Reduced amounts of cartilage collagen fibrils and growth plate anomalies in transgenic mice harboring a glycine-to-cysteine mutation in the mouse type II procollagen alpha 1-chain gene.
We have generated transgenic mice harboring a glycine-to-cysteine mutation in residue 85 of the triple helical domain of mouse type II collagen. The offspring of different founders displayed a phenotype of severe chondrodysplasia characterized by short limbs and trunk, cranio-facial deformities, and cleft palate. The affected pups died of acute respiratory distress caused by an inability to inflate lungs at birth. Staining of the skeleton showed a severe retardation of growth for practically all bones. Light microscopic examination indicated a decrease in cartilage matrix density, a severe disorganization of growth plate architecture, and the presence of streaks of fibrillar material in the cartilage matrix. Electron microscopic analysis showed a pronounced decrease in the number of typical thin cartilage collagen fibrils, distension of the rough endoplasmic reticulum of chondrocytes, and the presence of abnormally large banded collagen fibril bundles. The level of expression of the mutant type II procollagen alpha 1 chain transgene in cartilage tissues was approximately equal to that of the endogenous gene in two of the strains. We propose that the principal consequence of the mutation is a considerable reduction in density of the typical thin cartilage collagen fibrils and that this phenomenon causes the severe disorganization of the growth plate. We also postulate that the abnormal thick collagen fibrils are probably related to a defect in crosslinking between the collagen molecules. The cartilage anomalies displayed by these transgenic mice are remarkably similar to those of certain human chondrodysplasias.
Garofalo
S
S
Department of Molecular Genetics, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Vuorio
E
E
Metsaranta
M
M
Rosati
R
R
Toman
D
D
Vaughan
J
J
Lozano
G
G
Mayne
R
R
Ellard
J
J
Horton
W
W
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002356:Cartilage / Q000648:ultrastructure*; D003094:Collagen / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D005121:Extremities / Q000196:embryology; D015870:Gene Expression; D006130:Growth Disorders / Q000235:genetics*; D006132:Growth Plate / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D015183:Restriction Mapping; D013329:Structure-Activity Relationship
D009841:Oligonucleotides; D012333:RNA, Messenger; D003094:Collagen; D004247:DNA