RT Journal Article
SR Electronic
T1 A ubiquitin-based mechanism for the oligogenic inheritance of heterotaxy and heart defects
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.25.113944
DO 10.1101/2020.05.25.113944
A1 Jennifer H. Kong
A1 Cullen B. Young
A1 Ganesh V. Pusapati
A1 Chandni B. Patel
A1 Sebastian Ho
A1 Arunkumar Krishnan
A1 Jiuann-Huey Ivy Lin
A1 William Devine
A1 Anne Moreau de Bellaing
A1 Tejas S. Athni
A1 L. Aravind
A1 Teresa M. Gunn
A1 Cecilia W. Lo
A1 Rajat Rohatgi
YR 2020
UL http://biorxiv.org/content/early/2020/05/26/2020.05.25.113944.abstract
AB The etiology of congenital heart defects (CHDs), amongst the most common human birth defects, is poorly understood partly because of its complex genetic architecture. Here we show that two genes previously implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a single-pass transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a transmembrane ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions between components of a receptor-like ubiquitin ligase complex that tunes morphogen signaling strength can cause a birth defect syndrome inherited in an oligogenic pattern.Competing Interest StatementThe authors have declared no competing interest.