Enigmatic missense mutations can cause disease via creation of de novo nuclear export signals.

Disease-causing missense mutations that occur within structurally and functionally unannotated protein regions can guide researchers to new mechanisms of protein regulation and dysfunction. Here, we report that the thrombocytopenia-, myelodysplastic syndromes-, and leukemia-associated P214L mutation in the transcriptional regulator ETV6 creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity. Mechanistic insight inspired the design of a 'humanized' ETV6 mice, which we employ to demonstrate that the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance. Beyond ETV6, we employed computational methods to uncover rare disease-associated missense mutations in unrelated proteins that create a nuclear export signal to disrupt protein function. Thus, missense mutations that operate through this mechanism should be predictable and may suggest rational therapeutic strategies for associated diseases.

Racial/ethnic variations in alcohol and cigarette use by pregnancy status among 20- to 44-year-old women, NHANES 2001-2018.

OBJECTIVES: This study examines alcohol consumption and smoking behaviors by pregnancy status and race/ethnicity in order to inform improved interventions designed to assist women of all races to avoid alcohol and tobacco use during pregnancy for their health and to prevent potential fetal exposure. METHODS: This retrospective secondary data analysis utilized nationally representative National Health and Nutrition Examination Survey data between 2001 and 2018. Smoking and alcohol use were evaluated by race/ethnicity and pregnancy risk. Sexual behavior, reproductive health, and prescription drug use determined pregnancy risk, categorized as low pregnancy risk, at risk of becoming pregnant, and pregnant. Binary and multinomial multivariable logistic regression were used to examine associations. RESULTS: The final sample consisted of 10,019 women of which 11.8% were Mexican American, 7.7% other Hispanic, 65.5% white, and 15% black (weighted percentages). White low pregnancy risk and pregnancy risk smoked most frequently in respective pregnancy risk groups (p < 0.001). Among pregnant women, smoking prevalence was highest among black women (14.0%, p < 0.01). Pregnancy risk women were more likely to smoke and pregnant women were less likely to smoke compared with low pregnancy risk. Low pregnancy risk and pregnancy risk Hispanics had a lower prevalence of binge drinking, but prevalence decreased less among pregnant Hispanics than other racial/ethnic groups. In adjusted analyses, pregnancy risk black women had more than 2 times the odds of combined smoking and alcohol consumption compared with low pregnancy risk black women. CONCLUSION: Women who may become pregnant need interventions and improved policy to prevent alcohol use and smoking. Culturally appropriate alcohol and smoking cessation interventions before pregnancy and improved contraception access are needed.