Abstract
Calcification of joints and arteries (CALJA; MIM 211800) is an extremely rare mendelian disorder of isolated calcification that is characterized by late onset calcification of the extremity arteries and hand and foot joint capsules. Mutations of NT5E, encoding cluster of differentiation 73, have been implicated in CALJA. Here we report on a Chinese family with CALJA and novel compound heterozygous mutations (c.1360G>A (p.Gly454Arg) and c.1387C>T (p.Arg463X)) in NT5E. Our study represents the second report on patients with CALJA associated with NT5E mutations. The clinical features expand the previously reported phenotype of NT5E mutations. The propositus has calcification of the lower extremity arteries and hand and foot joint capsules similar to those previously reported patients. However, he also has calcification of the upper extremity arteries. By protein structural modeling, we found the mutation p.Gly454Arg may disrupt the folding of β-pleated sheet and destabilize the protein structure. Our findings will provide clues to the phenotype–genotype relations and may assist not only in the clinical diagnosis but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
McCarthy, E. F. & Sundaram, M. Heterotopic ossification: a review. Skeletal Radiol. 34, 609–619 (2005).
Shore, E. M. & Kaplan, F. S. Inherited human diseases of heterotopic bone formation. Nat. Rev. Rheumatol. 6, 518–527 (2010).
St Hilaire, C., Ziegler, S. G., Markello, T. C., Brusco, A., Groden, C., Gill, F. et al. NT5E mutations and arterial calcifications. N. Engl. J. Med. 364, 432–442 (2011).
Lorenz-Depiereux, B., Schnabel, D., Tiosano, D., Hausler, G. & Strom, T. M. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am. J. Hum. Genet. 86, 267–272 (2010).
Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., du Moulin, M., Stella, J. et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am. J. Hum. Genet. 90, 25–39 (2012).
Sharp, J. Heredo-familial vascular and articular calcification. Ann. Rheum. Dis. 13, 15–27 (1954).
Mori, H., Yamaguchi, K., Fukushima, H., Oribe, Y., Kato, N., Wakamatsu, T. et al. Extensive arterial calcification of unknown etiology in a 29-year-old male. Heart Vessels 7, 211–214 (1992).
Hessle, L., Johnson, K. A., Anderson, H. C., Narisawa, S., Sali, A., Goding, J. W. et al. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc. Natl Acad. Sci. USA 99, 9445–9449 (2002).
Colgan, S. P., Eltzschig, H. K., Eckle, T. & Thompson, L. F. Physiological roles for ecto-5'-nucleotidase (CD73). Purinergic Signal. 2, 351–360 (2006).
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).
Choi, Y., Sims, G. E., Murphy, S., Miller, J. R. & Chan, A. P. Predicting the functional effect of amino acid substitutions and indels. PLoS One 7, e46688 (2012).
Arnold, K., Bordoli, L., Kopp, J. & Schwede, T. The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22, 195–201 (2006).
Schwede, T., Kopp, J., Guex, N. & Peitsch, M. C. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res. 31, 3381–3385 (2003).
Demer, L. L. & Tintut, Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation 117, 2938–2948 (2008).
Sage, A. P., Tintut, Y. & Demer, L. L. Regulatory mechanisms in vascular calcification. Nat. Rev. Cardiol. 7, 528–536 (2010).
Gan, X. T., Taniai, S., Zhao, G., Huang, C. X., Velenosi, T. J., Xue, J. et al. CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to alpha1 adrenoceptor activation. Mol. Cell. Biochem. 394, 237–246 (2014).
Fausther, M., Lavoie, E. G., Goree, J. R., Baldini, G. & Dranoff, J. A. NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein. PLoS One 9, e98568 (2014).
Tsukamoto, H., Chernogorova, P., Ayata, K., Gerlach, U. V., Rughani, A., Ritchey, J. W. et al. Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease. Blood 119, 4554–4564 (2012).
Acknowledgements
The study was supported by the National ‘973’ Program of China (2014CB942903), the National Natural Science Foundation of China (81401764 and 81370978), Academic Leaders in Health Sciences in Shanghai (XBR2011014), Science and Technology Commission of Shanghai Municipality (14JC1405000) and Chongqing Research Program of Basic Research and Frontier Technology (CSCT2013jcyjC00009).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Zhang, Z., He, JW., Fu, WZ. et al. Calcification of joints and arteries: second report with novel NT5E mutations and expansion of the phenotype. J Hum Genet 60, 561–564 (2015). https://doi.org/10.1038/jhg.2015.85
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2015.85
This article is cited by
-
Computational prognostic evaluation of Alzheimer’s drugs from FDA-approved database through structural conformational dynamics and drug repositioning approaches
Scientific Reports (2023)
-
Calcification of Joints and Arteries (CALJA) Is a Rare Cause of Arthritis and Lower Limb Ischemia: Case Report and Literature Review
SN Comprehensive Clinical Medicine (2023)
-
Effect of two non-synonymous ecto-5′-nucleotidase variants on the genetic architecture of inosine 5′-monophosphate (IMP) and its degradation products in Japanese Black beef
BMC Genomics (2017)
-
Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts
Current Osteoporosis Reports (2017)
