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PLOS ONE  2014 

Identification of Two Novel Mutations in the PHEX Gene in Chinese Patients with Hypophosphatemic Rickets/Osteomalacia

DOI: 10.1371/journal.pone.0097830

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Objective X-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia. Methods For this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced. Results The PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls. Conclusions Our study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.


[1]  Rowe PS (1994) Molecular biology of hypophosphataemic rickets and oncogenic osteomalacia. Hum Genet 94: 457–467. doi: 10.1007/bf00211008
[2]  Rowe PS, Oudet CL, Francis F, Sinding C, Pannetier S, et al. (1997) Distribution of mutations in the PHEX gene in families with X-linked hypophosphataemic rickets (HYP). Hum Mol Genet 6: 539–549. doi: 10.1093/hmg/6.4.539
[3]  Rowe PS (1998) The role of the PHEX gene (PEX) in families with X-linked hypophosphataemic rickets. Curr Opin Nephrol Hypertens 7: 367–376. doi: 10.1097/00041552-199807000-00004
[4]  Quarles LD, Drezner MK (2001) Pathophysiology of X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemia: a perPHEXing problem. J Clin Endocrinol Metab 86: 494–496. doi: 10.1210/jc.86.2.494
[5]  Albright F, Butler A, Bloomberg E (1939) Rickets resistant to vitamin D therapy. American Journal of Disease of Children 54: 529–547.
[6]  Davies M, Stanbury SW (1981) The rheumatic manifestations of metabolic bone disease. Clinics in Rheumatic Disease 7: 595–646.
[7]  Beck-Nielsen SS, Brock-jacobsen B, Gram J, Brixen K, Jensen TK (2009) Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol 160: 491–497. doi: 10.1530/eje-08-0818
[8]  Ruppe MD, Brosnan PG, Au KS, Tran PX, Dominguez BW, et al. (2011) Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. Clin Endocrinol (Oxf) 74: 312–318. doi: 10.1111/j.1365-2265.2010.03919.x
[9]  Quinlan C, Guegan K, Offiah A, Neill RO, Hiorns MP, et al. (2012) Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephro 27: 581–588. doi: 10.1007/s00467-011-2046-z
[10]  Clausmeyer S, Hesse V, Clemens PC, Engelbach M, Kreuzer M, et al. (2009) Mutational analysis of the PHEX gene: novel point mutations and detection of large deletions by MLPA in patients with X-linked hypophosphatemic rickets. Calcif Tissue Int 85: 211–220. doi: 10.1007/s00223-009-9260-8
[11]  Francis F, Strom TM, Hennig S, Boddrich A, Lorenz B, et al. (1997) Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. Genome Res 7: 573–585.
[12]  Du L, Desbarats M, Viel J, Glorieux FH, Cawthorn C, et al. (1996) cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone. Genomics 36: 22–28. doi: 10.1006/geno.1996.0421
[13]  Thompson DL, Sabbagh Y, Tenenhouse HS, Roche PC, Drezner MK, et al. (2002) Ontogeny of Phex/PHEX protein expression in mouse embryo and subcellular localization in osteoblasts. J Bone Miner Res 17: 311–320. doi: 10.1359/jbmr.2002.17.2.311
[14]  Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (2008) MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 23: 1638–1649. doi: 10.1359/jbmr.080601
[15]  Yang L, Yang J, Huang X (2013) PHEX gene mutation in a Chinese family with six cases of X-linked hypophosphatemic rickets. J Pediatr Endocrinol Metab 26: 1179–1183.
[16]  Xia W, Meng X, Jiang Y, Li M, Xing X, et al. (2007) Three Novel Mutations of the PHEX Gene in Three Chinese Families with X-linked Dominant Hypophosphatemic Rickets. Calcif Tissue Int 81: 415–420. doi: 10.1007/s00223-007-9067-4
[17]  Lo FS, Kuo MT, Wang CJ, Chang CH, Lee ZL, et al. (2006) Two novel PHEX mutations in Taiwanese patients with X-linked hypophosphatemic rickets. Nephron Physiol 103: 157–163. doi: 10.1159/000092916
[18]  Kang QL, Xu J, Zhang Z, He JW, Lu LS, et al. (2012) Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets. Biochem Biophys Res Commun 423: 793–798. doi: 10.1016/j.bbrc.2012.06.042
[19]  Jap TS, Chiu CY, Niu DM, Levine MA (2011) Three novel mutations in the PHEX gene in Chinese subjects with hypophosphatemic rickets extends genotypic variability. Calcif Tissue Int 88: 370–377. doi: 10.1007/s00223-011-9465-5
[20]  Qiu G, Liu C, Zhou J, Liu P, Wang J, et al. (2010) Prenatal diagnosis for a novel splice mutation of PHEX gene in a large Han Chinese family affected with X-linked hypophosphatemic rickets. Genet Test Mol Biomarkers 14: 385–91. doi: 10.1089/gtmb.2009.0175
[21]  Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249. doi: 10.1038/nmeth0410-248
[22]  Sunyaev S, Ramensky V, Bork P (2000) Towards a structural basis of human non-synonymous single nucleotide polymorphisms. Trends Genet 16: 198–200. doi: 10.1016/s0168-9525(00)01988-0
[23]  Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, et al. (2012) Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 44: 1249–1254. doi: 10.1038/ng.2421
[24]  Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, et al. (2012) Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. Bone 52: 286–291. doi: 10.1016/j.bone.2012.10.012
[25]  Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31: 3812–3814. doi: 10.1093/nar/gkg509
[26]  Filisetti D, Ostermann G, von Bredow M, Strom T, Filler G, et al. (1999) Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues. Eur J Hum Genet 7: 615–619. doi: 10.1038/sj.ejhg.5200341
[27]  Makova KD, Li WH (2002) Strong male-driven evolution of DNA sequences in humans and apes. Nature 416: 624–626. doi: 10.1038/416624a
[28]  Goetting-Minesky MP, Makova KD (2006) Mammalian male mutation bias: impacts of generation time and regional variation in substitution rates. J Mol Evol 63: 537–544. doi: 10.1007/s00239-005-0308-8
[29]  Zhu X, Li M, Pan H, Bao X, Zhang J, et al. (2010) Analysis of the parental origin of de novo MECP2 mutatiopns and X chromosome inactivation in 24 sporadic patients with Rett syndrome in China. J Child Neurol 25: 842–848. doi: 10.1177/0883073809350722
[30]  Beck-Nielsen SS1, Brixen K, Gram J, Brusgaard K (2012) Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet. 57: 453–458. doi: 10.1038/jhg.2012.56


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