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Background: Lung disease phenotype varies widely even in the F508del (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function in F508del homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between GJA1/GJA4 genotypes and the clinical disease phenotype. Methods: One-hundred-and-sixteen homozygous F508del patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for GJA1 and GJA4. The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers. Results: Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this GJA4 variant (rs41266431), homozygous G variant carriers (n = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, p < 0.040) and survival to end-stage lung disease was lower (p < 0.029). The frequency of P. aeruginosa colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, p < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, p < 0.052) and sputum leukocytes (2305/437.5 pg/ml, p < 0.025) were higher for the G/G genotype. Conclusions: In carriers of the A allele (27.6%) the GJA4 variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in F508del homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the CFTR genotype.
Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25–38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
Aims: We have provided evidence in former studies that cytokines (IL-8, TNF alpha, LBP, TGFß) measured in blood correlate negatively with lung function in deltaF508 homozygous patients. GAP junction proteins might be of importance for the influx of blood cells into the lung. Our aim was to assess the relationship between connexin genotypes and cytokines (IL-8, TNF-alpha, LBP, TGFß) in induced sputum and serum, and lung disease.
Methods: 36 patients homozygous for deltaF508 (median age 18 y, m/f 16/20, FEV1(%) 77) were examined. Sequence analysis was performed for genes encoding GAP junction protein alpha 1 (GJA1/connexin 43) and gap junction protein alpha 4 (GJA4/connexin 37). Cytokines were assessed in serum and induced sputum (IS) by chemiluminescence (DPC Biermann, Bad Homburg, Germany) as well as leukocyte counts.
Results: DNA analysis was performed in 35 patients. Whereas GJA1 showed only one rare heterozygous synonymous SNP (rs138386744) in one patient, four common SNPs were detected in GJA4. Two were synonymous changes, but the third variant (rs41266431) predicts an amino acid substitution (GTA → valine, ATA → isoleucine) as well as the fourth SNP (rs1764391: CCC→proline, TCC→serine). For rs41266431 patients with homozygosity for the G variant had higher IL-8 levels (median: 13.3/8.0 pg/ml, p=0.07) in serum as well as leukocytes in sputum (median: 2050/421 /µl p=0.041) than those showing heterozygosity (G/A). In individuals > 30 years lung function (FEV1 41.3/84.83 % predicted, p=0.07) was worse.
Conclusion: SNP rs41266431 seems a promising candidate for further investigations, suggesting GJA4 a potential disease modifying gene.
Vacuolar proton-translocating ATPase (holoATPase and free membrane sector) was isolated from bovine chromaffin granules by blue native polyacrylamide gel electrophoresis. A 5-fold excess of membrane sector over holoenzyme was determined in isolated chromaffin granule membranes. M9.2, a novel extremely hydrophobic 9.2-kDa protein comprising 80 amino acids, was detected in the membrane sector. It shows sequence and structural similarity to Vma21p, a yeast protein required for assembly of vacuolar ATPase. A second membrane sector-associated protein (M8-9) was identified and characterized by amino-terminal protein sequencing.
Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.