Linker Proteins Restore Basement Membrane and Correct -related Muscular Dystrophy in Mice

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2017 Jun 30

PMID 28659438

Citations 42

Authors

Judith R Reinhard

Shuo Lin

Karen K McKee

Sarina Meinen

Stephanie C Crosson

Maurizio Sury

Samantha Hobbs

Geraldine Maier

Peter D Yurchenco

Markus A Ruegg

Affiliations

Soon will be listed here.

Abstract

-related muscular dystrophy ( MD or MDC1A) is the most frequent form of early-onset, fatal congenital muscular dystrophies. It is caused by mutations in , the gene encoding laminin-α2, the long arm of the heterotrimeric (α2, β1, and γ1) basement membrane protein laminin-211 (Lm-211). We establish that despite compensatory expression of laminin-α4, giving rise to Lm-411 (α4, β1, and γ1), muscle basement membrane is labile in MD biopsies. Consistent with this deficit, recombinant Lm-411 polymerized and bound to cultured myotubes only weakly. Polymerization and cell binding of Lm-411 were enhanced by addition of two specifically designed linker proteins. One, called αLNNd, consists of the N-terminal part of laminin-α1 and the laminin-binding site of nidogen-1. The second, called mini-agrin (mag), contains binding sites for laminins and α-dystroglycan. Transgenic expression of mag and αLNNd in a mouse model for MD fully restored basement membrane stability, recovered muscle force and size, increased overall body weight, and extended life span more than five times to a maximum survival beyond 2 years. These findings provide a mechanistic understanding of MD and establish a strong basis for a potential treatment.

Citing Articles

Gene therapy for genetic diseases: challenges and future directions.

Qie B, Tuo J, Chen F, Ding H, Lyu L MedComm (2020). 2025; 6(2):e70091.

PMID: 39949979 PMC: 11822459. DOI: 10.1002/mco2.70091.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

Enzmann C, Steiner L, Pospieszny K, Zweier C, Plattner K, Baumann D J Neuromuscul Dis. 2024; 11(5):1021-1033.

PMID: 39213089 PMC: 11380305. DOI: 10.3233/JND-240023.

Congenital Muscular Dystrophy Due to Merosin Deficiency: Report of a New Mutation.

Herrera Malpica W, Ortiz-Corredor F, Sanchez Penarete D, Munetones Hernandez P Cureus. 2023; 15(6):e39988.

PMID: 37416022 PMC: 10321457. DOI: 10.7759/cureus.39988.

Nerve pathology is prevented by linker proteins in mouse models for -related muscular dystrophy.

Reinhard J, Porrello E, Lin S, Pelczar P, Previtali S, Ruegg M PNAS Nexus. 2023; 2(4):pgad083.

PMID: 37038437 PMC: 10082391. DOI: 10.1093/pnasnexus/pgad083.

Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy.

Oliveira-Santos A, Dagda M, Wittmann J, Smalley R, Burkin D Dis Model Mech. 2023; 16(6).

PMID: 37021539 PMC: 10184677. DOI: 10.1242/dmm.049916.

References

Briguet A, Courdier-Fruh I, Foster M, Meier T, Magyar J . Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse. Neuromuscul Disord. 2004; 14(10):675-82. DOI: 10.1016/j.nmd.2004.06.008. View

Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Ruegg M . Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice. EMBO Mol Med. 2011; 3(8):465-79. PMC: 3377088. DOI: 10.1002/emmm.201100151. View

Michele D, Barresi R, Kanagawa M, Saito F, Cohn R, Satz J . Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature. 2002; 418(6896):417-22. DOI: 10.1038/nature00837. View

Doe J, Wuebbles R, Allred E, Rooney J, Elorza M, Burkin D . Transgenic overexpression of the α7 integrin reduces muscle pathology and improves viability in the dy(W) mouse model of merosin-deficient congenital muscular dystrophy type 1A. J Cell Sci. 2011; 124(Pt 13):2287-97. PMC: 3113674. DOI: 10.1242/jcs.083311. View

Gawlik K, Durbeej M . Transgenic overexpression of laminin alpha1 chain in laminin alpha2 chain-deficient mice rescues the disease throughout the lifespan. Muscle Nerve. 2010; 42(1):30-7. DOI: 10.1002/mus.21616. View

