Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki-Lupski syndrome.

The Potocki-Lupski syndrome (PTLS) is associated with a microduplication of 17p11.2. Clinical features include multiple congenital and neurobehavioral abnormalities and autistic features. We have generated a PTLS mouse model, Dp(11)17/+, that recapitulates some of the physical and neurobehavioral phenotypes present in patients. Here, we investigated the social behavior and gene expression pattern of this mouse model in a pure C57BL/6-Tyr(c-Brd) genetic background. Dp(11)17/+ male mice displayed normal home-cage behavior but increased anxiety and increased dominant behavior in specific tests. A subtle impairment in the preference for a social target versus an inanimate target and abnormal preference for social novelty (the preference to explore an unfamiliar mouse versus a familiar one) was also observed. Our results indicate that these animals could provide a valuable model to identify the specific gene(s) that confer abnormal social behaviors and that map within this delimited genomic deletion interval. In a first attempt to identify candidate genes and for elucidating the mechanisms of regulation of these important phenotypes, we directly assessed the relative transcription of genes within and around this genomic interval. In this mouse model, we found that candidates genes include not only most of the duplicated genes, but also normal-copy genes that flank the engineered interval; both categories of genes showed altered expression levels in the hippocampus of Dp(11)17/+ mice.

Refractory depression in a patient with peripheral resistance to thyroid hormone (RTH) and the effect of triiodothyronine treatment.

We here described a 39-year-old woman with a severe chronic mood disorder, refractory to antidepressive therapy who showed a significant improvement after a self-prescription of high doses of liothyronine (T(3)). A modified Refetoff protocol was carried out to study the role of thyroid hormones on her clinical and biochemical responses. Depression severity was assessed by the HAM-D and MADRS Depression Rating Scales. Sequencing of Thyroid Receptors (TR) alpha1 and beta1 genes was done. At the final stage of the study, plasma T3 and free T3 were >800 ng/dl (80-180) and 1409 pg/dl (230-420), respectively. No changes in the cardiovascular parameters, alkaline phosphatase isoenzymes, creatinine kinase, or ferritin were observed. However, an improvement in mood was detected by specific scores (HAM-D 24 to 8; MADRS 40 to 11). No mutations in DNA- and hormone-binding-domains of TRbeta1 and TRalpha1 genes were found in proband, suggesting that the defect could be due to an unknown mutation in either the TR gene or a post receptor abnormality. These results support the existence of a peripheral RTH manifestation as a refractory chronic depression reverted by high doses of T(3). Screening for RTH in refractory chronic depression may provide an alternative treatment for this psychiatric condition.

A polymorphic GT short tandem repeat affecting beta-ENaC mRNA expression is associated with low renin essential hypertension.

BACKGROUND: The epithelial sodium channel (ENaC) is a candidate gene associated with the development of essential hypertension. A potentially polymorphic repetitive region (GT dinucleotide short tandem repeat [STR]) was identified in intron 8 of beta-ENaC gene (SCNN1B). The aim of this study was to identify the prevalence and distribution of a polymorphic GT-STR in SCNN1B in Chilean essential hypertensive (EH) patients and to analyze the correlation between the different genotypes with plasma renin activity (PRA) and serum aldosterone (SA), and furthermore, to evaluate the beta-ENaC gene expression in vitro. METHODS: We studied 133 patients with EH and 69 normotensive (NT). In both EH and NT subjects we measured PRA, SA, urine sodium, and genotyped them according to the GT-STR length using sequencing analysis. We detected 11, 13 and 14 GT alleles in EH and NT subjects. Both groups were classified according to genotype: 14/14, 14/13, 13/13, 13/11, and 11/11. Influence of the GT-STR on beta-ENaC minigene expression was evaluated by real-time polymerase chain reaction. RESULTS: In EH, PRA decreased with the length of the STR region 11/13, 1.40 +/- 0.69; 13/13, 1.16 +/- 0.61; 13/14, 0.90 +/- 0.56; 14/14, 0.32 +/- 0.09 ng/mL/h; P < .01. Likewise, PRA in patients with EH with 14/14 or 14/13 genotypes were lower than EH with 13/13 or 13/11 genotypes (0.77 +/- 0.5 v 1.24 +/- 0.6 ng/mL/h; P < .01). Real-time polymerase chain reaction demonstrated an increased beta-ENaC expression in minigenes containing 14 GT-STR. CONCLUSIONS: We have identified a polymorphic GT-STR in the beta-ENaC gene, which is present in the EH and NT Chilean population. Biochemical analysis showed a possible linkage between this polymorphic region and low renin hypertension. The in vitro assay suggests that GT-STR could regulate the beta-ENaC expression.