Rare Genetic Diseases: Nature's Experiments on Human Development

• Type of Material: Article
• Authors: Chelsea E. Lee, Emory University; Kaela S. Singleton, Emory University; Melissa Wallin, Emory University; Victor Faundez, Emory University
• Language: English
• Date: 2020-05-22
• Publisher: Cell Press
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.isci.2020.101123
• Title of Journal or Parent Work: iScience
• Volume: 23
• Issue: 5
• Start Page: 101123
• End Page: 101123
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health 1RF1AG060285, the Rett Syndrome Research Trust, and the Loulou Foundation to V.F.
• Keywords: Biological networks; Mutations; Copper; Science & Technology; Model; Menkes-disease; Occipital hprn syndrom; Science & Technology - Other Topics; Candidate gene; Cell division; Transport; Multidisciplinary Sciences; Mechanisms
• Research Categories: Biology, Genetics; Biology, Cell; Health Sciences, Pathology

Abstract

Rare genetic diseases are the result of a continuous forward genetic screen that nature is conducting on humans. Here, we present epistemological and systems biology arguments highlighting the importance of studying these rare genetic diseases. We contend that the expanding catalog of mutations in ∼4,000 genes, which cause ∼6,500 diseases and their annotated phenotypes, offer a wide landscape for discovering fundamental mechanisms required for human development and involved in common diseases. Rare afflictions disproportionately affect the nervous system in children, but paradoxically, the majority of these disease-causing genes are evolutionarily ancient and ubiquitously expressed in human tissues. We propose that the biased prevalence of childhood rare diseases affecting nervous tissue results from the topological complexity of the protein interaction networks formed by ubiquitous and ancient proteins encoded by childhood disease genes. Finally, we illustrate these principles discussing Menkes disease, an example of the discovery power afforded by rare diseases.