Xq27 FRAXA locus is a strong candidate for dyslexia: evidence from a genome-wide scan in French families.

Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences (CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 50 UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227–DXS8091) to 4 Mb also disclosing a higher LOD score

Stimulation of lactate production in human granulosa cells by metformin and potential involvement of adenosine 5' monophosphate-activated protein kinase

Context: production of 3-carbon units (as lactate) by granulosa cells (GCs) is important in follicular and oocyte development and may be modulated by metformin.Objective: the aim of the study was to examine the action of metformin on GC lactate production and potential mediation via AMP-activated protein kinase (AMPK).Design: GCs were prepared from follicular aspirates. After exposure to metformin and other potential modulators of AMPK in culture, aspects of cellular function were examined.Setting: the study was conducted in a private fertility clinic/university academic center.Patients: women undergoing routine in vitro fertilization participated in the study.Interventions: all agents were added in culture.Main outcome measures: lactate output of GCs was measured. Cell extracts were prepared after culture, and phosphorylated forms of AMPK and acetyl CoA carboxylase (ACC) were assayed using Western analysis.Results: metformin led to a rapid increase in lactate production by GCs [minimum effective dose, 250 mu M; maximum dose studied, 1 mM (1.22-fold; P &lt; 0.01)]. This dose range of metformin was similar to that required for stimulation of phospho-AMPK in GCs [minimum effective dose, 250 mu M; maximum effect, 500 mu M (2.01-fold; P &lt; 0.001)]. Increasing phospho-ACC, as a representative downstream target regulated by AMPK, was apparent over a lower range (minimum effective dose, 31 mu M; maximum effect, 250 mu M; P &lt; 0.001). A level of metformin (125 mu M) insufficient for the stimulation of lactate output when used alone potentiated the effects of suboptimal doses of insulin on lactate production. Adiponectin (2.5 mu g/ml) had a small but significant effect on lactate output.Conclusions: metformin activates AMPK in GCs, stimulating lactate production and increasing phospho-ACC. Metformin also enhances the action of suboptimal insulin concentrations to stimulate lactate production. (J Clin Endocrinol Metab 94: 670-677, 2009<br/