Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma

IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

See all formats and pricing
More options …
Volume 29, Issue 5


De novo mutation of PHEX in a type 1 diabetes patient

Chen Fang
  • Department of Endocrinology, 2nd Affiliated Hospital of Soochow University, Suzhou, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Hui Li / Xiaozhen Li
  • Department of Intensive Care Unit, 2nd Affiliated Hospital of Soochow University, Suzhou, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Wenjin Xiao
  • Department of Endocrinology, 2nd Affiliated Hospital of Soochow University, Suzhou, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Yun Huang
  • Department of Endocrinology, 2nd Affiliated Hospital of Soochow University, Suzhou, P.R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Wu Cai / Yi Yang / Ji Hu
  • Corresponding author
  • Department of Endocrinology, 2nd Affiliated Hospital of Soochow University, Suzhou, P.R. China
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-02-19 | DOI: https://doi.org/10.1515/jpem-2015-0399


A new missense mutation on the X chromosome (PHEX) at exon 4(c.442C>T) in a 4-generation Chinese Han pedigree is reported. The proband and four family members were clinically identified as the X-linked hypophosphatemic rickets (XLH) which is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. The proband is identified as hemizygous with the four female family members to be heterozygous genotypes. The discovery was made through the complete sequencing of the exons and the intron-exon boundaries of the PHEX gene of this family. The mutation caused the S141 residue to change to Phe from Ser which is perfectly conserved among humans, mice, rats, cows and chickens. PolyPhen-2 software analysis of the mutation indicated it was probably damaging. The proband was also diagnosed with type 1 diabetes (T1D) and the relationship between XLH and diabetes phenotypes was discussed in the paper.

Keywords: diabetes; mutation; PHEX; X-linked hypophosphatemic rickets


  • 1.

    Holm IA, Nelson AE, Robinson BG, Mason RS, Marsh DJ, et al. Mutational analysis and genotype-phenotype correlation of the PHEX gene in Xlinked hypophosphatemic rickets. J Clin Endocrinol Metab 2001;86:3889–99.Google Scholar

  • 2.

    Francis F, Henning S, Korn B, Reinhardt R, de Jong P, et al. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995;11:130–6.Google Scholar

  • 3.

    Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003;17:1656–63.Google Scholar

  • 4.

    Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemicrickets/osteomalacia. J Clin Endocrinol Metab 2002;87:4957–60.Google Scholar

  • 5.

    ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000;26:345–8.Google Scholar

  • 6.

    Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006;38:1310–5.Google Scholar

  • 7.

    Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010;86:273–8.Google Scholar

  • 8.

    Fukumoto S, Martin TJ. Bone as an endocrine organ. Trends Endocrinol Metab 2009;20:230–6.Google Scholar

  • 9.

    Vervloet MG, Massy ZA, Brandenburg VM, Mazzaferro S, Cozzolino M, et al. Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders. Lancet Diabetes Endocrinol 2014;2:427–36.Google Scholar

  • 10.

    Chen X, Tian HM, Pei FX, Yu XJ. Bone functions as a novel endocrine organ in energy metabolism. Chin Med J 2012;125:4117–21.Web of ScienceGoogle Scholar

  • 11.

    Garcia-Martin A, Reyes-Garcia R, Avila-Rubio V, Munoz-Torres M. Osteocalcin: a link between bone homeostasis and energy metabolism. Endocrinol Nutr 2013;60:260–3.Google Scholar

  • 12.

    Pi M, Quarles LD. Novel bone endocrine networks integrating mineral and energy metabolism. Curr Osteop Rep 2013;11:391–9.Web of ScienceGoogle Scholar

  • 13.

    Todd JA. Etiology of type 1 diabetes. Immunity 2010;32:457–67.Web of ScienceGoogle Scholar

  • 14.

    Lorenz-Depiereux B, Bastepe M, Benet-Pagès A, Amyere M, Wagenstaller J, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bonematrix protein in the regulation of phosphate homeostasis. Nat Genet 2006;38:1248–50.Google Scholar

  • 15.

    Larsson T, Yu X, Davis SI, Draman MS, Mooney SD, et al. A novel recessive mutation in fibroblast growth factor-23 causes familial tumoral calcinosis. J Clin Endocr Metab 2005;90:2424–7.Google Scholar

  • 16.

    Goji K, Ozaki K, Sadewa AH, Nishio H, Matsuo M. Clinical case seminar: somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait. J Clin Endocr Metab 2006;91:365–70.Google Scholar

  • 17.

    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9.Web of ScienceGoogle Scholar

  • 18.

    Sabbagh Y, Jones AO, Tenenhouse HS. PHEXdb, a locus-specific database for mutations causing X-linked hypophosphatemia. Hum Mutat 2000;16:1–6.Google Scholar

  • 19.

    Tyynismaa H, Kaitila I, Nanto-Salonen K, Ala-Houhala M, Alitalo T. Identification of fifteen novel PHEX gene mutations in Finnish patients with hypophosphatemic rickets. Hum Mutat 2000;15:383–4.Google Scholar

  • 20.

    Zou J, Xiong X, Lai B, Sun M, Tu X, et al. Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model. Sci China Life Sci 2015;58:359–67.Web of ScienceGoogle Scholar

  • 21.

    Muhlbauer RC, Fleisch H. Abnormal renal glucose handling in X-linked hypophosphataemic mice. Clin Sci (Lond) 1991;80:71–6.Google Scholar

  • 22.

    Capparelli AW, Roh D, Dhiman JK, Jo OD, Yanagawa N. Altered proximal tubule glucose metabolism in X-linked hypophosphatemic mice. Endocrinology 1992;130:328–34.Google Scholar

  • 23.

    Rifas L, Gupta A, Hruska KA, Avioli LV. Altered osteoblast gluconeogenesis in X-linked hypophosphatemic mice is associated with a depressed intracellular pH. Calcif Tissue Int 1995;57:60–3.Google Scholar

  • 24.

    Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, et al. X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults. Medicine 1989;68:336–52.Google Scholar

  • 25.

    Rosenthall L. EXA bone densitometry measurements in adults with X-linked hypophosphatemia. Clin Nucl Med 1993;D18:564–6.Google Scholar

  • 26.

    Beck-Nielsen SS, Brusgaard K, Rasmussen LM, Brixen K, Brock-Jacobsen B, et al. Phenotype presentation of hypophosphatemic rickets in adults. Calcif Tissue Int 2010;87:108–19.Google Scholar

  • 27.

    Marie PJ, Glorieux FH. Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. Metab Bone Dis Relat Res 1982;4:249–53.Google Scholar

About the article

Corresponding author: Ji Hu, Department of Endocrinology, 2nd Affiliated Hospital of Soochow University, Suzhou, 215004, P.R. China, E-mail:

aChen Fang, Hui Li and Xiaozhen Li: These authors contributed equally to this work.

Received: 2015-10-07

Accepted: 2015-12-14

Published Online: 2016-02-19

Published in Print: 2016-05-01

Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 29, Issue 5, Pages 621–626, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2015-0399.

Export Citation

©2016 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Yi Jiang, Zhongshan Li, Zhenwei Liu, Denghui Chen, Wanying Wu, Yaoqiang Du, Liying Ji, Zi-Bing Jin, Wei Li, and Jinyu Wu
Nucleic Acids Research, 2017, Volume 45, Number D1, Page D796

Comments (0)

Please log in or register to comment.
Log in