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Genetic and enzymatic analysis for two Japanese patients with idiopathic infantile arterial calcification

Abstract

Idiopathic infantile arterial calcification (IIAC) is a life-threatening disorder in young infants. Cardiovascular symptoms are usually apparent within the first month of life. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries. Most of the patients die by 6 months of age because of heart failure. Recently, homozygous or compound heterozygous mutations for the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate (PPi), a major inhibiter of extracellular matrix calcification. Two Japanese patients with IIAC were studied. One, from first-cousin parents, showed a typical clinical course. The onset in the second patient was late. Both of the patients were clinically compatible for IIAC; arterial calcification was shown, and hypertension was prominent. We sequenced all the exons and exon-intron boundaries of the gene and measured nucleotide pyrophosphohydrolase (NPPH) activity of ENPP1. Homozygous Arg730Stop was detected in the typical IIAC patient. The mutation was a novel nonsense mutation and not detected in 60 healthy controls. His NPPH activity was 4% of normal. On the other hand, the late-onset patient was not shown to have any mutations. NPPH activity in this patient was 70% of normal. We confirmed that ENPP1 was also responsible for the Japanese patient with IIAC. The atypical late-onset phenotype may not be associated with ENPP1 abnormalities. IIAC is considered to be a clinically and genetically heterogeneous disorder.

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References

  1. C Maayan O Peleg F Eyal P Mogle E Rosenmann J Bar Ziv (1984) ArticleTitleIdiopathic infantile arterial calcification: a case report and review of the literature Eur J Pediatr 142 211–215 Occurrence Handle6468446 Occurrence Handle10.1007/BF00442452 Occurrence Handle1:STN:280:BiuB1crkvFw%3D

    PubMed  Article  CAS  Google Scholar 

  2. M Van Dyck W Proesmans E Van Hollebeke G Marchal P Moerman (1989) ArticleTitleIdiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement Eur J Pediatr 148 374–377 Occurrence Handle2707283 Occurrence Handle1:STN:280:BiaB3M%2FpvVI%3D

    PubMed  CAS  Google Scholar 

  3. J Vera J Lucaya JA Garcia Conesa C Aso A Balaguer (1990) ArticleTitleIdiopathic infantile arterial calcification: unusual features Pediatr Radiol 20 585–587 Occurrence Handle2251001 Occurrence Handle10.1007/BF02129060 Occurrence Handle1:STN:280:By6D28jjtVU%3D

    PubMed  Article  CAS  Google Scholar 

  4. F Rutsch P Schauerte H Kalhoff M Petrarulo C August L Diekmann (2000) ArticleTitleLow levels of urinary inorganic pyrophosphate indicating systemic pyrophosphate deficiency in a boy with idiopathic infantile arterial calcification Acta Paediatr 89 1265–1269 Occurrence Handle11083387 Occurrence Handle1:STN:280:DC%2BD3MzgtlSqtQ%3D%3D

    PubMed  CAS  Google Scholar 

  5. F Rutsch S Vaingankar K Johnson I Goldfine B Maddux P Schauerte H Kalhoff K Sano WA Boisvert A Superti-Furga R Terkeltaub (2001) ArticleTitlePC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification Am J Pathol 158 543–554 Occurrence Handle11159191 Occurrence Handle1:CAS:528:DC%2BD3MXhsFWmt7g%3D

    PubMed  CAS  Google Scholar 

  6. F Rutsch N Ruf S Vaingankar MR Toliat A Suk et al. (2003) ArticleTitleMutations in ENPP1 are associated with “idiopathic” infantile arterial calcification Nat Genet 34 379–381 Occurrence Handle12881724 Occurrence Handle10.1038/ng1221 Occurrence Handle1:CAS:528:DC%2BD3sXmt1Skurg%3D

    PubMed  Article  CAS  Google Scholar 

  7. NF Rebbe BD Tong EM Finley S Hickman (1991) ArticleTitleIdentification of nucleotide pyrophosphatase/alkaline phosphodiesterase I activity associated with the mouse plasma cell differentiation antigen PC-1 Proc Natl Acad Sci USA 88 5192–5196 Occurrence Handle1647027 Occurrence Handle1:CAS:528:DyaK3MXltlSnsb4%3D

    PubMed  CAS  Google Scholar 

  8. SI Belli IR van Driel JW Goding (1993) ArticleTitleIdentification and characterization of a soluble form of the plasma cell membrane glycoprotein PC-1 (5′-nucleotide phosphodiesterase) Eur J Biochem 217 421–428 Occurrence Handle8223581 Occurrence Handle10.1111/j.1432-1033.1993.tb18261.x Occurrence Handle1:CAS:528:DyaK3sXmtVSitLg%3D

