Dissecting NGLY1 deficiency
Collaborators: Carolyn Bertozzi & Lars Steinmetz
NGLY1 Deficiency & The Grace Science Foundation
Over 8,000 rare diseases are estimated to affect more than 350 million people worldwide, and treatment strategies are often not available. In 2014, Grace Wilsey was diagnosed with N-Glycanase-1 (NGLY1) deficiency, which is a rare disease which is diagnosed in less than 50 other cases. Her parents, Matt and Kristen Wilsey, dedicated their lives to establishing the Grace Science Foundation: a worldwide team of researchers who are committed to finding a cure for NGLY1 deficiency and pioneering methods for identifying, treating and ultimately curing other rare diseases in the process.
Rare disease biology - dissecting NGLY1 deficiency
NGLY1 deficiency is a rare condition caused by loss of function mutations in the NGLY1 gene. Consequently, protein deglycosylation and degradation are impaired, leading to an accumulation of debris within cells. Symptoms of NGLY1 deficiency include impaired motor control, global developmental delay, seizures, and a lack of tear production called alacrima.
Led by the Grace Science Foundation, a consortium of researchers from academia and industry is searching for new therapeutic approaches to effectively manage and treat NGLY1 deficiency. Within this consortium, Dr. Carolyn Bertozzi and Dr. Lars M. Steinmetz are studying the impact of NGLY1 deficiency on the integrity of the proteasome. They have shown that functional NGLY1 is required for processing the transcription factor NFE2L1, and they hope to translate this finding into clinical applications in the future.
Mueller WF, Jakob P, Sun H, Clauder-Münster S, Ghidelli-Disse S, Ordonez D, Boesche M, Bantscheff M, Collier P, Haase B, Benes V, Paulsen M, Sehr P, Lewis J, Drewes G, Steinmetz LM. Loss of N-glycanase 1 alters transcriptional and translational regulation in K562 cell lines. G3: Genes Genomes Genetics; (2020).
Fujihira H, Masahara-Negishi Y, Akimoto Y, Hirayama H, Lee HC, Story BA, Mueller WF, Jakob P, Clauder-Münster S, Steinmetz LM, Radhakrishnan SK, Kawakami H, Kamada Y, Miyoshi E, Yokomizo T, Suzuki T. Liver-specific deletion of Ngly1 causes abnormal nuclear morphology and lipid metabolism under food stress. Biochim Biophys Acta, Mol Basis Dis. (2019).
Tomlin FM, Gerling-Driessen U, Liu YC, Flynn RA, Vangala JR, Lentz CS, Clauder-Münster S, Jakob P, Mueller WF, Ordoñez-Rueda D, Paulsen M, Matsui N, Foley D, Rafalko A, Suzuki T, Bogyo M, Steinmetz LM, Radhakrishnan SK, Bertozzi CR. Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity. ACS Central Sci. (2017).
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Are you interested in finding out more about the NGLY1 deficiency project? Would you like to help us study and find a cure for rare diseases? Get in touch! We would love to hear from you.
June 14, 2018
Biobank, foundation team up to accelerate research into a rare disease
October 4, 2017