Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Increased High Mobility Group Protein A2/SMAD3 Relates to Ovarian Cancer Progression

Introduction: The high mortality associated with ovarian cancer is generally related to the development of drug-resistant disease. HMGA2 protein, a member of the high-mobility group AT-hook (HMGA) family of non-histone chromatin binding factors, is overexpressed in high-grade serous ovarian and tubal carcinomas, though little is known about its contribution to disease progression and drug resistance. We sought to assess whether compositional changes in HMGA2 production were associated with ovarian cancer progression. Methods: We performed computational characterization of HMGA2 protein disorder, aggregation propensity and interactability. Cultures of established human ovarian cancer cell lines and immortalized ovarian surface epithelial cells were subjected to MTS growth assays, western immunoblotting and immunoprecipitation analyses for HMGA2, SMAD3 and SNAIL1 expression. Lastly, urine samples from healthy controls, women with benign gynecologic disease and women with ovarian cancer were analyzed by western immunoblotting for HMGA2 and SMAD3 levels. Results: HMGA2 is a highly disordered protein with the potential to bind multiple protein partners, including SMAD3. Characteristics of HMGA2 binding partners suggested possible recruitment of HMGA2 for extracellular transport. We verified overexpression and secretion of HMGA2 and SMAD3 in cultures of ovarian cancer cells, especially with emergence of drug resistance. In agreement with computational analyses, we demonstrated that HMGA2 and SMAD3 protein can associate into a larger protein complex in ovarian cancer cells. Lastly, elevated levels of HMGA2 and SMAD3 were found in urine samples from ovarian cancer patients. Conclusion: Our data suggest that the presence of and/or changes in the levels of a unique HMGA2/SMAD3 protein complex might serve as a useful biomarker and/or therapeutic target for ovarian cancer