Progressive osseous heteroplasia: Diagnosis, treatment, and prognosis

Application of Clinical Genetics

Volumn 8, Issue , 2015, Pages 37-48

  Pignolo, Robert J ^a   Ramaswamy, Girish ^a   Fong, John T ^a   Shore, Eileen M ^a   Kaplan, Frederick S ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

GNAS; Heterotopic ossification; Progressive osseous heteroplasia

Indexed keywords

CYCLIC AMP DEPENDENT PROTEIN KINASE; GUANINE NUCLEOTIDE BINDING PROTEIN; RETINOIC ACID DERIVATIVE; RETINOIC ACID RECEPTOR GAMMA; RETINOIC ACID RECEPTOR GAMMA AGONIST; UNCLASSIFIED DRUG;

BINDING AFFINITY; BONE DEVELOPMENT; BONE MALFORMATION; CELL DIFFERENTIATION; CLINICAL FEATURE; DISEASE COURSE; ENZYME ACTIVATION; GENE; GENE MUTATION; GENETIC ASSOCIATION; GENETIC TRANSCRIPTION; GENOME IMPRINTING; GNAS GENE; GROWTH RETARDATION; HETEROTOPIC OSSIFICATION; HUMAN; HYDROLYSIS; MORBIDITY; MORTALITY; MUSCLE DEVELOPMENT; NONHUMAN; PROGRESSIVE OSSEOUS HETEROPLASIA; PROTEIN BINDING; PROTEIN DOMAIN; REVIEW; SIGNAL TRANSDUCTION;

EID: 84922201211     PISSN: None     EISSN: 1178704X     Source Type: Journal    
DOI: 10.2147/TACG.S51064     Document Type: Review

References (99)

1. Kaplan FS, Craver R, MacEwen GD, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases. J Bone Joint Surg Am. 1994;76(3):425–436.
2. Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346(2):99–106.
3. Bastepe M. Relative functions of Gαs and its extra-large variant XLαs in the endocrine system. Horm Metab Res. 2012;44(10): 732–740.
4. Bastepe M, Jüppner H. GNAS locus and pseudohypoparathyroidism. Horm Res. 2005;63(2):65–74.
5. Weinstein LS, Liu J, Sakamoto A, Xie T, Chen M. Minireview: GNAS: normal and abnormal functions. Endocrinology. 2004;145(12): 5459–5464.
6. Adegbite NS, Xu M, Kaplan FS, Shore EM, Pignolo RJ. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. 2008;146A(14):1788–1796.
7. Thiele S, Werner R, Ahrens W, et al. Selective deficiency of Gsalpha and the possible role of alternative gene products of GNAS in Albright hereditary osteodystrophy and pseudohypoparathyroidism type Ia. Exp Clin Endocrinol Diabetes. 2010;118(2):127–132.
8. Turan S, Bastepe M. The GNAS complex locus and human diseases associated with loss-of-function mutations or epimutations within this imprinted gene. Horm Res Paediatr. 2013;80(4):229–241.
9. Ahmed S F, Dixon PH, Bonthron DT, et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf). 1998;49(4):525–531.
10. Ahrens W, Hiort O, Staedt P, Kirschner T, Marschke C, Kruse K. Analysis of the GNAS1 gene in Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab. 2001;86(10):4630–4634.
11. Aldred MA, Trembath RC. Activating and inactivating mutations in the human GNAS1 gene. Hum Mutat. 2000;16(3):183–189.
12. Farfel Z, Iiri T, Shapira H, Roitman A, Mouallem M, Bourne HR. Pseudohypoparathyroidism, a novel mutation in the betagamma-contact region of Gsalpha impairs receptor stimulation. J Biol Chem. 1996;271(33):19653–19655.
13. Fischer JA, Egert F, Werder E, Born W. An inherited mutation associated with functional deficiency of the alpha-subunit of the guanine nucleotide-binding protein Gs in pseudo- and pseudopseudohypoparathyroidism. J Clin Endocrinol Metab. 1998;83(3):935–938.
14. Jan De Beur SM, O’Connell JR, Peila R, et al. The pseudohypoparathy-roidism type lb locus is linked to a region including GNAS1 at 2 0q13.3. J Bone Miner Res. 2003;18(3):424–433.
15. Linglart A, Carel JC, Garabédian M, Lé T, Mallet E, Kottler ML. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab. 2002;87(1): 189–197.
16. Luttikhuis ME, Wilson LC, Leonard J V, Trembath RC. Characterization of a de novo 43-bp deletion of the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. Genomics. 1994;21(2):455–457.
17. Miric A, Vechio JD, Levine MA. Heterogeneous mutations in the gene encoding the alpha-subunit of the stimulatory G protein of adenylyl cyclase in Albright hereditary osteodystrophy. J Clin Endocrinol Metab. 1993;76(6):1560–1568.
18. Nakamoto JM, Sandstrom AT, Brickman AS, Christenson RA, Van Dop C. Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsalpha gene mutation. Am J Med Genet. 1998;77(4): 261–267.
19. Nakamoto JM, Zimmerman D, Jones EA, et al. Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene. Biochem Mol Med. 1996;58(1):18–24.
20. Patten JL, Johns DR, Valle D, et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med. 1990;322(20):1412–1419.
21. Schwindinger WF, Miric A, Zimmerman D, Levine MA. A novel Gs alpha mutant in a patient with Albright hereditary osteodystrophy uncouples cell surface receptors from adenylyl cyclase. J Biol Chem. 1994;269(41):25387–25391.
22. Shapira H, Mouallem M, Shapiro MS, Weisman Y, Farfel Z. Pseudohypoparathyroidism type Ia: two new heterozygous frameshift mutations in exons 5 and 10 of the Gs alpha gene. Hum Genet. 1996; 97(1):73–75.
23. Walden U, Weissörtel R, Corria Z, et al. Stimulatory guanine nucleotide binding protein subunit 1 mutation in two siblings with pseudohypopara-thyroidism type 1 a and mother with pseudopseudohypoparathyroidism. Eur J Pediatr. 1999;158(3):200–203.
24. Warner DR, Gejman PV, Collins RM, Weinstein LS. A novel mutation adjacent to the switch III domain of G(S alpha) in a patient with pseudo-hypoparathyroidism. Mol Endocrinol. 1997;11(11):1718–1727.
25. Warner DR, Weng G, Yu S, Matalon R, Weinstein LS. A novel mutation in the switch 3 region of Gsalpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation. J Biol Chem. 1998;273(37):23976–23983.
26. Weinstein LS, Gejman PV, de Mazancourt P, American N, Spiegel AM. A heterozygous 4-bp deletion mutation in the Gs alpha gene (GNAS1) in a patient with Albright hereditary osteodystrophy. Genomics. 1992;13(4):1319–1321.
27. Weinstein LS, Gejman PV, Friedman E, et al. Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA. 1990;87(21):8287–8290.
28. Wilson LC, Oude Luttikhuis ME, Clayton PT, Fraser WD, Trembath RC. Parental origin of Gs alpha gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 1994;31(11):835–839.
29. Yokoyama M, Takeda K, Iyota K, Okabayashi T, Hashimoto K. A 4-base pair deletion mutation of Gs alpha gene in a Japanese patient with pseudohypoparathyroidism. J Endocrinol Invest. 1996;19(4): 236–241.
30. Yu D, Yu S, Schuster V, Kruse K, Clericuzio CL, Weinstein LS. Identification of two novel deletion mutations within the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy. J Clin Endocrinol Metab. 1999;84(9):3254–3259.
31. Yu S, Yu D, Hainline BE, et al. A deletion hot-spot in exon 7 of the Gs alpha gene (GNAS1) in patients with Albright hereditary osteodystrophy. Hum Mol Genet. 1995;4(10):2001–2002.
32. Baltoumas FA, Theodoropoulou MC, Hamodrakas SJ. Interactions of the α-subunits of heterotrimeric G-proteins with GPCRs, effectors and RGS proteins: a critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials. J Struct Biol. 2013;182(3):209–218.
33. Oldham WM, Hamm HE. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol. 2008;9(1):60–71.
34. Wettschureck N, Offermanns S. Mammalian G proteins and their cell type specific functions. Physiol Rev. 2005;85(4):1159–1204.
35. Heydorn A, Ward RJ, Jorgensen R, et al. Identification of a novel site within G protein alpha subunits important for specificity of receptor-G protein interaction. Mol Pharmacol. 2004;66(2):250–259.
36. McCudden CR, Hains MD, Kimple RJ, Siderovski DP, Willard FS. G-protein signaling: back to the future. Cell Mol Life Sci. 2005;62(5): 551–577.
37. Huang C, Hepler JR, Gilman AG, Mumby SM. Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells. Proc Natl Acad Sci USA. 1997;94(12):6159–6163.
38. Roy AA, Lemberg KE, Chidiac P. Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors refects functional interactions. Mol Pharmacol. 2003;64(3):587–593.
39. Zheng B, Ma YC, Ostrom RS, et al. RGS-PX1, a GAP for GalphaS and sorting nexin in vesicular traffcking. Science. 2001;294(5548): 1939–1942.
40. Bastepe M. The GNAS Locus: Quintessential Complex Gene Encoding Gsalpha, XLalphas, and other Imprinted Transcripts. Curr Genomics. 2007;8(6):398–414.
41. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol. 2008;196(2):193–214.
42. Ishikawa Y, Bianchi C, Nadal-Ginard B, Homcy CJ. Alternative promoter and 5′ exon generate a novel Gs alpha mRNA. J Biol Chem. 1990;265(15):8458–8462.
43. Puzhko S, Goodyer CG, Kerachian MA, et al. Parathyroid hormone signaling via Gαs is selectively inhibited by an NH(2)-terminally truncated Gαs: implications for pseudohypoparathyroidism. J Bone Miner Res. 2011;26(10):2473–2485.
44. Mantovani G, Bondioni S, Locatelli M, et al. Biallelic expression of the Gsalpha gene in human bone and adipose tissue. J Clin Endocrinol Metab. 2004;89(12):6316–6319.
45. Weinstein LS, Yu S, Warner DR, Liu J. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Endocr Rev. 2001;22(5):675–705.
46. Chen M, Gavrilova O, Liu J, et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci U S A. 2005;102(20):7386–7391.
47. Germain-Lee EL, Schwindinger W, Crane JL, et al. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology. 2005;146(11): 4697–4709.
48. Turan S, Fernandez-Rebollo E, Aydin C, et al. Postnatal establishment of allelic Gαs silencing as a plausible explanation for delayed onset of parathyroid hormone resistance owing to heterozygous Gαs disruption. J Bone Miner Res. 2014;29(3):749–760.
49. Plagge A, Isles AR, Gordon E, et al. Imprinted Nesp55 infuences behavioral reactivity to novel environments. Mol Cell Biol. 2005;25(8): 3019–3026.
50. Richard N, Molin A, Coudray N, Rault-Guillaume P, Jüppner H, Kottler ML. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development. J Clin Endocrinol Metab. 2013;98(9):E1549–E1556.
51. Kobayashi NR, Hawes SM, Crook JM, Pébay A. G-protein coupled receptors in stem cell self-renewal and differentiation. Stem Cell Rev. 2010;6(3):351–366.
52. Pignolo RJ, Xu M, Russell E, et al. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J Bone Miner Res. 2011;26(11):2647–2655.
53. Wu JY, Aarnisalo P, Bastepe M, et al. Gsα enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteo-blast differentiation in mice. J Clin Invest. 2011;121(9):3492–3504.
54. Berdeaux R, Stewart R. cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. Am J Physiol Endocrinol Metab. 2012;303(1):E1–E17.
55. Liu JJ, Russell E, Zhang D, Kaplan FS, Pignolo RJ, Shore EM. Paternally inherited gsα mutation impairs adipogenesis and potentiates a lean phenotype in vivo. Stem Cells. 2012;30(7):1477–1485.
56. Sinha P, Aarnisalo P, Chubb R, et al. Loss of Gsα early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors. J Bone Miner Res. 2014;29(11):2414–2426.
57. Sakamoto A, Chen M, Kobayashi T, Kronenberg HM, Weinstein LS. Chondrocyte-specific knockout of the G protein G(s)alpha leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J Bone Miner Res. 2005;20(4):663–671.
58. Doze VA, Perez DM. G-protein-coupled receptors in adult neurogenesis. Pharmacol Rev. 2012;64(3):645–675.
59. Huso DL, Edie S, Levine MA, et al. Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy. PLoS ONE. 2011;6(6):e21755.
60. Gharibi B, Abraham AA, Ham J, Evans BA. Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J Bone Miner Res. 2011;26(9):2112–2124.
61. Gharibi B, Abraham AA, Ham J, Evans BA. Contrasting effects of A1 and A2b adenosine receptors on adipogenesis. Int J Obes. 2012;36(3): 397–406.
62. Bachman ES, Dhillon H, Zhang C Y, et al. betaAR signaling required for diet-induced thermogenesis and obesity resistance. Science. 2002;297(5582):843–845.
63. Li H, Fong C, Chen Y, Cai G, Yang M. Beta-adrenergic signals regulate adipogenesis of mouse mesenchymal stem cells via cAMP/PKA pathway. Mol Cell Endocrinol. 2010;323(2):201–207.
64. Li H, Fong C, Chen Y, Cai G, Yang M. beta2- and beta3-, but not beta1-adrenergic receptors are involved in osteogenesis of mouse mesenchymal stem cells via cAMP/PKA signaling. Arch Biochem Biophys. 2010;496(2):77–83.
65. Torres B, Zambon AC, Insel PA. P2Y11 receptors activate adenylyl cyclase and contribute to nucleotide-promoted cAMP formation in MDCK-D(1) cells. A mechanism for nucleotide-mediated autocrine-paracrine regulation. J Biol Chem. 2002;277(10):7761–7765.
66. Lee H, Jun DJ, Suh BC, et al. Dual roles of P2 purinergic receptors in insulin-stimulated leptin production and lipolysis in differentiated rat white adipocytes. J Biol Chem. 2005;280(31):28556–28563.
67. Regard JB, Malhotra D, Gvozdenovic-Jeremic J, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med. 2013;19(11):1505–1512.
68. Regard JB, Cherman N, Palmer D, et al. Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia. Proc Natl Acad Sci USA. 2011;108(50):20101–20106.
69. James AW. Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation. Scientifica (Cairo). 2013;2013:684736.
70. James AW, Leucht P, Levi B, et al. Sonic Hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells. Tissue Eng Part A. 2010;16(8):2605–2616.
71. Sheng T, Chi S, Zhang X, Xie J. Regulation of Gli1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem. 2006;281(1):9–12.
72. Epstein DJ, Marti E, Scott M P, McMahon A P. Antagonizing cAMP-dependent protein kinase A in the dorsal CNS activates a conserved Sonic hedgehog signaling pathway. Development. 1996;122(9): 2885–2894.
73. Makinodan E, Marneros AG. Protein kinase A activation inhibits onco-genic Sonic hedgehog signalling and suppresses basal cell carcinoma of the skin. Exp Dermatol. 2012;21(11):847–852.
74. Tuson M, He M, Anderson K V. Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development. 2011;138(22):4921–4930.
75. Lian JB, Stein GS, Javed A, et al. Networks and hubs for the tran-scriptional control of osteoblastogenesis. Rev Endocr Metab Disord. 2006;7(1–2):1–16.
76. Matsubara T, Kida K, Yamaguchi A, et al. BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem. 2008;283(43):29119–29125.
77. Zhang S, Kaplan FS, Shore EM. Different roles of GNAS and cAMP signaling during early and late stages of osteogenic differentiation. Horm Metab Res. 2012;44(10):724–731.
78. Lemos MC, Thakker RV. GNAS mutations in pseudohypoparathyroidism type 1a and related disorders. Hum Mutat. Epub September 13, 2014.
79. Lebrun M, Richard N, Abeguilé G, et al. Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans. J Clin Endocrinol Metab. 2010;95(6):3028–3038.
80. Elli FM, Barbieri AM, Bordogna P, et al. Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series. Bone. 2013;56(2):276–280.
81. Cairns DM, Pignolo RJ, Uchimura T, et al. Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J Clin Invest. 2013;123(8):3624–3633.
82. Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res. 2000;15(11):2084–2094.
83. Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38(5):525–527.
84. Bastepe M, Fröhlich LF, Linglart A, et al. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nat Genet. 2005;37(1): 25–27.
85. Jüppner H, Schipani E, Bastepe M, et al. The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds to chromosome 20q13.3. Proc Natl Acad Sci USA. 1998;95(20):11798–11803.
86. Ruggieri M, Pavone V, Polizzi A, et al. Familial osteoma of the cranial vault. Br J Radiol. 1998;71(842):225–228.
87. Athanasou NA, Benson MK, Brenton B P, Smith R. Progressive osseous heteroplasia: a case report. Bone. 1994;15(5):471–475.
88. Rosenfeld SR, Kaplan FS. Progressive osseous heteroplasia in male patients. Two new case reports. Clin Orthop Relat Res. 1995;(317): 243–245.
89. Schmidt AH, Vincent KA, Aiona MD. Hemimelic progressive osseous heteroplasia. A case report. J Bone Joint Surg Am. 1994;76(6): 907–912.
90. Urtizberea JA, Testart H, Cartault F, Boccon-Gibod L, Le Merrer M, Kaplan FS. Progressive osseous heteroplasia. Report of a family. J Bone Joint Surg Br. 1998;80(5):768–771.
91. Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. J Clin Endocrinol Metab. 2007;92(3):1073–1079.
92. Eddy MC, Jan De Beur SM, Yandow SM, et al. Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification. J Bone Miner Res. 2000;15(11):2074–2083.
93. Tresserra L, Tresserra F, Grases PJ, Badosa J, Tresserra M. Congenital plate-like osteoma cutis of the forehead: an atypical presentation form. J Craniomaxillofac Surg. 1998;26(2):102–106.
94. Yeh GL, Mathur S, Wivel A, et al. GNAS1 mutation and Cbfa1 mis-expression in a child with severe congenital platelike osteoma cutis. J Bone Miner Res. 2000;15(11):2063–2073.
95. Aynaci O, Müjgan Aynaci F, Cobanoğlu U, Alpay K. Progressive osseous heteroplasia. A case report and review of the literature. J Pediatr Orthop B. 2002;11(4):339–342.
96. Hou J W. Progressive osseous heteroplasia controlled by intravenous administration of pamidronate. Am J Med Genet A. 2006;140(8): 910–913.
97. Trinh TN, McLaughlin EA, Gordon C P, McCluskey A. Hedgehog signalling pathway inhibitors as cancer suppressing agents. Med Chem Comm. 2014;5(2):117–133.
98. Shimono K, Tung WE, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med. 2011;17(4):454–460.
99. Chan SD, Strewler GJ, Nissenson RA. Transcriptional activation of Gs alpha expression by retinoic acid and parathyroid hormone-related protein in F9 teratocarcinoma cells. J Biol Chem. 1990;265(33): 20081–20084.