Effects of the CASR rs104893706 (A843E) gain- of-function mutation on bone mineral density in postmenopausal women by advanced age and smoking

Year 2022, Volume: 52 Issue: 2, 129 - 135, 30.08.2022

Özlem Kurnaz Gömleksiz Aysegul Basak Teker Fatih Yanar Ezgi Aslan Özlem Kurt Şirin Mehmet Uyar Ayse Can Hülya Yılmaz Aydoğan

Abstract

Background and Aims: The G protein-coupled calcium-sensing receptor (CaSR) plays an important role in extracellular cal- cium homeostasis and regulation of parathyroid hormone (PTH) secretion. There are more than 300 activating/inactivating mutations in the CASR gene. However, the effects of both CaSR protein and CASR gene on bone mineral density (BMD) have not been investigated enough. The aim of this study was therefore to determine the effect of rs104893706 (A843E, (Ala to Glu at codon843)), a gain-of-function mutation of the CASR gene, on BMD in postmenopausal women.

Methods: We studied the CASR A843E variation using Polymerase Chain Reaction-Restriction Fragment Length Polymor- phism methods in 180 postmenopausal women. Statistical analyses were performed using SPSS software package (version 21.0 SPSS Inc.,Chicago,IL,U.S.A.).
Results: No minor A allele, homozygous (AA) or heterozygous (CA), was observed in the study population. In other words, the frequency of the CASR A843E common CC genotype was 100%. BMD levels of the lumbar spine (L1-L4), femoral neck, and total hip were 1.03±0.13g/cm2, 0.87±0.11g/cm2, and 0.93±0.11g/cm2, respectively. Although the femoral neck (p=0.017), upper neck (p=0.040), lower neck (p=0.011), and Ward’s triangle BMD values (p=0.005) were found significantly higher in younger postmenopausal women (age<55 years) compared to older postmenopausal women (age>=55 years), there were no significant differences on BMD value of the lumbar spines, trochanter, and total hip between the age groups (p>0.05).

Conclusion: Our findings confirm the effects of advanced age in favor of decreased BMD in postmenopausal women. This study suggests that the CASR A843E gain-of-function mutation may not be associated with bone mineral density and osteo- porosis risk since we did not detect the A843E variation in Turkish postmenopausal women.

Keywords

Osteoporosis, Calcium-sensing receptor, Gain-of-function mutation, Bone mineral density, Smoking

