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Published in: Calcified Tissue International 5/2015

01-05-2015 | Original Research

A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin

Authors: Xianglan Huang, Xuan Qi, Mei Li, Ou Wang, Yan Jiang, Xiaoping Xing, Ying Ying Hu, Weibo Xia

Published in: Calcified Tissue International | Issue 5/2015

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Abstract

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acro-osteolysis, frequent fractures, and skull deformities. Mutation in the gene encoding cathepsin K (CTSK), which is a lysosomal cysteine protease, has been found to be responsible for this disease. Here we reported a consanguineous Chinese family with 1 affected individual demonstrating autosomal recessive pycnodysostosis with recurrent kidney stone, a new clinical manifestation which has not been reported in patients of pycnodysostosis before. To identify the pathogenic mutation, we evaluated the patient clinically, biochemically, and radiographically. To screen for mutations in the CTSK gene of the patient and his family members, all of its exons and exon–intron junctions were PCR amplified from genomic DNA and sequenced. Sequence analysis of the patient’s CTSK gene revealed homozygosity for a missense mutation (c.746T>C) in exon 6, which leads to amino change (p.Ile249Thr) in the mature CTSK protein. This mutation was firstly reported by Michela Donnarumma and his colleagues in 2007 in a Spanish family. Our study strengthens the role of this particular mutation in the pathogenesis of pycnodysostosis.
Literature
1.
go back to reference Maroteaux P, Lamy M (1962) La pycnodysostose. Presse Med 70:999–1002PubMed Maroteaux P, Lamy M (1962) La pycnodysostose. Presse Med 70:999–1002PubMed
3.
go back to reference Soliman AT, Ramadan MA, Sherif A, Aziz BE, Rizk MM (2001) Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. Metabolism 50:905–911CrossRefPubMed Soliman AT, Ramadan MA, Sherif A, Aziz BE, Rizk MM (2001) Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. Metabolism 50:905–911CrossRefPubMed
4.
go back to reference Varol A, Sabuncuoglu FA, Sencimen M, Akcam T, Olmez H, Basa S (2011) Rigid external maxillary distraction and rhinoplasty for pyknodysostosis. J Craniofac Surg 22:901–904CrossRefPubMed Varol A, Sabuncuoglu FA, Sencimen M, Akcam T, Olmez H, Basa S (2011) Rigid external maxillary distraction and rhinoplasty for pyknodysostosis. J Craniofac Surg 22:901–904CrossRefPubMed
5.
go back to reference Della MG, Scarano E, Leoni C, Dittoni S, Losurdo A, Testani E, Colicchio S, Gnoni V, Vollono C, Zampino G (2012) Pycnodysostosis with extreme sleep apnea: a possible alternative to tracheotomy. Sleep Breath 16:5–10CrossRef Della MG, Scarano E, Leoni C, Dittoni S, Losurdo A, Testani E, Colicchio S, Gnoni V, Vollono C, Zampino G (2012) Pycnodysostosis with extreme sleep apnea: a possible alternative to tracheotomy. Sleep Breath 16:5–10CrossRef
6.
go back to reference Hernandez-Alfaro F, Arenaz BJ, Serra SM, Mareque BJ (2011) Orthognathic surgery in pycnodysostosis: a case report. Int J Oral Maxillofac Surg 40:110–113CrossRefPubMed Hernandez-Alfaro F, Arenaz BJ, Serra SM, Mareque BJ (2011) Orthognathic surgery in pycnodysostosis: a case report. Int J Oral Maxillofac Surg 40:110–113CrossRefPubMed
8.
go back to reference Gelb BD, Edelson JG, Desnick RJ (1995) Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat Genet 10:235–237CrossRefPubMed Gelb BD, Edelson JG, Desnick RJ (1995) Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat Genet 10:235–237CrossRefPubMed
9.
go back to reference Polymeropoulos MH, Ortiz DLR, Ide SE, Torres R, Rubenstein J, Francomano CA (1995) The gene for pycnodysostosis maps to human chromosome 1cen-q21. Nat Genet 10:238–239CrossRefPubMed Polymeropoulos MH, Ortiz DLR, Ide SE, Torres R, Rubenstein J, Francomano CA (1995) The gene for pycnodysostosis maps to human chromosome 1cen-q21. Nat Genet 10:238–239CrossRefPubMed
10.
go back to reference Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238CrossRefPubMed Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238CrossRefPubMed
11.
