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01.05.2015 | Original Research

Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization

verfasst von: L. Masi, G. Beltrami, S. Ottanelli, F. Franceschelli, A. Gozzini, R. Zonefrati, G. Galli, S. Ciuffi, C. Mavilia, F. Giusti, G. Marcucci, F. Cioppi, E. Colli, C. Fossi, A. Franchi, C. Casentini, R. Capanna, Maria Luisa Brandi

Erschienen in: Calcified Tissue International | Ausgabe 5/2015

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Abstract

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

Olsen KM, Chew FS (2006) Tumoral calcinosis: pearls, polemics, and alternative possibilities. Radiographics 26:871–885CrossRefPubMed

Ghanchi F, Ramsay A, Coupland S, Barr D, Lee W (1996) Ocular tumoral calcinosis. A clinicopathologic study. Arch Ophthalmol 114:341–345CrossRefPubMed

Araya K, Fukumoto S, Backenroth R, Takeuchi Y, Nakayama K, Ito N, Yoshii N, Yamazaki Y, Yamashita T, Silver J, Igarashi T, Fujita T (2005) A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis. J Clin Endocrinol Metab 90:5523–5527CrossRefPubMed

Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14:385–390CrossRefPubMed

Chefetz I, Heller R, Galli-Tsinopoulou A, Richard G, Wollnik B, Indelman M, Koerber F, Topaz O, Bergman R, Sprecher E, Schönau E (2005) A novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Hum Genet 118:261–266CrossRefPubMed

Larsson T, Yu X, Davis SI, Draman MS, Mooney SD, Cullen MJ, White KE (2005) A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocrinol Metab 90:2424–2427CrossRefPubMed

Masi L, Gozzini A, Franchi A, Campanacci D, Amedei A, Falchetti A, Franceschelli F, Marcucci G, Tanini A, Capanna R, Brandi ML (2009) Tumoral calcinosis (TC) is a rare disease characterized A novel recessive mutation of fibroblast growth factor-23 (FGF23) in tumoral calcinosis. J Bone Joint Surg Am 91:1190–1198CrossRefPubMed

Campagnoli MF, Pucci A, Garelli E, Carando A, Defilippi C, Lala R, Ingrosso G, Dianzani I, Forni M, Ramenghi U (2006) Familial tumoral calcinosis and testicular microlithiasis associated with a new mutation of GALNT3 in a white family. J Clin Pathol 59:440–442CrossRefPubMedCentralPubMed

Ichikawa S, Lyles KW, Econs MJ (2005) A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: evidence that the disorder is autosomal recessive. J Clin Endocrinol Metab 90:2420–2423CrossRefPubMed

10.

Specktor P, Cooper JG, Indelman M, Sprecher E (2006) Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred. J Hum Genet 51:487–490CrossRefPubMed

11.

Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, Khamaysi Z, Behar D, Petronius D, Friedman V, Zelikovic I, Raimer S, Metzker A, Richard G, Sprecher E (2004) Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet 36:579–581CrossRefPubMed

12.

Firishberg Y, Topaz O, Begman R, Behar D, Gordon D, Richiard G, Sprecher E (2005) Identification of a recurrent mutation in GALNT3 demonstrates that hyperostosis-hyperphosphatemia syndrome and familial tumoral calcinosis are allelic disorders. J Mol Med 83:33–38CrossRef

13.

Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, Juppner H, Lanske B (2004) Homozygous ablation of fibroblast growth facotor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23:421–432CrossRefPubMedCentralPubMed

14.

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Ida T, Nishikawa S, Nagai R, Yi Nebeshima (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51CrossRefPubMed

15.

Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2684–2691CrossRefPubMedCentralPubMed

16.

Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, Hui SL, Econs MJ (2009) Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression. Endocrinology 150:2543–2550CrossRefPubMedCentralPubMed

17.

Ichikawa S, Baujat G, Seyahi A, Garoufali AG, Imel EA, Padgett LR, Austin AM, Sorenson AH, Pejin Z, Topouchian V, Quartier P, Cormier-Daire V, Dechaux M, Malandrinou FCh, Singhellakis PN, Le Merrer M, Econs MJ (2010) Clinical variability of familial tumoral calcinosis caused by novel GALNT3 mutations. Am J Med Genet 152:896–903CrossRef

18.

Barth JH, Jones RG, Payne RB (2000) Ann Clin Biochem 37:79–81CrossRefPubMed

19.

Walton RJ, Bijvoet OLM (1975) Nomogram for derivation of renal threshold phosphate concentration. Lancet 16:309–310CrossRef

20.

