Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone

Yuval Yogev, Zamir Shorer, Arie Koifman, Ohad Wormser, Max Drabkin, Daniel Halperin, Vadim Dolgin, Regina Proskorovski-Ohayon, Noam Hadar, Geula Davidov, Hila Nudelman, Raz Zarivach, Ilan Shelef, Yonatan Perez, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review


Myopathy is the main adverse effect of the widely prescribed statin drug class. Statins exert their beneficial effect by inhibiting HMG CoA-reductase, the rate-controlling enzyme of the mevalonate pathway. The mechanism of statin myopathy is yet to be resolved, and its treatment is insufficient. Through homozygosity mapping and whole exome sequencing, followed by functional analysis using confocal microscopy and biochemical and biophysical methods, we demonstrate that a distinct form of human limb girdle muscular disease is caused by a pathogenic homozygous loss-of-function missense mutation in HMG CoA reductase (HMGCR), encoding HMG CoA-reductase. We biochemically synthesized and purified mevalonolactone, never administered to human patients before, and establish the safety of its oral administration in mice. We then show that its oral administration is effective in treating a human patient with no significant adverse effects. Furthermore, we demonstrate that oral mevalonolactone resolved statin-induced myopathy in mice. We conclude that HMGCR mutation causes a late-onset severe progressive muscular disease, which shows similar features to statin-induced myopathy. Our findings indicate that mevalonolactone is effective both in the treatment of hereditary HMGCR myopathy and in a murine model of statin myopathy. Further large clinical trials are in place to enable the clinical use of mevalonolactone both in the rare orphan disease and in the more common statin myopathy.

Original languageAmerican English
Article numbere2217831120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
StatePublished - 6 Feb 2023


  • limb girdle muscular dystrophy
  • mutation
  • statins

All Science Journal Classification (ASJC) codes

  • General


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