Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization

被引:53
作者
Fujita, Y
Nakata, K
Yasui, N
Matsui, Y
Kataoka, E
Hiroshima, K
Shiba, R
Ochi, T
机构
[1] Osaka Univ, Sch Med, Dept Orthoped Surg, Suita, Osaka 5650871, Japan
[2] Osaka Med Ctr Maternal & Child Hlth, Dept Orthoped Surg, Osaka 5941101, Japan
[3] Osaka Natl Hosp, Dept Orthoped Surg, Osaka 5400006, Japan
[4] Hyogo Nojigiku Med Ctr Disabled Children, Dept Orthoped Surg, Kobe, Hyogo 6512215, Japan
关键词
D O I
10.1210/jc.85.1.425
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acroosteolysis, bone fragility, and skull deformities. Recently, mutations in the gene encoding cathepsin K (CK), a lysosomal cysteine protease localized exclusively in osteoclasts, were found to be responsible for this disease. We analyzed genomic DNA from four unrelated Japanese patients with this disorder and identified three different mutations of their CK genes: a previously reported missense mutation (A277 V), a novel single base deletion mutation (531 del T) causing a frame shift from codon 142 that results in a premature termination codon, and a novel missense mutation (L9P) in the signal peptide region. To investigate whether the L9P mutation disrupts signal peptide function and decreases protein synthesis, mutant and wild-type CK complementary DNAs driven by the cytomegalovirus promoter were transfected into COS-7 cells, and their gene products were detected by immunohistochemistry and Western blotting. Expression of the mutant protein was markedly reduced, suggesting decreased mature CK production in this patient, which may have been due to dysfunction of the signal peptide. These results provide evidence that a structural change in the signal peptide of the CX protein was involved in the pathogenesis of pycnodysostosis.
引用
收藏
页码:425 / 431
页数:7
相关论文
共 29 条
[1]  
ANDREN L., 1962, ACTA CHIR SCAND, V124, P496
[2]   MUTATION OF THE SIGNAL PEPTIDE-ENCODING REGION OF THE PREPROPARATHYROID HORMONE GENE IN FAMILIAL ISOLATED HYPOPARATHYROIDISM [J].
ARNOLD, A ;
HORST, SA ;
GARDELLA, TJ ;
BABA, H ;
LEVINE, MA ;
KRONENBERG, HM .
JOURNAL OF CLINICAL INVESTIGATION, 1990, 86 (04) :1084-1087
[3]   Proteolytic activity of human osteoclast cathepsin K - Expression, purification, activation, and substrate identification [J].
Bossard, MJ ;
Tomaszek, TA ;
Thompson, SK ;
Amegadzie, BY ;
Hanning, CR ;
Jones, C ;
Kurdyla, JT ;
McNulty, DE ;
Drake, FH ;
Gowen, M ;
Levy, MA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) :12517-12524
[4]   HUMAN CATHEPSIN O2, A NOVEL CYSTEINE PROTEASE HIGHLY EXPRESSED IN OSTEOCLASTOMAS AND OVARY MOLECULAR-CLONING, SEQUENCING AND TISSUE DISTRIBUTION [J].
BROMME, D ;
OKAMOTO, K .
BIOLOGICAL CHEMISTRY HOPPE-SEYLER, 1995, 376 (06) :379-384
[5]   Fucosidosis: Genetic and biochemical analysis of eight cases [J].
Cragg, H ;
Williamson, M ;
Young, E ;
OBrien, J ;
Alhadeff, J ;
FangKircher, S ;
Paschke, E ;
Winchester, B .
JOURNAL OF MEDICAL GENETICS, 1997, 34 (02) :105-110
[6]   Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts [J].
Drake, FH ;
Dodds, RA ;
James, IE ;
Connor, JR ;
Debouck, C ;
Richardson, S ;
LeeRykaczewski, E ;
Coleman, L ;
Rieman, D ;
Barthlow, R ;
Hastings, G ;
Gowen, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) :12511-12516
[7]  
EDELSON JG, 1992, CLIN ORTHOP RELAT R, P263
[8]   MUTATIONAL ALTERATIONS AFFECTING THE EXPORT COMPETENCE OF A TRUNCATED BUT FULLY FUNCTIONAL MALTOSE-BINDING PROTEIN SIGNAL PEPTIDE [J].
FIKES, JD ;
BANKAITIS, VA ;
RYAN, JP ;
BASSFORD, PJ .
JOURNAL OF BACTERIOLOGY, 1987, 169 (06) :2345-2351
[9]   Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis [J].
Gelb, BD ;
Willner, JP ;
Dunn, TM ;
Kardon, NB ;
Verloes, A ;
Poncin, J ;
Desnick, RJ .
AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (04) :848-854
[10]   LINKAGE OF PYCNODYSOSTOSIS TO CHROMOSOME 1Q21 BY HOMOZYGOSITY MAPPING [J].
GELB, BD ;
EDELSON, JG ;
DESNICK, RJ .
NATURE GENETICS, 1995, 10 (02) :235-237