Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan.
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.
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.
Maria
M
Marchese
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.
Andrea
A
Pappalardo
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.
Jacopo
J
Baldacci
Department of Biological and Environmental Sciences and Technologies, University of Salento, S.P. 6 Lecce-Monteroni, 73100, Lecce, Italy.
Tiziano
T
Verri
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.
Stefano
S
Doccini
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.
Denise
D
Cassandrini
Center of Myology and Neurodegenerative Disorders, Department of Neuroscience, Istituto G. Gaslini, Largo Gaslini 5, 16147, Genoa, Italy.
Claudio
C
Bruno
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy.
Chiara
C
Fiorillo
Department of Biology, University of Pisa, Via Luca Ghini 13, 56126, Pisa, Italy.
Mercedes
M
Garcia-Gil
IRCCS Bambino Gesù Hospital, Viale S. Paolo 15, 00146, Rome, Italy.
Enrico
E
Bertini
IFC-CNR, Via Moruzzi 1, 56124, Pisa, Italy.
Letizia
L
Pitto
Molecular Medicine, IRCCS Stella Maris, Via dei Giacinti 2, 56128, Pisa, Italy. Electronic address: filippo3364@gmail.com.
Filippo M
FM
Santorelli
D000818:Animals; D049030:Dystroglycans / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D008297:Male; D008364:Mannosyltransferases / Q000145:classification / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009136:Muscular Dystrophies / Q000473:pathology*; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics; D015027:Zebrafish / Q000378:metabolism*
D012333:RNA, Messenger; D049030:Dystroglycans; D008364:Mannosyltransferases; C022755:dolichyl-phosphate beta-D-mannosyltransferase
Congenital muscular dystrophy; Glycosylation; Mannosylation; Zebrafish; α-dystroglycan