Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.     

A copy number variation morbidity map of developmental delay

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ～14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.     

Chronotropic changes due to pericardial distension in isolated frog hearts perfused in situ

Résumé On a démontré que la distension péricardiale produit des changements chronotropiques dans le cur de grenouille isolé en perfusion. Sur 26 curs, l'accélération cardiaque (18 a 148%) se produit dans 12 avec un volume de fluide péricardique atteignant 4 ml. Dans les 14 curs restant nous avons observé une bradycardie, des irrégularities de conduction, un blocage cardiaque et une arythmie. On en conclut que ces effects chronotropiques et les variations du paramètre d'impulsion sont dues aux changements dans l'activité du «pacemaker».     

Protection from body weight loss by 2-mercaptopropionylglycine (MPG) in growing mice irradiated in utero with gamma radiation

Summary 2-Mercaptopropionylglycine administered during fetal growth period, protected significantly young mice against loss of body weight during postnatal development induced by 50 R gamma irradiation.Acknowledgment. The work was supported by a grant from CSIR, New Delhi, to P.K.D. which is gratefully acknowledged. The authors are also thankful to Prof. P. Navlakha for the irradiation facilities.