Faculty Collaboration Database

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb. Acta Neuropathol Commun 2020 Feb 17;8(1):18

Date

02/19/2020

Pubmed ID

32066503

Pubmed Central ID

PMC7027239

DOI

10.1186/s40478-020-0893-1

Scopus ID

2-s2.0-85079597530 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb^{Y2303H, Y935X}, has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb^Y2303H,Y935X mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.

Author List

Laitila JM, McNamara EL, Wingate CD, Goullee H, Ross JA, Taylor RL, van der Pijl R, Griffiths LM, Harries R, Ravenscroft G, Clayton JS, Sewry C, Lawlor MW, Ottenheijm CAC, Bakker AJ, Ochala J, Laing NG, Wallgren-Pettersson C, Pelin K, Nowak KJ

Author

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Codon, Nonsense
Disease Models, Animal
Female
Male
Mice, Inbred C57BL
Muscle Proteins
Muscle, Skeletal
Mutation, Missense
Myopathies, Nemaline