    PubMed  Article  CAS  Google Scholar 

  9. Y Hasegawa K Fujii M Yamada Y Igarashi K Tachibana T Tanaka K Onigata Y Nishi S Kato T Hasegawa (2000) ArticleTitleIdentification of novel human GH-1 gene polymorphisms that are associated with growth hormone secretion and height J Clin Endocrinol Metab 85 1290–1295 Occurrence Handle10720078 Occurrence Handle10.1210/jc.85.3.1290 Occurrence Handle1:CAS:528:DC%2BD3cXisFOqsLc%3D

    PubMed  Article  CAS  Google Scholar 

  10. A Cardenal I Masuda AL Haas W Ono DJ McCarty (1996) ArticleTitleIdentification of a nucleotide pyrophosphohydrolase from articular tissues in human serum Arthritis Rheum 39 252–256 Occurrence Handle8849375 Occurrence Handle1:CAS:528:DyaK28Xhs1OhtLk%3D

    PubMed  CAS  Google Scholar 

  11. OH Lowry NJ Rosebrough AL Farr RJ Randall (1951) ArticleTitleProtein measurement with the Folin phenol reagent J Biol Chem 193 265–275 Occurrence Handle14907713 Occurrence Handle1:CAS:528:DyaG38XhsVyrsw%3D%3D

    PubMed  CAS  Google Scholar 

  12. JH Bryant WA White (1901) ArticleTitleCase of calcification of the arteries and obliterative endarteritis associated with hydronephrosis in a child aged six months Guys Hosp Rep 55 17

    Google Scholar 

  13. T Schinke MD McKee R Kiviranta G Karsenty (1998) ArticleTitleMolecular determinants of arterial calcification Ann Med 30 538–541 Occurrence Handle9920355 Occurrence Handle1:CAS:528:DyaK1MXht1Cnsrk%3D Occurrence Handle10.3109/07853899809002601

    PubMed  CAS  Article  Google Scholar 

  14. T Schinke MD McKee G Karsenty (1999) ArticleTitleExtracellular matrix calcification: where is the action? Nat Genet 21 150–151 Occurrence Handle9988260 Occurrence Handle10.1038/5928 Occurrence Handle1:CAS:528:DyaK1MXpsVClsw%3D%3D

    PubMed  Article  CAS  Google Scholar 

  15. IR van Driel JW Goding (1987) ArticleTitlePlasma cell membrane glycoprotein PC-1: primary structure deduced from cDNA clones J Biol Chem 262 4882–4887 Occurrence Handle3104326 Occurrence Handle1:CAS:528:DyaL2sXksFCgsbk%3D

    PubMed  CAS  Google Scholar 

  16. H Kawagoe O Soma J Goji N Nishimura M Narita J Inazawa H Nakamura K Sano (1995) ArticleTitleMolecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2) Genomics 30 380–384 Occurrence Handle8586446 Occurrence Handle10.1006/geno.1995.0036 Occurrence Handle1:CAS:528:DyaK2MXpvVSkt7o%3D

    PubMed  Article  CAS  Google Scholar 

  17. P Jin-Hua JW Goding H Nakamura K Sano (1997) ArticleTitleMolecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new member of the human phosphodiesterase I genes Genomics 45 412–415 Occurrence Handle9344668 Occurrence Handle10.1006/geno.1997.4949 Occurrence Handle1:STN:280:DyaK1c%2FgvV2gsQ%3D%3D

    PubMed  Article  CAS  Google Scholar 

  18. K Johnson S Hashimoto M Lotz K Pritzker J Goding R Terkeltaub (2001) ArticleTitleUp-regulated expression of the phosphodiesterase nucleotide pyrophosphatase family member PC-1 is a marker and pathogenic factor for knee meniscal cartilage matrix calcification Arthritis Rheum 4 1071–1081

    Google Scholar 

  19. K Johnson S Vaingankar Y Chen A Moffa MB Goldring K Sano P Jin-Hua A Sali J Goding R Terkeltaub (1999) ArticleTitleDifferential mechanisms of inorganic pyrophosphate production by plasma cell membrane glycoprotein-1 and B10 in chondrocytes Arthritis Rheum 42 1986–1997 Occurrence Handle10513816 Occurrence Handle10.1002/1529-0131(199909)42:9<1986::AID-ANR26>3.0.CO;2-O Occurrence Handle1:CAS:528:DyaK1MXmsl2msb4%3D

    PubMed  Article  CAS  Google Scholar 

  20. KA Johnson L Hessle S Vaingankar C Wennberg S Mauro S Narisawa JW Goding K Sano JL Millan R Terkeltaub (2000) ArticleTitleOsteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1 Am J Physiol Regul Integr Comp Physiol 279 R1365–R1377 Occurrence Handle11004006 Occurrence Handle1:CAS:528:DC%2BD3cXns1egtLg%3D

    PubMed  CAS  Google Scholar 

  21. RA Terkeltaub (2001) ArticleTitleInorganic pyrophosphate generation and disposition in pathophysiology Am J Physiol Cell Physiol 281 C1–C11 Occurrence Handle11401820 Occurrence Handle1:CAS:528:DC%2BD3MXltVKiurc%3D

    PubMed  CAS  Google Scholar 

  22. AM Ho MD Johnson DM Kingsley (2000) ArticleTitleRole of the mouse ank gene in control of tissue calcification and arthritis Science 289 265–270 Occurrence Handle10894769 Occurrence Handle10.1126/science.289.5477.265 Occurrence Handle1:CAS:528:DC%2BD3cXltFejs7k%3D

    PubMed  Article  CAS  Google Scholar 

  23. E Reichenberger V Tiziani S Watanabe L Park Y Ueki et al. (2001) ArticleTitleAutosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK Am J Hum Genet 68 1321–1326 Occurrence Handle11326338 Occurrence Handle10.1086/320612 Occurrence Handle1:CAS:528:DC%2BD3MXltFeqs7Y%3D

    PubMed  Article  CAS  Google Scholar 

  24. P Nurnberg H Thiele D Chandler W Hohne ML Cunningham H Ritter G Leschik K Uhlmann C Mischung K Harrop J Goldblatt ZU Borochowitz D Kotzot F Westermann S Mundlos HS Braun N Laing S Tinschert (2001) ArticleTitleHeterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia Nat Genet 28 37–41 Occurrence Handle11326272 Occurrence Handle1:CAS:528:DC%2BD3MXjt1Wqu78%3D

    PubMed  CAS  Google Scholar 

  25. T Sivula A Salminen AN Parfenyev P Pohjanjoki A Goldman BS Cooperman AA Baykov R Lahti (1999) ArticleTitleEvolutionary aspects of inorganic pyrophosphatase FEBS Lett 454 75–80 Occurrence Handle10413099 Occurrence Handle10.1016/S0014-5793(99)00779-6 Occurrence Handle1:CAS:528:DyaK1MXks1CrtLk%3D

    PubMed  Article  CAS  Google Scholar 

  26. KW Lam LC Lai PT Burkart LT Yam (1977) ArticleTitleKinetic properties of tartrate-resistant acid phosphatase isolated from human spleen with leukemic reticuloendotheliosis J Biol Chem 252 3371–3373 Occurrence Handle863887 Occurrence Handle1:CAS:528:DyaE2sXktlGjsLo%3D

    PubMed  CAS  Google Scholar 

  27. K Marshall K Nash G Haussman I Cassady D Hume J de Jersey S Hamilton (1997) ArticleTitleRecombinant human and mouse purple acid phosphatases: expression and characterization Arch Biochem Biophys 345 230–236 Occurrence Handle9308894 Occurrence Handle10.1006/abbi.1997.0250 Occurrence Handle1:CAS:528:DyaK2sXmtVKrtb4%3D

    PubMed  Article  CAS  Google Scholar 

  28. MP Whyte (1994) ArticleTitleHypophosphatasia and the role of alkaline phosphatase in skeletal mineralization Endocr Rev 15 439–461 Occurrence Handle7988481 Occurrence Handle10.1210/er.15.4.439 Occurrence Handle1:CAS:528:DyaK2cXmtVWqt70%3D

    PubMed  Article  CAS  Google Scholar 

  29. PS Henthorn MP Whyte (1992) ArticleTitleMissense mutations of the tissue-nonspecific alkaline phosphatase gene in hypophosphatasia Clin Chem 38 2501–2505 Occurrence Handle1360878 Occurrence Handle1:CAS:528:DyaK3sXnvVKnsg%3D%3D

    PubMed  CAS  Google Scholar 

  30. PA Siraganian JJ Mulvihill RA Mulivor RW Miller (1989) ArticleTitleBenign familial hyperphosphatasemia JAMA 261 1310–1312 Occurrence Handle2915457 Occurrence Handle10.1001/jama.261.9.1310 Occurrence Handle1:STN:280:BiaC38rosF0%3D

    PubMed  Article  CAS  Google Scholar 

  31. M Patel S Andronikou R Solomon P Sinclair M McCulloch (2004) ArticleTitleIdiopathic arterial calcification in childhood Pediatr Radiol 34 652–655 Occurrence Handle15029465 Occurrence Handle10.1007/s00247-004-1166-z

    PubMed  Article  Google Scholar 

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Correspondence to Chikahiko Numakura.

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Numakura, C., Yamada, M., Ariyasu, D. et al. Genetic and enzymatic analysis for two Japanese patients with idiopathic infantile arterial calcification. J Bone Miner Metab 24, 48–52 (2006). https://doi.org/10.1007/s00774-005-0645-0

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  • DOI: https://doi.org/10.1007/s00774-005-0645-0

Key words

  • idiopathic infantile arterial calcification (IIAC)
  • ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)
  • inorganic pyrophosphate