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GENETIC CODES OF X-LINKED HYPOPHOSPHATEMIA

Year 2020, Volume: 83 Issue: S-1, 17 - 20, 13.05.2020

Abstract

X-linked hypophosphatemia (XLH, OMIM 307800) is the most common form of hereditary rickets and it is an X-linked dominantly inherited disorder. Loss of function mutations in the PHEX (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome) gene are responsible for XLH. These mutations in the PHEX gene cause an elevation in FGF23 levels via an unknown mechanism. The first mutation in the PHEX gene was identified in 1955 and since then 467 different causal mutations have been identified. Mutations in the PHEX gene are distributed across all coding exons and exon-intron boundaries and there is no specific mutation hotspot in the gene. A genotype-phenotype correlation has not been well established. PHEX mutation screening is performed in a two-tier strategy. Sequencing of the coding exons and exon-intron boundaries can detect 85% of all causal mutations. Deletions/duplications are responsible for the remaining mutations and the MLPA (Multiple Ligation dependent Probe Amplification) method must be used in order to detect these mutations. Sibling/family screening is important in order to diagnose cases who have a high risk of developing XLH.

References

  • 1. Zhang C, Zhao Z, Sun Y, Xu L, JiaJue R, Cui L, et al. Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia. Bone 2019;121:212-20.
  • 2. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429-35.
  • 3. Acar S, Demir K, Shi Y. Genetic Causes of Rickets. J Clin Res Pediatr Endocrinol 2017;9:88-105.
  • 4. Guven A, Al-Rijal RA, Binessa H, Dogan D, Kor Y, Zou M, et al.Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets. Clin Endocrinol (Oxf) 2017;87:103-12.
  • 5. Şıklar Z, Turan S, Bereket A, Baş F, Güran T, Akberzade A, et al.Nationwide Hypophosphatemic Rickets Cohort Study. JCRPE 2019.
  • 6. Bitzan M, Goodyer PR. Hypophosphatemic Rickets. Pediatr Clin N Am 2019;66:179-207.
  • 7. Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, Bircan I, et al. Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. Bone 2013;52:286-91.
  • 8. Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity Orphanet Journal of Rare Diseases 2019;14:58.
  • 9. Owen JC, Habeb A, Pearce SH, Wright M, Ichikawa S, Sorenson AH, et al. Discordance of X linked hypophosphatemic rickets in identical twin girls. Horm Res, 2009;71:237-44.
  • 10. Sabbagh Y, Boileau G, DesGroseillers L, Tenenhouse HS. Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein. Hum Mol Genet 2001;10:1539-46.
  • 11. Popowska E, Pronicka E, Sułek A, Jurkiewicz D, Rowińska E, Sykut-Cegielska J, et al. J Appl Genet 2001;42(1):73-88.
  • 12. Song HR, Park JW, Cho DY, Yang JH, Yoon HR, Jung SC. PHEX gene mutations and genotype-phenotype analysis of Korean patients with hypophosphatemic rickets. J Korean Med Sci 2007;22:981-6.

X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI

Year 2020, Volume: 83 Issue: S-1, 17 - 20, 13.05.2020

Abstract

X’e bağlı hipofosfatemi (XLH, OMIM 307800) kalıtsal raşitizmin en sık gözlenen formudur ve X’e bağlı dominant bir kalıtım şekli gösterir. Hastalığın genetik temelini PHEX (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome) genindeki fonksiyon kaybettirici mutasyonlar oluşturur. PHEX genindeki bu mutasyonlar, henüz bilinmeyen bir mekanizmayla FGF23’ün aşırı üretimine neden olur. Bu gendeki mutasyonlar X’e bağlı dominant olarak kalıtılır. PHEX genindeki ilk mutasyon 1955 yılında tanımlanmıştır ve o günden günümüze kadar hastalıkla ilgili toplam 467 farklı mutasyon bildirilmiştir. PHEX genindeki mutasyonlar gen boyunca dağınık olarak bulunurlar ve herhangibir mutasyon sıcak noktası bulunmamaktadır. XLH’de belirgin bir genotip-fenotip korelasyonu bulunmamaktadır. XLH’de PHEX mutasyon taraması iki basamaklı yapılmalıdır. Öncelikle dizi analizi yöntemi ile nokta mutasyonlar araştırılmalıdır. Tüm olguların yaklaşık %15’inde dizi analizi yöntemi ile saptanamayan büyük delesyon/duplikasyonlar bulunmaktadır ve bu mutasyonlar MLPA (Multiple Ligation dependent Probe Amplification) yöntemi ile taranmalıdır. Mutasyon saptanan olguların ailelerinde kardeş/aile taraması yapılması erken tanı için oldukça önemlidir.

