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

Study of chromosomal structural variations in autism and mental retardation

L’autisme et la déficience mentale sont deux syndromes neuro-développementaux impliquant des facteurs génétiques. Notre travail a consisté à rechercher de nouveaux gènes candidats ou facteurs de susceptibilité chez 106 patients atteints d’autisme et 68 de déficience mentale non syndromique sporadique.Nous avons observé une association entre l’allèle 4 d’un marqueur microsatellite GXAlu localisé en 17q11.2 dans l’intron 27b du gène NF1 et des patients atteints de déficience mentale non-syndromique.Nous avons contribué à la mise en évidence d’une augmentation d’expression du transcrit NLGN4X, chez un patient autiste avec un retard mental non-syndromique présentant une mutation dans le promoteur du gène NLGN4X.L’étude de la région 22q13 par MLPA, nous a permis de mettre en évidence une délétion de novo d’au moins 1Mb chez un patient autiste.Les variations de nombre de copies (CNV) ont été étudiées chez des autistes par QPCR. Nous avons identifié 27 variations réparties sur 17 gènes parmi les 36 explorés. Les CNV observés dans les gènes ITGA6, TAGLN3, HOXA1, DLG4 et UBE2C sont intéressants en raison de l’implication de ces gènes dans le développement cérébral ou la fonction neuronale.L’ensemble de ces résultats nécessite des expériences complémentaires de validation.Autism and mental retardation are two neurodevelopmental syndromes involving genetic factors. Our work consists in finding new candidate genes or susceptibility factors. 106 autistic patients and 68 sporadic non-syndromic mentally retardated patients were studied.We have shown an association between allele 4 of a microsatellite marker GXAlu locasized in 17q11.2, in intron 27b of the NF1 gene and patients with non-syndromic mental retardation.We contributed to the study on the NLGN4X gene. We demonstrated an increase of expression of NLGN4X transcript, in an autistic patient with non-syndromic mental retardation linked to a mutation in the NLGN4X gene promoter.We study the 22q13 region with MLPA method, we have demonstrated a deletion de novo of at least 1Mb in an autistic patient.The copy number variations (CNV) have been investigated in an autistic population by QPCR. We identified 27 variations on 17 genes among the 36 investigated. The CNV observed in ITGA6, TAGLN3, HOXA1, DLG4 and UBE2C genes are interesting because of the involvement of these genes in brain development or neuronal function.These results require further experiments for validation

Transmission disequilibrium study of an oligodendrocyte and myelin glycoprotein gene allele in 431 families with an autistic proband

Autistic disorder is a neurodevelopmental disorder where genetic factors play an important role. We previously described an association between a subgroup of French autistic patients and an allele of a non-synonymous single nucleotide polymorphism (nsSNP: OMGP62 G > A or rs11080149) in the gene coding for the oligodendrocyte and myelin glycoprotein (OMG), located at 7 Mb from the marker D17S250, linked to autism in two independent genome scan studies. We report a study on 431 families with 1 affected child from different origins: French Canada (n = 262), Italy (n = 123) and United States (n = 46). We analyzed the transmission of the rs11080149 alleles from parents to their affected children. There was a preferential transmission of the G allele from parents to affected children ( p = 0.0017) in the overall sample. Paternal and maternal transmission rates were both skewed. Taking into account our previous results obtained in a French group of patients, where we observed an association with allele A, a direct role of this polymorphism is improbable in autism. The associations observed in Japanese and French patients, the linkage studies and the present work speak in favor of the existence of a susceptibility gene for autism in the NF1 locus

Effect of the oligodendrocyte myelin glycoprotein (OMgp) on the expansion and neuronal differentiation of rat neural stem cells

The oligodendrocyte myelin glycoprotein (OMgp) inhibits axon regeneration after injury in the adult mammalian central nervous system. However its function during brain development remains largely unknown. The present study aims to analyze a possible role for OMgp during neurogenesis. We showed that neural stem cells (NSC) extracted from the whole mesencephalon of rat embryos (E14) and cultured as free floating neurospheres expressed both OMgp and its receptor Nogo-R1. An over-expression of OMgp affected NSC expansion by reducing cell proliferation, but did not affect their differentiation into neurons. These findings indicate a new role for OMgp during brain development as a possible regulator of neurogenesis. Moreover, they suggest a possible implication for OMG gene in the etiology of neurofibromatosis type 1 forms characterized by a deletion of the NF1 gene locus containing OMG

Association study of the ubiquitin conjugating enzyme gene UBE2H in sporadic ALS.

International audienceUbiquitin inclusions represent a cytopathological hallmark of ALS. The ubiquitin-dependent protein degradation pathway may also be involved in the pathophysiology of SOD1 mutated ALS cases as demonstrated in transgenic animals. UBE2H is an ubiquitin conjugating enzyme known to act on histones and cytoskeletal proteins, both involved in the degenerative pathway of the motor neuron. We screened the whole coding sequence of the UBE2H gene in 24 sporadic ALS (SALS) patients using single strand conformation polymorphism (SSCP). All variants detected by SSCP were analysed by genomic DNA sequencing. We found one known polymorphism (rs12539800) and two new synonymous single nucleotide polymorphisms (SNP) (nG78A and nG501A). The allele distribution of the rs12539800 (A336G) SNP were tested for association in 252 SALS patients and 357 controls. The allele and genotype distributions were identical in the two groups. The UBE2H gene is not implicated in SALS; however, the ubiquitin pathway is worthy of further investigation in ALS