An empirical pipeline for personalized diagnosis of Lafora disease mutations

M. Kathryn Brewer, Maria Machio-Castello, Rosa Viana, Jeremiah L. Wayne, Andrea Kuchtová, Zoe R. Simmons, Sarah Sternbach, Sheng Li, Maria Adelaida García-Gimeno, Jose M. Serratosa, Pascual Sanz, Craig W. Vander Kooi, Matthew S. Gentry

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identified EPM2A mutations, providing clinicians and researchers genetic information to guide treatment of LD patients.

Original languageEnglish
Article number103276
JournaliScience
Volume24
Issue number11
DOIs
StatePublished - Nov 19 2021

Bibliographical note

Funding Information:
The authors thank Nancy R. Gough (BioSerendipity, LLC) for editing support as well as members of the Gentry and Vander Kooi labs for vigorous discussions regarding the data. This work was supported by the National Institutes of Health (P01 NS097197 to M.S.G. J.M.S. and P.S. R35 NS116824 to M.S.G. and F31 NS093892 to M.K.B), National Science Foundation (DBI2018007 and MCB1817414 to M.S.G.), and Epilepsy Foundation New Therapy Commercialization Grant to M.S.G. M.K.B. received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (No. 754510M). This project also received funding from the Spanish Ministry of Science and Innovation (SAF2017-83151-R to P.S. and RTI2018-095784b-100SAF to J.M.S). M.S.G. and C.W.V.K. conceived the study. M.M.C. and J.S. collected and analyzed clinical data. M.K.B. and J.W. generated mutants. M.K.B. M.S.G. C.W.V.K. Z.S. S.S. and J.W. purified proteins, performed assays, and analyzed data. R.V. M.A.G.G. and P.S. performed Y2H experiments. S.L. performed HDX experiments and analyzed data. M.K.B. C.W.V.K. and M.S.G. analyzed data and wrote the paper. M.S.G. is a consultant for Maze Therapeutics, Enable Therapeutics, Glut1 Deficiency Syndrome Foundation, and Chelsea's Hope. M.S.G. and C.V.K. are founders of Atterogen, LLC.

Funding Information:
The authors thank Nancy R. Gough (BioSerendipity, LLC) for editing support as well as members of the Gentry and Vander Kooi labs for vigorous discussions regarding the data. This work was supported by the National Institutes of Health ( P01 NS097197 to M.S.G., J.M.S. and P.S., R35 NS116824 to M.S.G., and F31 NS093892 to M.K.B), National Science Foundation ( DBI2018007 and MCB1817414 to M.S.G.), and Epilepsy Foundation New Therapy Commercialization Grant to M.S.G. M.K.B. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (No. 754510M ). This project also received funding from the Spanish Ministry of Science and Innovation ( SAF2017-83151-R to P.S. and RTI2018-095784b-100SAF to J.M.S).

Publisher Copyright:
© 2021 The Authors

Keywords

  • Biochemistry
  • Biophysics
  • Disease
  • Structural biology

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'An empirical pipeline for personalized diagnosis of Lafora disease mutations'. Together they form a unique fingerprint.

Cite this