Study of the serotonin transporter (SLC6A4) and BDNF genes in French patients with non syndromic mental deficiency

<p>Abstract</p> <p>Background</p> <p>Mental deficiency has been linked to abnormalities in cortical neuronal network connectivity and plasticity. These mechanisms are in part under the control of two interacting signalling pathways, the serotonergic and the brain-derived neurotrophic (BDNF) pathways. The aim of the current paper is to determine whether particular alleles or genotypes of two crucial genes of these systems, the serotonin transporter gene (<it>SLC6A4</it>) and the brain-derived neurotrophic factor gene (<it>BDNF</it>), are associated with mental deficiency (MD).</p> <p>Methods</p> <p>We analyzed four functional polymorphisms (rs25531, 5-HTTLPR, VNTR, rs3813034) of the <it>SLC6A4 </it>gene and one functional polymorphism (Val66 Met) of the <it>BDNF </it>gene in 98 patients with non-syndromic mental deficiency (NS-MD) and in an ethnically matched control population of 251 individuals.</p> <p>Results</p> <p>We found no significant differences in allele and genotype frequencies in the five polymorphisms studied in the <it>SLC6A4 </it>and <it>BDNF </it>genes of NS-MD patients versus control patients. While the comparison of the patterns of linkage disequilibrium (D') in the control and NS-MD populations revealed a degree of variability it did not, however, reach significance. No significant differences in frequencies of haplotypes and genotypes for VNTR/rs3813034 and rs25531/5-HTTLPR were observed.</p> <p>Conclusion</p> <p>Altogether, results from the present study do not support a role for any of the five functional polymorphisms of <it>SLC6A4 </it>and <it>BDNF </it>genes in the aetiology of NS-RM. Moreover, they suggest no epistatic interaction in NS-MD between polymorphisms in <it>BDNF </it>and <it>SLC6A4</it>. However, we suggest that further studies on these two pathways in NS-MD remain necessary.</p

Place des génopathies mendeliennes dans les déficiences mentales sporadiques et non spécifiques

Nous avons étudié une translocation réciproque équilibrée 46,XY,t (2;5)(q32.3; p 15.2), de novo observée chez un garçon présentant une déficience mentale modérée. L'examen clinique et l'imagerie cérébrale par IRM n'ont révélé aucune anomalie. Le clonage positionnel par FISH a permis de montrer (i) qu'aucun gène n'est présent dans la région du point de cassure du chromosome 2, et (ii) que le point de cassure du chromosome 5 passe dans le deuxième intron du gène de la delta caténine CTNND2. Le gène de la delta caténine est exprimé exclusivement dans l'encéphale ; elle est notamment fortement impliquée dans la morphogenèse dentritique (1999 , Lu et al. ). Dans le syndrome du cri du chat (del 5p), il a été montré que la DM est plus sévère quand le territoire de la délétion inclut le gène de la delta caténine (2000, Medina et al.). La souris KO homozygote ctnnd2 -/- manifeste un dysfonctionnement cognitif et une altération de la plasticité synaptique hippocampique (2004, Israely et al.).TOURS-BU Médecine (372612103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Etude du profil d'inactivation des chromosomes X chez les conductrices de pathologies liées au sexe avec déficience mentale

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Le syndrome FG (recherche des gènes impliqués)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Determination of the gene structure of human oligophrenin-1 and identification of three novel polymorphisms by screening of DNA from 164 patients with non-specific X-linked mental retardation

International audienceWe have recently shown that mutations in oligophrenin-1 (OPHN1) are responsible for non-specific X-linked mental retardation (MRX). The structure of the gene encoding the OPHN1 protein was determined by isolation of genomic DNA clones from the human cosmid library. Genomic fragments containing exons were sequenced, and the sequences of the exons and flanking introns were defined. Knowledge of the genomic structure of the OPHN1 gene, which spans at least 500 kb and consists of 25 exons, will facilitate the search for additional mutations in OPHN1. OPHN1 was screened for mutations in 164 subjects with non-specific mental retardation. Three nucleotide substitutions were identified, one of which was a silent mutation in the codon threonine 301 at position 903 (G-->C). The other substitutions were located in exon 2, a G-->A substitution at position 133 (A45T), and in exon 10, a C-->T substitution at position 902 (T301M), but these are common polymorphisms rather than disease-causing mutations

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

International audienceLinkage 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

A New Chromosome X Exon-Specific Microarray Platform for Screening of Patients with X-Linked Disorders

Recent studies and advances in high-density oligonucleotide arrays have shown that microdeletions; and microduplications occur at a high frequency in the human genome, causing various genetic conditions including mental retardation. Thus far little is known about the pathways leading to this disease, and implementation of microarrays is hampered by their increasing cost and complexity, underlining the need for new diagnostic tools. The aim of this study was to introduce a new targeted platform called "chromosome X exon-specific array" and to apply this new platform to screening of 20 families (including one blind positive control) with suspected X-linked mental retardation, to identify new causative X-linked mental retardation genes. The new microarray contains of 21,939 oligonucleotides covering 92.9% of all exons of all genes on chromosome X. Patient screening resulted in successful identification of the blind positive control included in the sample of 20 families, and one of the remaining 19 families was found to carry a 1.78-kilobase deletion involving all exons of pseudogene BRAF2. The BRAF2 deletion segregated in the family and was not found in 200 normal male samples, and no copy number variations are reported in this region. Further studies and focused investigation of X-linked disorders have the potential to reveal the molecular basis of human genetic pathological conditions that are caused by copy-number changes in chromosome X genes. (J Mol Diagn 2009, 11:562-568; DOI: 10.2353/jmoldx.2009.090086)status: publishe

Specific clinical and brain MRI features in mentally retarded patients with mutations in theOligophrenin-1 gene

International audienceOligophrenin-1 (OPHN-1) gene disruption is known as responsible for so called "non-specific" X-linked mental retardation (MR) Billuart et al. [1998: Nature 392:923-926]. In order to search for a possible specific clinical and radiological profile for mutation in the OPHN-1 gene, clinical and 3D brain MRI studies were performed in the two families with a known mutation in OPHN-1 reported so far: a 19-year-old female with an X;12 balanced translocation encompassing OPHN-1, and four affected males of family MRX60 sharing a frameshift mutation in OPHN-1. Clinical data shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early onset complex partial seizures, and moderate to severe MR. Brain MRIs performed in three individuals exhibited a specific vermian dysgenesis including an incomplete sulcation of anterior and posterior vermis with the most prominent defect in lobules VI and VII. In addition, a non-specific cerebral cortico-subcortical atrophy was also observed. These clinical and radiological features suggest a distinct clinico-radiological syndrome. These preliminary data need to be confirmed in other families and will be helpful for further targeted mutation screening of the OPHN-1 gene in male patients with similar clinico-radiological features. In addition, OPHN-1 inactivation should be considered as a relevant model of developmental vermis disorganization, leading to a better understanding of the possible role of the cerebellum in MR

Exclusion of nine candidate genes for their involvement in X-linked FG syndrome (FGS1) in three families

International audienc