Low renal mineralocorticoid receptor expression at birth contributes to partial aldosterone resistance in neonates.: MR and renal maturation.

International audienceThe human neonatal period is characterized by renal immaturity with impaired capacity to regulate water and sodium homeostasis, resembling partial aldosterone resistance. Because aldosterone effects are mediated by the mineralocorticoid receptor (MR), we postulated that this hormonal unresponsiveness could be related to low MR expression in the distal nephron. We measured aldosterone and renin levels in umbilical cord blood of healthy newborns. We used quantitative real-time PCR and immunohistochemistry to analyze the expression of MR and key players of the mineralocorticoid signaling pathway during human and mouse renal development. High aldosterone and renin levels were found at birth. MR mRNA was detected in mouse kidney at d 16 postcoitum, peaking at d 18 postcoitum, but its expression was surprisingly very low at birth, rising progressively afterward. Similar biphasic temporal expression was observed during human renal embryogenesis, with a transient expression between 15 and 24 wk of gestation but an undetectable immunoreactive MR in late gestational and neonatal kidneys. This cyclic MR expression was tightly correlated with the evolution of the 11beta-hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel alpha-subunit. In contrast, glucocorticoid and vasopressin receptors and aquaporin 2 followed a progressive and sustained evolution during renal maturation. Our study provides the first evidence for a low renal MR expression level at birth, despite high aldosterone levels, which could account for compromised postnatal sodium handling. Elucidation of regulatory mechanisms governing MR expression should lead to new strategies for the management of sodium waste in preterms and neonates

Bilateral periventricular heterotopias in an X-linked dominant transmission in a family with two affected males

International audienceWe report on the case of dizygotic twin boys, born prematurely to an asymptomatic mother. Bilateral periventricular heterotopias with enlarged ventricles were discovered at birth in both twins. One of the twins died prematurely of bronchopulmonary complications, and was shown to have several neuropathological anomalies (microgyria, thin corpus callosum, and reduced white matter). The surviving twin had mental retardation, without epilepsy. MRI of the mother showed asymptomatic periventricular heterotopias without ventricular enlargement. She had two affected daughters also with asymptomatic periventricular heterotopias. A point mutation in the last coding exon 48 of the Filamin A (FLNA) gene (7922c > t) was discovered on sequencing and segregated with the affected individuals. This family has a classical X-linked dominant BPNH pathology, with greater severity in males than females. The location of the FLNA mutation is discussed in light of the neuropathological anomalies and mental retardation in male patients

Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1–MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM–resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS

New insights into genotype-phenotype correlation for GLI3 mutations

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