Yamauchi J, Kumar A, Duarte L, Mehuron T, Girgenrath M . Triggering regeneration and tackling apoptosis: a combinatorial approach to treating congenital muscular dystrophy type 1 A. Hum Mol Genet. 2013; 22(21):4306-17. DOI: 10.1093/hmg/ddt280. View

Brooks S, Faulkner J . Contractile properties of skeletal muscles from young, adult and aged mice. J Physiol. 1988; 404:71-82. PMC: 1190815. DOI: 10.1113/jphysiol.1988.sp017279. View

Turturro A, Duffy P, Hass B, Kodell R, Hart R . Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction. J Gerontol A Biol Sci Med Sci. 2002; 57(11):B379-89. DOI: 10.1093/gerona/57.11.b379. View

Moll J, Barzaghi P, Lin S, Bezakova G, Lochmuller H, Engvall E . An agrin minigene rescues dystrophic symptoms in a mouse model for congenital muscular dystrophy. Nature. 2001; 413(6853):302-7. DOI: 10.1038/35095054. View

10.

Li S, Harrison D, Carbonetto S, Fassler R, Smyth N, Edgar D . Matrix assembly, regulation, and survival functions of laminin and its receptors in embryonic stem cell differentiation. J Cell Biol. 2002; 157(7):1279-90. PMC: 2173546. DOI: 10.1083/jcb.200203073. View

11.

Rooney J, Knapp J, Hodges B, Wuebbles R, Burkin D . Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy. Am J Pathol. 2012; 180(4):1593-602. PMC: 3349899. DOI: 10.1016/j.ajpath.2011.12.019. View

12.

McKee K, Capizzi S, Yurchenco P . Scaffold-forming and Adhesive Contributions of Synthetic Laminin-binding Proteins to Basement Membrane Assembly. J Biol Chem. 2009; 284(13):8984-94. PMC: 2659255. DOI: 10.1074/jbc.M809719200. View

13.

Patton B, Miner J, Chiu A, Sanes J . Distribution and function of laminins in the neuromuscular system of developing, adult, and mutant mice. J Cell Biol. 1998; 139(6):1507-21. PMC: 2132624. DOI: 10.1083/jcb.139.6.1507. View

14.

Patton B, Connoll A, Martin P, Cunningham J, Mehta S, Pestronk A . Distribution of ten laminin chains in dystrophic and regenerating muscles. Neuromuscul Disord. 1999; 9(6-7):423-33. DOI: 10.1016/s0960-8966(99)00033-4. View

15.

Talts J, Sasaki T, Miosge N, Gohring W, Mann K, Mayne R . Structural and functional analysis of the recombinant G domain of the laminin alpha4 chain and its proteolytic processing in tissues. J Biol Chem. 2000; 275(45):35192-9. DOI: 10.1074/jbc.M003261200. View

16.

Denzer A, Brandenberger R, Gesemann M, Chiquet M, Ruegg M . Agrin binds to the nerve-muscle basal lamina via laminin. J Cell Biol. 1997; 137(3):671-83. PMC: 2139873. DOI: 10.1083/jcb.137.3.671. View

17.

Yurchenco P . Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol. 2011; 3(2). PMC: 3039528. DOI: 10.1101/cshperspect.a004911. View

18.

Gesemann M, Cavalli V, Denzer A, Brancaccio A, Schumacher B, Ruegg M . Alternative splicing of agrin alters its binding to heparin, dystroglycan, and the putative agrin receptor. Neuron. 1996; 16(4):755-67. DOI: 10.1016/s0896-6273(00)80096-3. View

19.

Norwood F, Harling C, Chinnery P, Eagle M, Bushby K, Straub V . Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. 2009; 132(Pt 11):3175-86. PMC: 4038491. DOI: 10.1093/brain/awp236. View

20.

Clement E, Feng L, Mein R, Sewry C, Robb S, Manzur A . Relative frequency of congenital muscular dystrophy subtypes: analysis of the UK diagnostic service 2001-2008. Neuromuscul Disord. 2012; 22(6):522-7. DOI: 10.1016/j.nmd.2012.01.010. View