Montomoli M, Gonnelli S, Giacchi M, Mattei R, Cuda C, Rossi S, Gennari C (2002) Validation of a food frequency questionnaire for nutritional calcium intake assessment in Italian women. Eur J Clin Nutr 56:21–30CrossRefPubMed

21.

Tognarini I, Sorace S, Zonefrati R, Galli G, Gozzini A, Carbonell Sala S, Thyrion GD, Carossino AM, Tanini A, Mavilia C, Azzari C, Sbaiz F, Facchini A, Capanna R, Brandi ML (2008) In vitro differentiation of human mesenchymal stem cells on Ti6Al4V surfaces. Biomaterials 29:809–2469CrossRefPubMed

22.

Heijboer AC, Blankenstein MA, Hoenderop J, de Borst MH, Vervloet MG, NIGRAM consortium (2013) Laboratory aspects of circulating α-Klotho. Nephrol Dial Transpl 28(9):2283–2287CrossRef

23.

Yancovitch A, Hershkovitz D, Indelman M, Galloway P, Whiteford M, Sprecher E, Kılıç E (2011) Novel mutations in GALNT3 causing hyperphosphatemic familial tumoral calcinosis. J Bone Miner Metab 29:621–625CrossRefPubMed

24.

Laleye A, Alao MJ, Gbessi G, Adjagba M, Marche M, Coupry I, Redonnet-Vernhet I, Lepreux S, Ayivi B, Darboux RB, Lacombe D, Arveiler B (2008) Tumoral calcinosis due to GALNT3 C.516-2A > T mutation in a black African family. Genet Couns 19:183–192PubMed

25.

Olauson H, Krajisnik T, Larsson C, Lindberg B, Larsson TE (2008) A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome. Eur J Endocrinol 158:929–934CrossRefPubMed

26.

Garringer HJ, Mortazavi SM, Esteghamat F, Malekpour M, Boztepe H, Tanakol R, Davis SI, White KE (2007) Two novel GALNT3 mutations in familial tumoral calcinosis. Am J Med Genet A 15:2390–2396CrossRef

27.

Barbieri AM, Filopanti M, Bua G, Beck-Peccoz P (2007) Two novel nonsense mutations in GALNT3 gene are responsible for familial tumoral calcinosis. J Hum Genet 52:464–468CrossRefPubMed

28.

Ichikawa S, Guigonis V, Imel EA, Courouble M, Heissat S, Henley JD, Sorenson AH, Petit B, Lienhardt A, Econs MJ (2007) Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 92:1943–1947CrossRefPubMed

29.

Ichikawa S, Imel EA, Sorenson AH, Severe R, Knudson P, Harris GJ, Shaker JL, Econs MJ (2006) Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene. J Clin Endocrinol Metab 91:4472–4475CrossRefPubMed

30.

Dumitrescu CE, Kelly MH, Khosravi A, Hart TC, Brahim T, White KE, Farrow EG, Nathan MH, Murphey MD, Collins MT (2009) A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features. Osteoporos Int 20:1273–1278CrossRefPubMedCentralPubMed

31.

Chefetz I, Sprecher E (2008) Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis. Biochim Biophys Acta 1792:61–67CrossRefPubMedCentralPubMed

32.

Bergwitz C, Banerjee S, Abu-Zahra H, Kaji H, Miyauchi A, Sugimoto T, Jüppner H (2009) Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis. J Clin Endocrinol Metab 94:4267–4274CrossRefPubMedCentralPubMed

33.

Topaz O, Bergman R, Mandel U, Maor G, Goldberg R, Richard G, Sprecher E (2005) Absence of intraepidermal glycosyltransaminase ppGalNAc-T3 expression in familial tumoral calcinosis. Am J Dermatopathol 27:211–215CrossRefPubMed

34.

Kato K, Jeanneau C, Tarp MA, Benet-Pagès A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H (2006) Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires. J Biol Chem 281:18370–18377CrossRefPubMed

35.

Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan de Beur SM, Mentzel T, Montgomery E, Michal M, Miettinen M, Mills SE, Reith JD, O’Connell JX, Rosenberg AE, Rubin BP, Sweet DE, Vinh TN, Wold LE, Wehrli BM, White KE, Zaino RJ, Weiss SW (2004) Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol 28:1–30CrossRefPubMed

36.

Yuji Yamazakia Y, Imurab A, Urakawa I, Shimada T, Murakami J, Aono Y, Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N, Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H, Ichikawa S, Imel EA, Econs MJ, Nabeshima Y (2010) Establishment of sandwich ELISA for soluble alpha-Klotho measurement: age-dependent change of soluble alpha-Klotho levels in healthy subjects) in healthy children. Biochem Biophys Res Commun 398:513–518CrossRef

37.

