Faculty Collaboration Database

Selenoprotein N deficiency in mice is associated with abnormal lung development. FASEB J 2013 Apr;27(4):1585-99

Date

01/18/2013

Pubmed ID

23325319

Pubmed Central ID

PMC3606527

DOI

10.1096/fj.12-212688

Scopus ID

2-s2.0-84875702360 (requires institutional sign-in at Scopus site)   35 Citations

Abstract

Mutations in the human SEPN1 gene, encoding selenoprotein N (SepN), cause SEPN1-related myopathy (SEPN1-RM) characterized by muscle weakness, spinal rigidity, and respiratory insufficiency. As with other members of the selenoprotein family, selenoprotein N incorporates selenium in the form of selenocysteine (Sec). Most selenoproteins that have been functionally characterized are involved in oxidation-reduction (redox) reactions, with the Sec residue located at their catalytic site. To model SEPN1-RM, we generated a Sepn1-knockout (Sepn1(-/-)) mouse line. Homozygous Sepn1(-/-) mice are fertile, and their weight and lifespan are comparable to wild-type (WT) animals. Under baseline conditions, the muscle histology of Sepn1(-/-) mice remains normal, but subtle core lesions could be detected in skeletal muscle after inducing oxidative stress. Ryanodine receptor (RyR) calcium release channels showed lower sensitivity to caffeine in SepN deficient myofibers, suggesting a possible role of SepN in RyR regulation. SepN deficiency also leads to abnormal lung development characterized by enlarged alveoli, which is associated with decreased tissue elastance and increased quasi-static compliance of Sepn1(-/-) lungs. This finding raises the possibility that the respiratory syndrome observed in patients with SEPN1 mutations may have a primary pulmonary component in addition to the weakness of respiratory muscles.

Author List

Moghadaszadeh B, Rider BE, Lawlor MW, Childers MK, Grange RW, Gupta K, Boukedes SS, Owen CA, Beggs AH

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
Humans
Lung
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Proteins
Muscle, Skeletal
Muscular Diseases
Mutation
Oxidative Stress
Ryanodine Receptor Calcium Release Channel
Selenocysteine
Selenoproteins