Project Number

T-68/15122006

References

• Aida, K., Koishi, S., Tawata, M., & Onaya, T. (1995). Molecular cloning of a putative Ca2+-sensing receptor cDNA from human kidney. Biochemical and Biophysical Research Communications, 214(2), 524–529.
• Al-Azzawie, A. F. (2001). Molecular assessment of calcium-sensing receptor gene polymorphism rs1801725 in Iraqi women with os- teoporosis, Asian Journal of Agriculture and Biology, 3, 1-9. https:// doi.org/10.35495/ajab.2020.04.252
• Bjarnason, N. H., & Christiansen, C. (2000). The influence of thin- ness and smoking on bone loss and response to hormone re- placement therapy in early postmenopausal women. Journal of Clinical Endocrinology & Metabolism, 85(2), 590–596. https://doi. org/10.1210/jcem.85.2.6364
• Brown, E. M., Gamba, G., & Riccardi, D. (1993). Cloning and charac- terization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature, 366, 575-580.
• Brown, E. M., & Hansen, J. T. (2005). The calcium-sensing recep- tor in normal physiology and pathophysiology: a review. Critical Reviews in Clinical Laboratory Sciences, 42(1), 35–70.
• Brown, E. M., & MacLeod, R. J. (2001). Extracellular calcium sens- ing and extracellular calcium signaling. Physiological Reviews, 81(1), 239-297.
• Brown, E. M. (1999). Physiology and pathophysiology of the extra- cellular calcium-sensing receptor. American Journal of Medicine, 106(2), 238-253.
• Cetani, F., Pardi, E., Borsari, S., Vignali, E., Dipollina, G., Braga, V., … Marcocci, C. (2003). Calcium-sensing receptor gene poly- morphism is not associated with bone mineral density in Italian postmenopausal women. EuropeanJournal of Endocrinology,148, 603–607.
• D’Souza-Li, L. (2006). The calcium-sensing receptor and related diseases. Arquivos Brasileiros de Endocrinologia e Metabologia, 50, 628–636. doi:10.1111/j.1365-2036.2011.04905.x
• Donáth, J., Speer, G., Poór, G., Gergely, P., Tabák, Jr. A., Lakatos, P. (2004). Vitamin D receptor, oestrogen receptor-α and calcium- sensing receptor genotypes, bone mineral density and biochem- ical markers in Paget’s disease of bone. Rheumatology (Oxford), 43 (6), 692-695. doi: 10.1093/rheumatology/keh162
• Egbuna, O. I., & Brown, E. M. (2008). Hypercalcaemic and hypocal- caemic conditions due to calcium-sensing receptor mutations. Best Practice & Research: Clinical Rheumatology, 22(1), 129–148. doi: 10.1016/j.berh.2007.11.006.
• Eller-Vainicher, C., Battista, C., Guarnieri, V., Muscarella, S., Palmieri, S., Salcuni, A. S., … Scillitani A. (2014). Factors associated with vertebral fracture risk in patients with primary hyperparathyroidism. European Journal of Endocrinology, 171(3): 399-406. doi: 10.1530/EJE-14-0343.
• Garrett, J. E., Capuano, I. V., Hammerland, L. G., Hung, B. C., Brown, E. M., Hebert, S. C., Nemeth, E. F., Fuller, F. (1995). Molecular cloning and functional expression of human parathyroid calcium recep- tor cDNAs. Journal of Biological Chemistry, 270(21), 12919–12925.
• Guha, M., Bankura, B., Ghosh, S., Pattanayak, A. K., Ghosh, S., Pal, D.K., … Das M. (2015). Polymorphisms in CaSR and CLDN14 genes associated with increased risk of kidney stone disease in patients from the eastern part of india. PLoS One,10(6): e0130790
• Hannan, F. M., Kallay, E., Chang, W., Brandi, M. L., Thakker, R. V. (2018). The calcium-sensing receptor in physiology and in calci- tropic and noncalcitropic diseases. Nature Reviews Endocrinology, 15(1): 33-51. doi: 10.1038/s41574-018-0115-0.
• Hend, G. N., Guarnieri, V., Canaff, L. (2009). Calcium-sensing receptor and associated diseases. Progress in Molecular Biol- ogy and Translational Science, 89, 31-95. doi: 10.1016/S1877- 1173(09)89003-0.
• Ioannidis, J. P., Stavrou, I., Trikalinos, T. A., Zois, C., Brandi, M. L., Gen- nari, L., … Tsatsoulis, A. (2002). ER-alpha genetics meta-analysis. As- sociation of polymorphisms of the estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-anal- ysis. Journal of Bone and Mineral Research, 17, 2048–2060.
• Jeong, S., Kim, I. W., Oh, K. H., Han, N., Joo, K. W., Kim, H. J., Oh, J. M. (2016). Pharmacogenetic analysis of cinacalcet response in sec- ondary hyperparathyroidism patients. Drug Design, Development and Therapy, 10, 2211-2225. doi: 10.2147/DDDT.S103370.
• Jung, J., Foroud, T. M., Eckert, G. J., Flury-Wetherill, L., Edenberg,
• H. J., Xuei, X., …Pratt, J. H. (2009). Association of the calcium- sensing receptor gene with blood pressure and urinary calcium in African-Americans. Journal of Clinical Endocrinology & Metabo- lism,94(3), 1042-1048. doi: 10.1210/jc.2008-1861.
• Kinoshita, Y., Hori, M., Taguchi, M., Watanabe, S., Fukumoto, S. (2014). Functional activities of mutant calcium-sensing recep- tors determine clinical presentations in patients with autosomal dominant hypocalcemia. Journal of Clinical Endocrinology & Me- tabolism, 99, 363–368. doi:10.1210/jc.2013-3430
• Kuo, CW., Chang, T. H., Chi, W. L., Chu, T. C. (2008). Effect of Ciga- rette Smoking on Bone Mineral Density in Healthy Taiwanese Middle-Aged Men. Journal of Clinical Densitometry, 11(4), 518-524. doi: 10.1016/j.jocd.2008.07.005.
