Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

Abstract

Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.

Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

“…As whole-exome (WES) and whole-genome sequencing (WGS) become part of the general medical practice in the era of personalized medicine (Posey et al, 2019), the number of variants of unknown significance (VUS) in NOTCH and related genes will likely increase at a rapid pace. Understanding the precise mechanism of how each mutation affects protein function is critical since different therapeutic strategies may need to be used based on the specific type of variant an individual carries (Bellen, Wangler, & Yamamoto, 2019;Harnish, Deal, Chao, Wangler, & Yamamoto, 2019;Wangler et al, 2017).…”

A genetic screen for genes that impact peroxisomes in Drosophila identifies candidate genes for human disease

“…Rbcn-3B, which produced a Category A phenotype, encodes a protein involved in Notch signaling during oogenesis through its role in endocytic trafficking and lysosomal function (YAN et al 2009). Coq8, which produced a Category A phenotype, encodes a mitochondrial inner membrane protein that is predicted to be involved in electron transport (ZHU et al 2017) In contrast, many of the genes we identified, including Usp16-45 which is predicted to encode an ubiquitin specific protease, have not been extensively characterized in vivo and it is likely that these proteins also have additional functions as most genes are pleiotropic (WANGLER et al 2017b). These results indicate that screening for the GFP-SKL peroxisomal marker is an effective method to identify new genes that can impact peroxisome dynamics or morphology.…”

Large-scale transgenicDrosophilaresource collections for loss- and gain-of-function studies

“…Notable areas in which Drosophila models are having an impact include a wide variety of neurological diseases [reviews include (Okray and Hassan 2013;Coll-Tane et al 2019)]; cancer (Sonoshita and Cagan 2017); metabolic disease and diabetes (Park et al 2014); responses to infection by human pathogens (Apidianakis and Rahme 2011); immune disorders (Bergman et al 2017); heart disease (Viswanathan et al 2014); and inherited disorders (Wangler et al 2017;Mishra-Gorur et al 2019). Drosophila is also increasingly being used to help identify causative variants associated with previously undiagnosed genetic disorders (Wangler et al 2017;Splinter et al 2018). Despite the impressive set of tools currently available for Drosophila genetic studies, locating and/or generating disease models in Drosophila can be time consuming, and at the start of our project, wellcharacterized loss-of-function alleles or validated RNAi and/or sgRNA strains were not available.…”