TY - JOUR
T1 - An empirical pipeline for personalized diagnosis of Lafora disease mutations
AU - Brewer, M. Kathryn
AU - Machio-Castello, Maria
AU - Viana, Rosa
AU - Wayne, Jeremiah L.
AU - Kuchtová, Andrea
AU - Simmons, Zoe R.
AU - Sternbach, Sarah
AU - Li, Sheng
AU - García-Gimeno, Maria Adelaida
AU - Serratosa, Jose M.
AU - Sanz, Pascual
AU - Vander Kooi, Craig W.
AU - Gentry, Matthew S.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/11/19
Y1 - 2021/11/19
N2 - 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.
AB - 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.
KW - Biochemistry
KW - Biophysics
KW - Disease
KW - Structural biology
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U2 - 10.1016/j.isci.2021.103276
DO - 10.1016/j.isci.2021.103276
M3 - Article
AN - SCOPUS:85123022671
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 11
M1 - 103276
ER -