👤 C A Stratakis

This study aimed to investigate the genetic cause of food-dependent Cushing syndrome (FDCS) observed in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) and adrenal ectopic expression of the glucose-dependent insulinotropic polypeptide receptor. Germline ARMC5 alterations have been reported in about 25% of PBMAH index cases but are absent in patients with FDCS. A multiomics analysis of PBMAH tissues from 36 patients treated by adrenalectomy was performed (RNA sequencing, single-nucleotide variant array, methylome, miRNome, exome sequencing). The integrative analysis revealed 3 molecular groups with different clinical features, namely G1, comprising 16 patients with ARMC5 inactivating variants; G2, comprising 6 patients with FDCS with glucose-dependent insulinotropic polypeptide receptor ectopic expression; and G3, comprising 14 patients with a less severe phenotype. Exome sequencing revealed germline truncating variants of KDM1A in 5 G2 patients, constantly associated with a somatic loss of the KDM1A wild-type allele on 1p, leading to a loss of KDM1A expression both at messenger RNA and protein levels (P = 1.2 × 10 KDM1A inactivation explains about 90% of FDCS PBMAH. Genetic screening for ARMC5 and KDM1A can now be offered for most PBMAH operated patients and their families, opening the way to earlier diagnosis and improved management. Show less

Vertical transmission of Zika virus (ZIKV) is associated with congenital malformations but the mechanism of pathogenesis remains unclear. Although host genetics appear to play a role, no genetic association study has yet been performed to evaluate this question. In order to investigate if maternal genetic variation is associated with Congenital Zika Syndrome (CZS), we conducted a case-control study in a cohort of Brazilian women infected with ZIKV during pregnancy. A total of 100 women who reported symptoms of zika during pregnancy were enrolled and tested for ZIKV. Among 52 women positive for ZIKV infection, 28 were classified as cases and 24 as controls based on the presence or absence of CZS in their infants. Variations in the coding region of 205 candidate genes involved in cAMP signaling or immune response were assessed by high throughput sequencing and tested for association with development of CZS. From the 817 single nucleotide variations (SNVs) included in association analyses, 22 SNVs in 17 genes were associated with CZS under an additive model (alpha = 0.05). Variations c.319T>C (rs11676272) and c.1297G>A, located at ADCY3 and ADCY7 genes showed the most prominent effect. The association of ADCY3 and ADCY7 genes was confirmed using a Sequence Kernel Association Test to assess the joint effect of common and rare variations, and results were statistically significant after adjustment for multiple comparisons (P < 0.002). These results suggest that maternal ADCY genes contribute to ZIKV pathogenicity and influence the outcome of CZS, being promising candidates for further replication studies and functional analysis. Show less

GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations. Show less