaries, 15 corticotroph pituitary adenomas and 6 ACTH-secreting bronchial carcinoids. RESULTS: The V3 mRNA structure and sequence were found to be identical in normal and tumoural pituitary indicating that the tumoural Vs mRNA codes for a normal receptor. POMC RT-PCR signals in the pituitary tumour group were approximately 7-fold higher than in the normal pituitary group. Similarly, V3 and CRH-R signal were increased in pituitary tumors (mean +/- SEM: 5.87 x 10(-6) +/- 1.73 x 10(-6), and 2.33 x 10(-4) +/- 1.4 x 10(-4), respectively), when compared to normal pituitaries (1.19 x 10(-7) +/- 2.39 x 10(-8), and 1.7 x 10(-6) +/- 4.65 x 10(-7), respectively) suggesting that these two genes are expressed at very high levels in corticotroph tumours. When expressed relative to the corresponding POMC signals, increases in V3 and CRH-R signals reached 49-fold and 137-fold, respectively, in pituitary tumours. In ACTH-secreting bronchial carcinoids V3 gene expression level was also higher than in normal pituitary, whereas CRH-R signals were detected in only 4 of the 6 tumours with wide variations. CONCLUSION: Our results show that both vasopressin and CRH receptor genes are overexpressed in ACTH-secreting pituitary tumours. They suggest that overexpression of G protein-coupled receptors may be an additional mechanism through which membrane receptors may play a role in human tumours.

Adenoma↗
PubMed1998

Prevalence of fragile-X syndrome and FRAXE among children with intellectual disability in a Caribbean island, Guadeloupe, French West Indies.

Fragile-X syndrome (FXS) is the most common cause of inherited intellectual disability. Although FXS has been identified in all the main ethnic groups, little is known about its prevalence with respect to ethnicity. Since the identification of the FXS primary defect, diagnosis involving DNA analysis has been made possible, allowing efficient screening strategies to be considered. The present authors have carried out FXS screening among children belonging mainly to the Afro-Caribbean ethnic group (163 boys and 85 girls) affected with moderate to severe intellectual disability of previously unknown origin. We have found a 6.7% and 0% prevalence among boys and girls, respectively, yielding a minimum FXS incidence of 0.42 per 1000 male births per year. Family studies have resulted in genetic counselling for several individuals. FRAXE screening was also achieved and no FRAXE case was detected in this study.

Adolescent↗
PubMed1998

doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH).

Subcortical laminar heterotopia (SCLH), or 'double cortex', is a cortical dysgenesis disorder associated with a defect in neuronal migration. Clinical manifestations are epilepsy and mental retardation. This disorder, which mainly affects females, can be inherited in a single pedigree with lissencephaly, a more severe disease which affects the male individuals. This clinical entity has been described as X-SCLH/LIS syndrome. Recently we have demonstrated that the doublecortin gene, which is localized on the X chromosome, is implicated in this disorder. We have now performed a systematic mutation analysis of doublecortin in 11 unrelated females with SCLH (one familial and 10 sporadic cases) and have identified mutations in 10/11 cases. The sequence differences include nonsense, splice site and missense mutations and these were found throughout the gene. These results provide strong evidence that loss of function of doublecortin is the major cause of SCLH. The absence of phenotype-genotype correlations suggests that X-inactivation patterns of neuronal precursor cells are likely to contribute to the variable clinical severity of this disorder in females.

Abnormalities, Multiple↗
PubMed1998

Non-specific X-linked semidominant mental retardation by mutations in a Rab GDP-dissociation inhibitor.

Non-specific X-linked mental retardation (MRX) is a very common disorder which affects approximately 1 in 600 males. Despite this high frequency, little is known about the molecular defects underlying this disorder, mainly because of the clinical and genetic heterogeneity which is evident from linkage studies. Recently, a collaborative study using the candidate gene approach demonstrated the presence of mutations in GDIalpha, a Rab GDP-dissociation inhibitor encoded by a gene localized in Xq28, associated with non-specific mental retardation. GDIalpha is mainly a brain-specific protein that plays a critical role in the recycling of Rab GTPases involved in membrane vesicular transport. The study presented here was designed to assess the prevalence of mutations in the GDIalpha in mentally retarded patients and to discuss the clinical phenotypes observed in affected individuals. Mutation screening of the whole coding region of the GDIalpha gene, using a combination of denaturing gradient gel electrophoresis and direct sequencing, was carried out in 164 patients found negative for expansions across the FRAXA GCC repeat. In addition to the nonsense mutation recently reported in MRX48, we have identified a novel missense mutation in exon 11 of the GDIalpha gene in one familial form of non-specific mental retardation. In this family (family R), all affected males show moderate to severe mental retardation, and the X-linked semidominant inheritance is strongly suggested by the severe phenotypes in males with respect to mildly affected females or unaffected obligatory carriers. This study showed that the prevalence of GDIalpha mutations in non-specific mental retardation could be estimated to be 0.5-1%, and molecular diagnosis and genetic counselling in some cases of non-specific mental handicap can now be provided.

