Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1–3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6–8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS) and 16 amniotic cell (AC) samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG) content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy.

ABSTR AC TIntroduction There is sufficient evidence showing the positive effects of physical exercise on various aspects of pregnancy. This study evaluates knowledge and status of physical exercise among pregnant women. MethodsThe standardised paper-pencil questionnaire "Pregnancy Physical Activity Questionnaire" (PPAQ) as well as general demographic questions were used to assess the exercise behaviour of study participants. 83 questionnaires completed by women presenting to the Kiel University Hospital for antenatal assessment were included in the analysis.Results At the time of questionnaire completion 10 women were in the first trimester of pregnancy, 64 in the second, and 9 in the third. Just less than 90 % of participants felt they had been informed "sufficiently" on the topic physical exercise during pregnancy, over 50 % felt they were "well" or "very well" informed. Just less than half of participants received their information from a doctor (either their gynaecologist or general practitioner) and none of these felt "insufficiently" informed. Almost 80 % of participants reported still doing no sport or less exercise than before falling pregnant. The maximum proportional energy expenditure for recreational activity -just under 20 % -was in the third trimester. Women who felt they had been well counselled tended to have higher activity levels.Conclusion Study participants demonstrated a clear decline in physical exercise during pregnancy despite clear evidence of the benefits of regular exercise for pregnant women, and despite participants feeling they were well informed. Detailed information on the recommendations for physical exertion in pregnancy should form an integral part of antenatal counselling. ZUSAMMENFASSUNGEinleitung Die positiven Effekte einer körperlichen Aktivität

BackgroundMaternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) concentrations are compromised in intrauterine growth restriction (IUGR). Generally, LDL-C catabolism is under control of PCSK9 by binding to the LDL-receptor leading to its degradation. Hence, we hypothesized a role for PCSK9 in the modulation of lipid metabolism and placental transport in IUGR.Methods172 women, 70 IUGR and 102 controls were included in the study. Maternal and fetal serum PCSK9 levels and lipid profiles including LDL-C were measured. Placental LDL-receptor and PCSK9 expressions were estimated by tissue microarray immunohistochemistry, and analyzed by two blinded observers using an immunoreactivity score. Non-parametric tests and multivariate regression analyses were used for statistical estimations.ResultsPCSK9 levels in the maternal and fetal compartment independently predicted LDL-C levels (maternal compartment: adjusted R 2 = 0.2526; coefficient b i = 0.0938, standard error sbi =0.0217, rpartial = 0.4420, t-value = 4.323, p < 0.0001; fetal compartment: adjusted R 2 = 0.2929; b i = 0.1156, sbi =0.020, rpartial = 0.5494, t-value = 5.81, p < 0.0001). We did not find significant differences in maternal PCSK9 concentrations between IUGR and controls. However, we found lower fetal serum PCSK9 concentrations in IUGR than in controls (IUGR median 137.1 ng/mL (95% CI 94.8-160.0) vs. controls 176.8 (154.6-202.5), p = 0.0005). When subgrouping according to early onset, late onset IUGR, and fetal gender differences remained consistent only for male neonates born before 34 weeks of gestation. In the placenta we found no correlation between PCSK9 and LDL-receptor expression patterns. However, the LDL-receptor was significantly upregulated in IUGR when compared to controls (p = 0.0063).ConclusionsOur results suggest that PCSK9 play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender. This underlines the need to identify subgroups of IUGR that may benefit from individualized and gender-specific pharmacotherapy in future studies.