Kuro-o M (2010) A potential link between phosphate and aging—lessons from Klotho-deficient mice. Mech Ageing Dev 131:270–275CrossRefPubMedCentralPubMed

38.

Nobeshima Y (2009) Discovery of alpha-Klotho unveiled new insights into calcium and phosphate homeostasis. Proc Jpn Acad Ser B 85:125–141CrossRef

39.

Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD (2006) Fibroblast Growth Factor 23 is a counter-regulatory phosphaturic hormone for Vitamin D. J Am Soc Nephrol 17:1305–1315CrossRefPubMed

40.

Tsujikawa H, Kurataki T, Fujimorifukuola K, Nabeshima Y (2003) Klotho a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocr 17:2393–2403CrossRef

41.

Yu X, Sabbagh Y, Davis SI, Demay MB, White KE (2005) Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 36:971–977CrossRefPubMed

42.

Urakawa I, Yamazaki Y, Shimada T, Iijima K, Ksegawa H, Okawa K, FujitaT Fukumoto S, Yamashita T (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 7:770–774CrossRef

43.

Lanske B, Razzaque MS (2007) Mineral metabolism and aging: the fibroblast growth factor 23 enigma. Curr Opin Nephrol Hypertens 16:311–318CrossRefPubMedCentralPubMed

44.

Memon F, El-Abbadi M, Nakatani T, Taguchi T, Lanske B, Razzaque MS (2008) Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism? Kidney Int 74:566–570CrossRefPubMedCentralPubMed

45.

Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568CrossRefPubMedCentralPubMed

46.

Shalhoub V, Ward SC, Su B, Stevens J, Renshaw L, Hawkins N, Richards WG (2011) Fibroblast growth factor 23 (FGF23) and alpha-klotho stimulate osteoblastic MC3T3.E1 cell proliferation and inhibit mineralization. Calcif Tisse Int 89:140–150CrossRef

47.

Hunte GK, Hauschaka PV, Poole AR, Rosenberg LC, Goldberg HA (1996) Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. Biochem J 317:59–64

48.

Duncan EL, Danoy P, Kemp JP, Leo PJ, McCloskey E, GeoffreyC Nicholson GC, Eastell R, Richard L, Prince RL, Eisman JA, Jones G, Sambrook PN, Reid IR, Dennison EL, Wark J, Richards JB, Uitterlinden AG, Spector TD, Esapa C, Cox RD, Brown SDM, Thakker RV, Addison KA, Bradbury LA, Center JR, Cooper C, Cremin C, Estrada K, Felsenberg D, Glüer C-C, Hadler J, Henry MJ, Hofman A, Kotowicz MA, Makovey J, Nguyen SC, Nguyen TV, Pasco JA, Pryce K, Reid DM, Rivadeneira F, Roux C, Stefansson K, Styrkarsdottir U, Thorleifsson G, Tichawangana R, Evans DM, Brown MA (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 4:e1001372CrossRef

49.

Li N, Wang X, Jiang Y, Wang W, Huang W, Zheng X, Wang Q, Ning Z, Pei Y, Li C, Nie M, Li M, Wang O, Xing X, He S, Yu W, Lin Q, Xu L, Xia W (2014) Association of GALNT3 gene polymorphisms with bone mineral density in Chinese postmenopausal women: the Peking Vertebral Fracture study. Menopause 21:515–521CrossRefPubMed

50.

Toyoma R, Fujimori T, Nebeshima Y, Itoh Y, Tsuji Y, Osamura RY, Nebeshima Y-I (2006) Impaired regulation of gonadotropins leads to the atrophy of the female reproductive system in klotho deficient mice. Endocrinology 147:120–129CrossRef

51.

Yamashita T, Yoshika M, Itoh N (2000) Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 22:494–498CrossRef

52.

Miramas M, Robinson BG, Mason RS, Nelson AE (2004) Bone as a source of FGF23: regulation by phosphate? Bone 5:1192–1199CrossRef

Titel: Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization
verfasst von: L. Masi
G. Beltrami
S. Ottanelli
F. Franceschelli
A. Gozzini
R. Zonefrati
G. Galli
S. Ciuffi
C. Mavilia
F. Giusti
G. Marcucci
F. Cioppi
E. Colli
C. Fossi
A. Franchi
C. Casentini
R. Capanna
Maria Luisa Brandi
Publikationsdatum: 01.05.2015
Verlag: Springer US
Erschienen in: Calcified Tissue International / Ausgabe 5/2015
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-015-9974-8

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