go back to reference Donnarumma M, Regis S, Tappino B, Rosano C, Assereto S, Corsolini F, Di Rocco M, Filocamo M (2007) Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Hum Mutat 28:524CrossRefPubMed Donnarumma M, Regis S, Tappino B, Rosano C, Assereto S, Corsolini F, Di Rocco M, Filocamo M (2007) Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Hum Mutat 28:524CrossRefPubMed
12.
go back to reference Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T (1995) Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun 206:89–96CrossRefPubMed Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T (1995) Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun 206:89–96CrossRefPubMed
13.
go back to reference Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 95:13453–13458CrossRefPubMedCentralPubMed Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 95:13453–13458CrossRefPubMedCentralPubMed
14.
go back to reference Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663CrossRefPubMed Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663CrossRefPubMed
15.
go back to reference Li CY, Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, Schaffler MB (2006) Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 21:865–875CrossRefPubMed Li CY, Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, Schaffler MB (2006) Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 21:865–875CrossRefPubMed
16.
go back to reference Uusitalo H, Hiltunen A, Soderstrom M, Aro HT, Vuorio E (2000) Expression of cathepsins B, H, K, L, and S and matrix metalloproteinases 9 and 13 during chondrocyte hypertrophy and endochondral ossification in mouse fracture callus. Calcif Tissue Int 67:382–390CrossRefPubMed Uusitalo H, Hiltunen A, Soderstrom M, Aro HT, Vuorio E (2000) Expression of cathepsins B, H, K, L, and S and matrix metalloproteinases 9 and 13 during chondrocyte hypertrophy and endochondral ossification in mouse fracture callus. Calcif Tissue Int 67:382–390CrossRefPubMed
17.
go back to reference Lazner F, Gowen M, Kola I (1999) An animal model for pycnodysostosis: the role of cathepsin K in bone remodelling. Mol Med Today 5:413–414CrossRefPubMed Lazner F, Gowen M, Kola I (1999) An animal model for pycnodysostosis: the role of cathepsin K in bone remodelling. Mol Med Today 5:413–414CrossRefPubMed
18.
go back to reference Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663CrossRefPubMed Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663CrossRefPubMed
19.
go back to reference Kiviranta R, Morko J, Alatalo SL, NicAmhlaoibh R, Risteli J, Laitala-Leinonen T, Vuorio E (2005) Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio. Bone 36:159–172CrossRefPubMed Kiviranta R, Morko J, Alatalo SL, NicAmhlaoibh R, Risteli J, Laitala-Leinonen T, Vuorio E (2005) Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio. Bone 36:159–172CrossRefPubMed
20.
go back to reference Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A 95:13453–13458CrossRefPubMedCentralPubMed Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A 95:13453–13458CrossRefPubMedCentralPubMed
21.
go back to reference Li HY, Ma HW, Wang HQ, Ma WH (2009) Molecular analysis of a novel cathepsin K gene mutation in a Chinese child with pycnodysostosis. J Int Med Res 37:264–269CrossRefPubMed Li HY, Ma HW, Wang HQ, Ma WH (2009) Molecular analysis of a novel cathepsin K gene mutation in a Chinese child with pycnodysostosis. J Int Med Res 37:264–269CrossRefPubMed
22.
go back to reference Zheng H, Zhang Z, He JW, Fu WZ, Zhang ZL (2013) A novel mutation (R122Q) in the cathepsin K gene in a Chinese child with Pyknodysostosis. Gene 521:176–179CrossRefPubMed Zheng H, Zhang Z, He JW, Fu WZ, Zhang ZL (2013) A novel mutation (R122Q) in the cathepsin K gene in a Chinese child with Pyknodysostosis. Gene 521:176–179CrossRefPubMed
Metadata
Title
A Mutation in CTSK Gene in an Autosomal Recessive Pycnodysostosis Family of Chinese Origin
Authors
Xianglan Huang
Xuan Qi
Mei Li
Ou Wang
Yan Jiang
Xiaoping Xing
Ying Ying Hu
Weibo Xia
Publication date
01-05-2015
Publisher
Springer US
Published in
Calcified Tissue International / Issue 5/2015
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-015-9963-y

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