A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development

Abstract

Somatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.

DACA Recipient Health Care Workers’ Barriers to Professionalization and Deployment of Navigational Capital in Pursuit of Health Equity for Immigrants

“…Large numbers of DACA recipients have also reported losing their jobs or having their work hours or pay reduced due to the pandemic, underscoring broader challenges they face in career attainment. [40] Given uncertainty about DACA, these case studies provide nuanced insight into DACA recipients' very-real concerns about program completion and licensure, interruptions in employment, and concerns about future employment. These barriers are pronounced even with DACA status, and thus illuminate how urgent more permanent immigration reform is to address these political determinants of health [37,38] so that DACA recipients can more effectively perform their brokerage on more secure legal ground.…”