Journal article

Cullin-3 dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy

Jordan Blondelle, Kavya Tallapaka, Jane T Seto, Majid Ghassemian, Madison Clark, Jenni M Laitila, Adam Bournazos, Jeffrey D Singer, Stephan Lange

JCI INSIGHT | AMER SOC CLINICAL INVESTIGATION INC | Published : 2019

Abstract

Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness, fiber atrophy and presence of nemaline bodies within myofibers. However, the understanding of underlying pathomechanisms is lacking. Recently, mutations in KBTBD13, KLHL40 and KLHL41, three substrate adaptors for the E3-ubiquitin ligase Cullin-3, have been associated with early-onset nemaline myopathies. We hypothesized that deregulation of Cullin-3 and its muscle protein substrates may be responsible for the disease development. Using Cullin-3 knockout mice, we identified accumulation of non-muscle alpha-Actinins (ACTN1 and ACTN4) in muscles of these mice, which we also observed in KBTBD13 patients. O..

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Grants

Awarded by Muscular Dystrophy Association


Awarded by NIH R01 grant


Awarded by American Heart Association


Awarded by NIH


Awarded by NIH National Institute of Neurological Disorders and Stroke (NINDS) P30 grant


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Awarded by OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH


Funding Acknowledgements

JB is supported by a Muscular Dystrophy Association grant (MDA 515518) and Philippe Foundation grant. Work in the laboratory of SL is supported by an NIH R01 grant (HL128457). MC was supported by the American Heart Association (17UFEL33520004). The work at the mass spectrometry core at UCSD is supported by NIH grants (S10 OD016234, S10 OD021724). We thank the UCSD Microscopy Core and Jennifer Santini, supported by an NIH National Institute of Neurological Disorders and Stroke (NINDS) P30 grant (NS047101). JL was supported by grants from the Association Francaise contre les Myopathies, Finska Lakaresallskapet, the Medicinska understodsforeningen Liv och Halsa r.f., and the Magnus Ehrnrooth Foundation. We thank Valeria Marroco, Farah Sheik, Yan Liang, Jing Zhang, Maria Manso, Paul Bushway, and William Bradford, as well as Carina Wallgren-Pettersson and Katarina Pelin for insightful discussions. We also thank Sandra Cooper and Kathryn N. North for providing patient samples and controls for this study, as well as Alan Beggs for providing antibodies.