title: Selenoprotein N deficiency in mice is associated with abnormal lung development.
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.
authors: Division of Genetics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Behzad
authors: B
authors: Moghadaszadeh
authors: Branden E
authors: BE
authors: Rider
authors: Michael W
authors: MW
authors: Lawlor
authors: Martin K
authors: MK
authors: Childers
authors: Robert W
authors: RW
authors: Grange
authors: Kushagra
authors: K
authors: Gupta
authors: Steve S
authors: SS
authors: Boukedes
authors: Caroline A
authors: CA
authors: Owen
authors: Alan H
authors: AH
authors: Beggs
mesh_terms: D000818:Animals; D006801:Humans; D008168:Lung / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D017279:Selenocysteine / Q000235:genetics; D051140:Selenoproteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D051140:Selenoproteins; D017279:Selenocysteine