4-Phenylbutyrate restores localization and membrane repair to human dysferlin mutations
Kana Tominaga,
Naoomi Tominaga,
Eric O. Williams,
Laura Rufibach,
Verena Schöwel,
Simone Spuler,
Mohan Viswanathan,
Leonard P. Guarente
Affiliations
Kana Tominaga
Paul F. Glenn Center for Biology of Aging, Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyoku, Tokyo 113-8421, Japan
Naoomi Tominaga
Paul F. Glenn Center for Biology of Aging, Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Eric O. Williams
Paul F. Glenn Center for Biology of Aging, Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Fitchburg State University, School of Heath and Natural Sciences, Antonucci Science Complex 235, Fitchburg, MA 01420, USA
Laura Rufibach
Jain Foundation, 9706 4th Avenue NE, Suite 101, Seattle, WA 98115, USA
Verena Schöwel
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a joint cooperation of Charité Universitätsmedizin Berlin and Max-Delbrück Center for Molecular Medicine, Berlin, Germany
Simone Spuler
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), a joint cooperation of Charité Universitätsmedizin Berlin and Max-Delbrück Center for Molecular Medicine, Berlin, Germany
Mohan Viswanathan
Paul F. Glenn Center for Biology of Aging, Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Corresponding author
Leonard P. Guarente
Paul F. Glenn Center for Biology of Aging, Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Corresponding author
Summary: Dysferlinopathies are muscular dystrophies caused by recessive loss-of-function mutations in dysferlin (DYSF), a membrane protein involved in skeletal muscle membrane repair. We describe a cell-based assay in which human DYSF proteins bearing missense mutations are quantitatively assayed for membrane localization by flow cytometry and identified 64 localization-defective DYSF mutations. Using this platform, we show that the clinically approved drug 4-phenylbutryric acid (4-PBA) partially restores membrane localization to 25 mutations, as well as membrane repair to cultured myotubes expressing 2 different mutations. Two-day oral administration of 4-PBA to mice homozygous for one of these mutations restored myofiber membrane repair. 4-PBA may hold therapeutic potential for treating a subset of humans with muscular dystrophy due to dysferlin deficiency.
