👤 Christina D Fenger

The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown. We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology. We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory. Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies. Show less

Signalling by Wnt proteins (Wingless in Drosophila) has diverse roles during embryonic development and in adults, and is implicated in human diseases, including cancer. LDL-receptor-related proteins 5 and 6 (LRP5 and LRP6; Arrow in Drosophila) are key receptors required for transmission of Wnt/beta-catenin signalling in metazoa. Although the role of these receptors in Wnt signalling is well established, their coupling with the cytoplasmic signalling apparatus remains poorly defined. Using a protein modification screen for regulators of LRP6, we describe the identification of Xenopus Casein kinase 1 gamma (CK1gamma), a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning to promote posteriorizing Wnt/beta-catenin signalling. CK1gamma is associated with LRP6, which has multiple, modular CK1 phosphorylation sites. Wnt treatment induces the rapid CK1gamma-mediated phosphorylation of these sites within LRP6, which, in turn, promotes the recruitment of the scaffold protein Axin. Our results reveal an evolutionarily conserved mechanism that couples Wnt receptor activation to the cytoplasmic signal transduction apparatus. Show less