Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism.

Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.

[Increase of the frequency of HLA DR4 antigens in recurrent arterial hypertension of pregnancy]. / Augmentation de la fréquence de l'antigène HLA DR4 dans l'hypertension artérielle récidivante de la grossesse.

We studied the frequency of HLA DR antigens in 96 women whose 50 with preeclampsia (PE = proteinuria greater than 0.5 g/l + HTA) and 46 with gestational HTA (GHTA = pregnancy-induced HTA without proteinuria). Sixty had later pregnancies (28 PE and 32 GHTA) and were followed for from 3 to 23 years (m = 8.5 yrs) after the first pregnancy. HLA DR antigen distribution was determined by a search on B lymphocytes for the 10 antigens of locus DR. The normal population included 38 control couples (76 mothers and fathers) with normotensive pregnancies (A) and 200 healthy controls recruited from a local blood donor population (B). The frequency of alleles was compared to that of the different group of primiparous women and whole group of women with later pregnancies. Significant variations were evaluated by the chi 2 test, using Woolf's method: the p values obtained was multiplied by the number of antigens looked for (p corrected or pc). Only the DR4 antigen, present in 19.7% of control couples (A) and 26.5% of the blood donor population (B), was increased in proportions that depended on clinical classification: 54.3% (pc less than 0.005 with A, less than 0.007 with B) in all primiparous women with GHTA, 38% (NS) in all primiparous women with PE. However significant variation was also observed when the frequency of DR4 in PE women was compared to that in only women of A (38% vs 5.2%, pc less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)