Deficient expression of decorin in infantile progeroid patients.
Fibroblasts from young patients exhibiting clinical features of progeroidal syndromes showed decreased biosynthesis of the small proteoglycan decorin. Cells in culture were metabolically labeled, and proteoglycans secreted into the medium were analyzed electrophoretically after immunoprecipitation with antibodies raised against decorin and biglycan. Fluorograms showed regularly a reduction to 15-30% of the normal amount of mature decorin and its core protein after chondroitin ABC lyase treatment. The size of the glycosaminoglycan chains was increased, but there was no obvious anomaly in the secretion kinetics of the mature proteoglycan. In addition, the patients' fibroblasts synthesized an increased amount of biglycan compared to control cells from healthy donors. Northern blot analysis clearly demonstrated a reduction by 85-94% in decorin mRNA, but biglycan mRNA was concomitantly increased, indicating that these alterations occur at the transcriptional level of protein expression. Transcription of decorin in fibroblasts from one of the patients was stimulated up to 3-fold by treatment with interleukin-1 beta. No response to interleukin-1 beta and transforming growth factor-beta was observed in the cells from another patient. In situ hybridization of cultured cells with an antisense decorin probe showed that decorin levels were reduced throughout the cell population. Surprisingly, subsequent examination of cells from one of the patients, now in mid-teenage, revealed a return to normal levels of decorin expression compared to age-matched controls. These studies suggest that, as in Marfan's syndrome where the primary defect concerns the fibrillin gene, reduced decorin expression contributes to the formation of an abnormal matrix and the pathogenesis of these disorders. They also indicate that this abnormality is likely to represent a secondary phenomenon which leads to a fault in the regulation of decorin gene transcription.
Beavan
L A
LA
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Germany.
Quentin-Hoffmann
E
E
Schönherr
E
E
Snigula
F
F
Leroy
J G
JG
Kresse
H
H
D001483:Base Sequence; D058578:Biglycan; D015152:Blotting, Northern; D002478:Cells, Cultured; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D058575:Decorin; D004591:Electrophoresis, Polyacrylamide Gel; D016326:Extracellular Matrix Proteins; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D017403:In Situ Hybridization; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D011371:Progeria / Q000235:genetics* / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C546884:BGN protein, human; D058578:Biglycan; C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D015345:Oligonucleotide Probes; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004247:DNA