• Kurt, O., Yilmaz-Aydogan, H., Uyar, M., Isbir, T., Seyhan, M., Can, A. (2012). Evaluation of ERα and VDR gene polymorphisms in rela- tion to bone mineral density in Turkish postmenopausal women. MolecularBiologyReports,39(6), 6723-6730. doi: 10.1007/s11033- 012-1496-0.
• Li, X., Kong, X., Jiang, L., Ma, T., Yan, S., …, Yang, Q. (2014). A ge- netic polymorphism (rs17251221) in the calcium-sensing re- ceptor is associated with breast cancer susceptibility and prog- nosis. Cellular Physiology and Biochemistry, 33(1), 165-172. doi: 10.1159/000356659.
• Li, Y., Zhao, Y., Tang, R., Qu, X. (2010). Preventive and therapeutic effects of antlercollagen on osteoporosis in ovariectomized rats. African Journal of Biotechnology, 9(38): 6437-6441. https://doi. org/10.5897/AJB10.251
• Lorentzon, M., Lorentzon, R., Lerner, U. H., Nordstrom, P. (2001). Calcium sensing receptor gene polymorphism, circulating con- centrations and bone mineral density in healthy adolescent girls. European Journal of Endocrinology, 144: 257–261.
• Miller, S. A., Dykes, D. D., Poleskey, H. S. (1988). A simple salting out procedure for extracting DNA from human nucleated cells, Nucleic Acids Research, 16: 1215.
• NIH consensus development panel on osteoporosis. (2001) Pre- vention diagnosis and therapy osteoporosis prevention, diagno- sis, and therapy. Journal of theAmericanMedicalAssociation, 285, 785–795. doi:10.1001/jama.285.6.785
• North American Menopause Society. (2010). NAMS continuing medical education activity. Menopause, 17(1), 25–54. https://doi. org/10.1097/gme.0b013e3181cdd4a7
• Nuti, R., Brandi, M. L., Checchia, G., Di Munno, O., Dominguez, L., Falaschi, P., …, Isaia, G. C. (2019). Guidelines for the management of osteoporosis and fragility fractures. Internal and Emergency Medicine, 14(1), 85-102. doi: 10.1007/s11739-018-1874-2.
• O’Seaghdha, C. M., Yang, Q., Glazer, N. L., Leak, T. S., Dehghan, A., Smith, A. V., …, Köttgen, A. (2010). Common variants in the calci- um-sensing receptor gene are associated with total serum calci- um levels. Human Molecular Genetics, 19, 4296–4303. doi:10.1093/ hmg/ddq342
• Pi, M., Garner, S. C., Flannery, P., Spurney, R. F., Quarles, L. D. (2000). Sensing of extracellular cations in CaSR-deficient osteoblasts. Evi- dence for a novel cation sensing mechanism. Journal of Biological Chemistry, 275, 3256–3263.
• Rapuri, P. B., Gallagher, J. C., Balhorn, K. E., Ryschon, K. L. (2000). Smoking and bone metabolism in elderly women. Bone, 27, 429–436. http://dx.doi.org/10.1016/S8756-3282(00)00341-0
• Regala, J., Cavaco, B., Domingues, R., Limbert, C., Lopes, L. (2015). Novel mutation in the CASR gene (p.Leu123Ser) in a case of auto- somal dominant Hypocalcemia. Journal of Pediatric Genetics, 4(1), 29-33. doi:10.1055/s-0035-1554979
• Sato, K., Hasegawa, Y., Nakae, J., Nanao, K., Takahashi, I., Tajima, T., …, Fujieda, K. (2002). Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of- function mutations of the calcium-sensing receptor gene. Jour- nal of ClinicalEndocrinology & Metabolism, 87(7), 3068-3073.
• Takács, I., Speer, G., Bajnok, É., Tabák, Á., Nagy, Z., Horváth, C., …, Lakatos, P. (2002). Lack of association between calcium-sensing receptor gene “A986S” polymorphism and bone mineral den- sity in Hungarian postmenopausal women. Bone, 30(6), 849–852. doi: http://dx.doi.org/10.1016/S8756-3282(02)00741-X
• Thakker, R. V. (2004). Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium, 35(3), 275-82
• Wang, Y. B., Guo, J. J., Liu, Y. J., Deng, F. Y., Jiang, D. K., Deng, H. W. (2006). The human calcium-sensing receptor and interleukin-6 genes are associated with bone mineral density in Chinese. Acta Genetica Sinica, 33(10), 870-880.
• Watanabe, S., Fukumoto, S., Chang, H., Takeuchi, Y., Hasegawa, Y., Okazaki, R., …, Fujita, T. (2002). Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet, 360(9334), 692-694.
• Willing, M., Sowers, M., Aran, D., Clark, M. K., Burns, T., Bunten, C. (1998). Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interac- tion. Journal of Bone and Mineral Research, 13, 695–705.
• Xie, P., Liu, B., Zhang, L., Chen, R., Yang, B., Dong, J., Rong, L. (2015). Association of COL1A1 polymorphisms with osteoporosis: a me- ta-analysis of clinical studies. International Journal of Experimen- tal and ClinicalMedicine,8(9), 14764–14781.
• Yamauchi, M., Sugimoto, T., Yamaguchi, T., Yano, S., Kanzawa, M., Kobayashi, A., Chihara, K. (2001). Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism. Clinical Endocrinology (Oxford),55, 373–379.
• Young, R., Wu, F., Van de Water, N., Ames, R., Gamble, G., Reid, I.R. (2003). Calcium sensing receptor gene A986S polymorphism and responsiveness to calcium supplementation in postmenopausal women. Journal of ClinicalEndocrinology & Metabolism, 88(2), 697- 700. doi: 10.1210/jc.2002-020355.
• Zhang, J., Jameson, K., Sayer, A. A., Robinson, S., Cooper, C., Den- nison, E. (2016). Accumulation of risk factors associated with poor bone health in older adults. Archives of Osteoporosis, 11, 3. doi: 10.1007/s11657-015-0250-3.
• Zhao, X. M., Hauache, O., Goldsmith, P. K., Collins, R., Spiegel, A. M. (1999). A missensemutation in the seventh transmembrane domain constitutively activates the human Ca2+receptor. FEBS Letters, 448(1), 180–184.