TY - JOUR
T1 - Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan
AU - Marchese, Maria
AU - Pappalardo, Andrea
AU - Baldacci, Jacopo
AU - Verri, Tiziano
AU - Doccini, S.
AU - Cassandrini, Denise Alessandra
AU - Bruno, Claudio
AU - Fiorillo, Chiara
AU - Garcia-Gil, Mercedes
AU - Bertini, Enrico Silvio
AU - Pitto, Letizia
AU - Santorelli, Filippo Maria
PY - 2016/8/12
Y1 - 2016/8/12
N2 - Defective dolichol-phosphate mannose synthase (DPMS) complex is a rare cause of congenital muscular dystrophy associated with hypoglycosylation of alpha-dystroglycan (α-DG) in skeletal muscle. We used the zebrafish (Danio rerio) to model muscle abnormalities due to defects in the subunits of DPMS. The three zebrafish ortholog subunits (encoded by the dpm1, dpm2 and dpm3 genes, respectively) showed high similarity to the human proteins, and their expression displayed localization in the midbrain/hindbrain area and somites. Antisense morpholino oligonucleotides targeting each subunit were used to transiently deplete the dpm genes. The resulting morphant embryos showed early death, muscle disorganization, low DPMS complex activity, and increased levels of apoptotic nuclei, together with hypoglycosylated α-DG in muscle fibers, thus recapitulating most of the characteristics seen in patients with mutations in DPMS. Our results in zebrafish suggest that DPMS plays a role in stabilizing muscle structures and in apoptotic cell death.
AB - Defective dolichol-phosphate mannose synthase (DPMS) complex is a rare cause of congenital muscular dystrophy associated with hypoglycosylation of alpha-dystroglycan (α-DG) in skeletal muscle. We used the zebrafish (Danio rerio) to model muscle abnormalities due to defects in the subunits of DPMS. The three zebrafish ortholog subunits (encoded by the dpm1, dpm2 and dpm3 genes, respectively) showed high similarity to the human proteins, and their expression displayed localization in the midbrain/hindbrain area and somites. Antisense morpholino oligonucleotides targeting each subunit were used to transiently deplete the dpm genes. The resulting morphant embryos showed early death, muscle disorganization, low DPMS complex activity, and increased levels of apoptotic nuclei, together with hypoglycosylated α-DG in muscle fibers, thus recapitulating most of the characteristics seen in patients with mutations in DPMS. Our results in zebrafish suggest that DPMS plays a role in stabilizing muscle structures and in apoptotic cell death.
KW - Congenital muscular dystrophy
KW - Glycosylation
KW - Mannosylation
KW - Zebrafish
KW - α-dystroglycan
UR - http://www.scopus.com/inward/record.url?scp=84976877542&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84976877542&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2016.06.033
DO - 10.1016/j.bbrc.2016.06.033
M3 - Article
VL - 477
SP - 137
EP - 143
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -