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Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.
Farris, Joseph; Calhoun, Barbara; Alam, Md Suhail; Lee, Shaun; Haldar, Kasturi.
Afiliación
  • Farris J; Boler-Parseghian Center for Rare and Neglected Disease, University of Notre Dame, Notre Dame, Indiana, United States of America.
  • Calhoun B; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United State of America.
  • Alam MS; Boler-Parseghian Center for Rare and Neglected Disease, University of Notre Dame, Notre Dame, Indiana, United States of America.
  • Lee S; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, United State of America.
  • Haldar K; Boler-Parseghian Center for Rare and Neglected Disease, University of Notre Dame, Notre Dame, Indiana, United States of America.
PLoS Comput Biol ; 16(5): e1007871, 2020 05.
Article en En | MEDLINE | ID: mdl-32421718
Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Fenotipo / Regulación Enzimológica de la Expresión Génica / Mutación Missense / Hiperglicinemia no Cetósica / Glicina-Deshidrogenasa (Descarboxilante) / Genotipo Límite: Humans Idioma: En Revista: PLoS Comput Biol Asunto de la revista: BIOLOGIA / INFORMATICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Fenotipo / Regulación Enzimológica de la Expresión Génica / Mutación Missense / Hiperglicinemia no Cetósica / Glicina-Deshidrogenasa (Descarboxilante) / Genotipo Límite: Humans Idioma: En Revista: PLoS Comput Biol Asunto de la revista: BIOLOGIA / INFORMATICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos