Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease

Autoři: Joseph Farris aff001;  Md Suhail Alam aff001;  Arpitha Mysore Rajashekara aff001;  Kasturi Haldar aff001
Působiště autorů: Boler-Parseghian Center for Rare and Neglected Disease, University of Notre Dame, Notre Dame, Indiana, United States of America aff001;  Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United State of America aff002
Vyšlo v časopise: Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease. PLoS Genet 17(2): e1009307. doi:10.1371/journal.pgen.1009307
Kategorie: Research Article


Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized.

Klíčová slova:

Hydrocephalus – Animal models of disease – Glycine – Homozygosity – Mouse models – Mutation – Substitution mutation – Formates


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PLOS Genetics

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