JAM2: A New Culprit at the Pathophysiology of Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is an uncommon degenerative neurological disease that can be hereditary or sporadic, and manifests equally in both sexes and at any age. Several studies initially identified variants in four different genes as the cause of the disorder, all with an autosomal dominant inheritance pattern: SLC20A2, PDGFRB, PDGFB and XPR1. However, there have been reports of the involvement of additional genes in the autosomal recessive inheritance pattern, such as MYORG and more recently JAM2, suggesting that the deregulation of the neurovascular unit (NVU) is important in the pathogenesis of PFBC. The recent study by Schottlaender and collaborators (2020) has added new data to foster these analyses and to enable a better understanding of this underdiagnosed and intriguing neuropsychiatric condition. A great challenge now is to design a model that explains how different pathways might lead to similar neuroimaging findings but with variable clinical outcome, and with marked severity in cases linked to MYORG and JAM2. Currently available databases of detailed gene expression in different vascular cell types from the mouse brain could be used to explore a possible integrative model.

Overlapping Diseases in a Brazilian Subject with Brain Calcification Linked to Novel Phenotypes.

Primary familial brain calcification (PFBC) is a well-known genetic condition that has recently had a surge of autosomal recessive cases. We recently reported a case of autosomal recessive PFBC on a 54-year-old Brazilian patient with a novel homozygous variant on MYORG. Interestingly, that patient also had a series of uncommon signs and symptoms, including Hashimoto's thyroiditis, polyneuropathy, optic nerve head drusen (ONHD), and persistent anemia. We chose to perform whole exome sequencing (WES) to possibly detect other unknown genetic conditions that could explain the extra-neurological findings reported. WES confirmed the presence of the MYORG variant previously reported by us, and determined the presence of a heterozygous nonsense variant on HBB (c.118C > T, p.Q40*), defining a diagnosis of beta-thalassemia. Based on literature review, the new WES finding explains the persistent anemia and polyneuropathy shown by the patient, while still leaving the ONHD and autoimmune thyroiditis without a clear genetic link. This way, we propose that these novel clinical findings could be linked to MYORG, but still encourage further studies to evaluate this possibility.

DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation.

Mutations in KDM5C (lysine (K)-specific demethylase 5C) were causally associated with up to 3% of X-linked intellectual disability (ID) in males. By exome and Sanger sequencing, a novel frameshift KDM5C variant, predicted to eliminate the JmjC catalytic domain from the protein, was identified in two monozygotic twins and their older brother, which was inherited from their clinically normal mother, who had completely skewed X-inactivation. DNA methylation (DNAm) data were evaluated using the Illumina 450 K Methylation Beadchip arrays. Comparison of methylation levels between the three patients and male controls identified 399 differentially methylated CpG sites, which were enriched among those CpG sites modulated during brain development. Most of them were hypomethylated (72%), and located mainly in shores, whereas the hypermethylated CpGs were more represented in open sea regions. The DNAm changes did not differ between the monozygotic twins nor between them and their older sibling, all presenting a global hypomethylation, similar to other studies that associated DNA methylation changes to different KDM5C mutations. The 38 differentially methylated regions (DMRs) were enriched for H3K4me3 marks identified in developing brains. The remarkable similarity between the methylation changes in the monozygotic twins and their older brother is indicative that these epigenetic changes were mostly driven by the KDM5C mutation.

Neonatal administration of fluoxetine decreased final Sertoli cell number in Wistar rats / Administración neonatal de fluoxetina disminuye el número final de células de Sertoli en ratas Wistar

The aim of the present study was to test the hypothesis that the application of fluoxetine a highly selective serotonin reuptake inhibitor (SSRI) ¡ in rats during the suckling period induces changes in testicular development. Groups of newborn male rats were randomly assigned with different doses of fluoxetine 24 hours after birth. Each litter stayed with its respective mother during 21 days. Body weight (BW) was measured daily from the 1st -21st day to calculate daily doses of fluoxetine. 5 mg (T1), 10 mg (T2) 20 mg (T3) or deionized water, were injected intraperitoneally. On the 21st day, animals were heparinized, anesthetized and blood was collected by cardiac puncture to determine by radioimmunoassay the follicle stimulating hormone (FSH) levels. Testis were removed, weighed, and processed for morphometric analysis. Fluoxetine groups presented decreased body and testicular weight when compared with the control group on the 21st day. Our findings show that the manipulation of the serotoninergic system with fluoxetine during the critical period of testicular development alters the Sertoli cell population and all testicular parameters related to this cell.

El propósito del presente estudio fue probar la hipótesis que el uso de fluoxetina - un inhibidor altamente selectivo de la serotonina (SSRI) - induce cambios en el desarrollo testicular de ratas durante el período de amamantamiento. Los grupos de ratas macho recién nacidas fueron asignados aleatoriamente con diversas dosis del fluoxetina, 24 horas después del nacimiento. Cada cría permanecía con su madre respectiva durante 21 días. El peso corporal (BW) fue medido diariamente desde el 21día 1 al 21, para calcular las dosis diarias del fluoxetina. 5 mg (T1), 10 mg (T2) y 20 (T3) o agua desionizada fueron inyectados intraperitonealmente. En el día 21, los animales fueron tratados con heparina, anestesiados y la sangre fue recogida por punción cardiaca para determinar por radioinmunoanálisis los niveles de la hormona folículo-estimulante (FSH). Los testículos fueron retirados, pesados y procesados para el análisis morfométrico. Los grupos tratados con fluoxetina presentaron disminución del tamaño y peso testiculares, en comparación con el grupo control día 21. Los resultados demuestran que la manipulación del sistema serotoninérgico con fluoxetina durante el período crítico del desarrollo testicular, altera la población de células de Sertoli y todos los parámetros testiculares relacionados con este tipo celular.