An amino acid substitution (Gly853-->Glu) in the collagen alpha 1(II) chain produces hypochondrogenesis

The spondyloepiphyseal dysplasia subclassification of bone dysplasias includes achondrogenesis, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita. The phenotypic expression of these disorders ranges from mild to perinatal lethal forms. We report the detection and partial characterizatio...

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Bibliographic Details
Published in:The Journal of biological chemistry 1992-11, Vol.267 (31), p.22522-22526
Main Authors: Bogaert, R, Tiller, G E, Weis, M A, Gruber, H E, Rimoin, D L, Cohn, D H, Eyre, D R
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Base Sequence
Bone Diseases, Developmental - genetics
Cartilage - abnormalities
Collagen - genetics
Glutamates - chemistry
Glycine - chemistry
Humans
Molecular Sequence Data
Oligodeoxyribonucleotides - chemistry
Peptide Fragments - analysis
Point Mutation
Structure-Activity Relationship
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Summary:The spondyloepiphyseal dysplasia subclassification of bone dysplasias includes achondrogenesis, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita. The phenotypic expression of these disorders ranges from mild to perinatal lethal forms. We report the detection and partial characterization of a defect in type II collagen in a perinatal lethal form of hypochondrogenesis. Electrophoresis in sodium dodecyl sulfate-polyacrylamide of CB peptides (where CB represents cyanogen bromide) from type II collagen of the diseased cartilage showed a doublet band for peptide alpha 1(II)CB10 and evidence for post-translational overmodification of the major peptides (CB8, CB10, and CB11) seen as a retarded electrophoretic mobility. Peptide CB10 was digested by endoproteinase Asp-N; and on reverse-phase high pressure liquid chromatography, fragments of abnormal mobility were noted. Sequence analysis of a unique peptide D12 revealed a single amino acid substitution (Gly-->Glu) at position 853 of the triple helical domain. This was confirmed by sequence analysis of amplified COL2A1 cDNA, which revealed a single nucleotide substitution (GGA-->GAA) in 5 of 10 clones. Electron micrographs of the diseased cartilage showed a sparse extracellular matrix and chondrocytes containing dilated rough endoplasmic reticulum, which suggested impaired assembly and secretion of the mutant protein. This case further documents the molecular basis of the spondyloepiphyseal dysplasia spectrum of chondrodysplasias as mutations in COL2A1.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)41703-6