References

  • 1. Zhang C, Zhao Z, Sun Y, Xu L, JiaJue R, Cui L, et al. Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia. Bone 2019;121:212-20.
  • 2. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429-35.
  • 3. Acar S, Demir K, Shi Y. Genetic Causes of Rickets. J Clin Res Pediatr Endocrinol 2017;9:88-105.
  • 4. Guven A, Al-Rijal RA, Binessa H, Dogan D, Kor Y, Zou M, et al.Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets. Clin Endocrinol (Oxf) 2017;87:103-12.
  • 5. Şıklar Z, Turan S, Bereket A, Baş F, Güran T, Akberzade A, et al.Nationwide Hypophosphatemic Rickets Cohort Study. JCRPE 2019.
  • 6. Bitzan M, Goodyer PR. Hypophosphatemic Rickets. Pediatr Clin N Am 2019;66:179-207.
  • 7. Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, Bircan I, et al. Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. Bone 2013;52:286-91.
  • 8. Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity Orphanet Journal of Rare Diseases 2019;14:58.
  • 9. Owen JC, Habeb A, Pearce SH, Wright M, Ichikawa S, Sorenson AH, et al. Discordance of X linked hypophosphatemic rickets in identical twin girls. Horm Res, 2009;71:237-44.
  • 10. Sabbagh Y, Boileau G, DesGroseillers L, Tenenhouse HS. Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein. Hum Mol Genet 2001;10:1539-46.
  • 11. Popowska E, Pronicka E, Sułek A, Jurkiewicz D, Rowińska E, Sykut-Cegielska J, et al. J Appl Genet 2001;42(1):73-88.
  • 12. Song HR, Park JW, Cho DY, Yang JH, Yoon HR, Jung SC. PHEX gene mutations and genotype-phenotype analysis of Korean patients with hypophosphatemic rickets. J Korean Med Sci 2007;22:981-6.
There are 12 citations in total.

Details

Primary Language Turkish
Subjects Health Care Administration
Journal Section Reviews
Authors

Hüseyin Onay This is me 0000-0002-0584-8866

Publication Date May 13, 2020
Submission Date March 11, 2020
Published in Issue Year 2020 Volume: 83 Issue: S-1

Cite

APA Onay, H. (2020). X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI. Journal of Istanbul Faculty of Medicine, 83(S-1), 17-20.
AMA Onay H. X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI. İst Tıp Fak Derg. May 2020;83(S-1):17-20.
Chicago Onay, Hüseyin. “X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI”. Journal of Istanbul Faculty of Medicine 83, no. S-1 (May 2020): 17-20.
EndNote Onay H (May 1, 2020) X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI. Journal of Istanbul Faculty of Medicine 83 S-1 17–20.
IEEE H. Onay, “X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI”, İst Tıp Fak Derg, vol. 83, no. S-1, pp. 17–20, 2020.
ISNAD Onay, Hüseyin. “X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI”. Journal of Istanbul Faculty of Medicine 83/S-1 (May 2020), 17-20.
JAMA Onay H. X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI. İst Tıp Fak Derg. 2020;83:17–20.
MLA Onay, Hüseyin. “X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI”. Journal of Istanbul Faculty of Medicine, vol. 83, no. S-1, 2020, pp. 17-20.
Vancouver Onay H. X’E BAĞLI HİPOFOSFATEMİ (XLH) VE GENETİK KODLARI. İst Tıp Fak Derg. 2020;83(S-1):17-20.

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