Female↗
PubMed1998

Inherited microdeletion in Xp21.3-22.1 involved in non-specific mental retardation.

X-linked mental retardation (XLMR) is a genetically and clinically heterogeneous common disorder. A cumulative frequency of about 1/600 male births was estimated by different authors, including the fragile X syndrome, which affects 1/4000 males. Given this very high cumulative frequency, identification of genes and molecular mechanisms involved in other XLMRs, represents a challenging task of considerable medical importance. In this report we describe clinical and molecular investigations in the family of a mentally retarded boy for whom a microdeletion in Xp21.3-22.1 was detected within the frame of a previously reported systematic search for deletion using STS-PCR screening. Thorough clinical investigation of the sibling showed that two affected brothers exhibit a moderate non-specific mental retardation without any additional neurological impairment, statural growth deficiency or characteristic dysmorphy. Molecular analysis revealed that the microdeletion observed in this family is an inherited defect which cosegregates with mental retardation as an X-linked recessive condition, since both non-deleted boys and transmitting mother are normal. These results and the inherited microdeletion detected within the same region associated with non-specific MR, reported by Raeymaekers et al., suggest that Xp21.3 MR locus is prone to deletions. Therefore, search for microdeletions in the eight families assigned by linkage analysis to this region might allow a better definition of the critical region and an identification of the gene involved in this X-linked mental retardation.

Child↗
PubMed1998

A novel missense mutation D513G in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in a French CBAVD patient. Mutations in brief no. 175. Online.

Congenital bilateal absence of the vas deferens (CBAVD) with obstructive azoospermia is a congenital reproductive disorder that affects one in 10000 male individuals. The observation that many men presenting with CBAVD have mutations in their CFTR genes had led to the proposal that CBAVD may be a primary genital form of cystic fibrosis. We report here one novel mutation located in exon 10 of the CFTR gene. This mutation, named D513G (A-->G at position 1670), has been found in one of 83 patients with CBAVD from France, the analysis of exon 10 using a chemical clamp DGGE assay allowed us to identify three CF mutations AEF508 (37/166; 22%), AE1507 (1/166; 0/6%) and D513G (1/166; 0.6%), and two variants M470V and E528E (1716 G>A). The novel D513G mutation has not been found in more than 200 non-CF chromosomes and in a sample of 300 CF chromosomes from French classical CF patients.

Animals↗
PubMed1998

A gene for non-specific X-linked mental retardation (MRX55) is located in Xp11.

A new family with a non-specific X-linked mental retardation (MRX55) is described. An X-linked recessive inheritance is suggested by the segregation from two healthy transmitting females of moderate mental retardation in three males, without any specific clinical, radiological or biological features. Two point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp11 (Zmax = 2.11, theta = 0); multipoint linkage analyses confirmed the significant linkage with a maximum lod score (Z = 2.11 at theta = 0, at DXS8012). Recombination events observed with the flanking markers DXS1068 and DXS1275 delineate a 34 centimorgan interval in the pericentromeric region. The interval of assignment pointed out in this family overlaps with several MRX loci previously reported in Xp11 which are reviewed here in.

Chromosome Mapping↗
PubMed1997

Gene for nonspecific X-linked mental retardation (MRX 47) is located in Xq22.3-q24.

We describe a large family with nonspecific X-linked mental retardation (MRX 47). An X-linked recessive transmission is suggested by the inheritance from the mothers in two generations of a moderate to severe form of mental retardation in six males, without any specific clinical findings. Two point linkage analysis demonstrated significant linkage between the disorder and two markers in Xq23 (Zmax = 3.75, theta = 0). Multipoint linkage analyses confirmed the significant linkage with a maximum lod score (Z = 3.96, theta = 0) at DXS1059. Recombination events observed with the flanking markers DXS1105 and DXS8067 delineate a 17 cM interval. This interval overlaps with several loci of XLMR disorders previously localized in Xq23-q24, which are reviewed herein.

Chromosome Mapping↗