A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion

作者：Guoliang Chai, E. Szenker-Ravi, Changuk Chung, Zhen Li, Lu Wang, Muznah Khatoo, T. Marshall, N. Jiang, Xiaoxu Yang, Jennifer McEvoy-Venneri, Valentina Stanley, Paula Anzenberg, Nhi Lang, V. Wazny, Jia Yu, D. Virshup, R. Nygaard, F. Mancia, R. Merdzanic, M. Toralles, P. Pitanga, R. Puri, R. Hernan, Wendy K. Chung, A. Bertoli-Avella, N. Al-Sannaa, M. Zaki, K. Willert, B. Reversade, J. Gleeson · 发表于：New England Journal of Medicine · 年份：2021 · DOI：10.1056/nejmoa2033911 · 被引用次数：33 · 研究领域：Medicine

BACKGROUND Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant “knocked in,” to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. K...