Advertisement

Current Medical Science

, Volume 38, Issue 5, pp 749–757 | Cite as

Updated Genetic Testing of Primary Hyperoxaluria Type 1 in a Chinese Population: Results from a Single Center Study and a Systematic Review

  • Dun-feng Du
  • Qian-qian Li
  • Chen Chen
  • Shu-mei Shi
  • Yuan-yuan Zhao
  • Ji-pin Jiang
  • Dao-wen Wang
  • Hui Guo
  • Wei-jie ZhangEmail author
  • Zhi-shui ChenEmail author
Article
  • 48 Downloads

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare but devastating autosomal recessive inherited disease caused by mutations in gene AGXT. Pathogenic mutations of AGXT were mostly reported in Caucasian but infrequently in Asian, especially in Chinese. To update the genotypes of PH1 in the Chinese population, we collected and identified 7 Chinese probands with PH1 from 2013 to 2017 in our center, five of whom had delayed diagnosis and failed in kidney transplantation. Samples of peripheral blood DNA from the 7 patients and their family members were collected and sequencing analysis was performed to test the mutations of gene AGXT. Western blotting and enzyme activity analysis were conducted to evaluate the function of the mutations. Furthermore, a systematic review from 1998 to 2017 was performed to observe the genetic characteristics between Chinese and Caucasian. The results showed that a total of 12 mutations were identified in the 7 pedigrees. To the best of our knowledge, 2 novel variants of AGXT, p.Gly41Trp and p.Leu33Met, were first reported. Bioinformatics and functional analysis showed that only 7 mutations led to a reduced expression of alanine-glyoxylate amino transferase (AGT) at a protein level. The systematic review revealed significant population heterogeneity in PH1. In conclusion, new genetic subtypes and genetic characteristics of PH1 are updated in the Chinese population. Furthermore, a genotype-phenotype correlation is found in PH1.

Key words

primary hyperoxaluria type 1 gene sequencing AGXT Chinese population 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol, 2012,8(8):467–475CrossRefGoogle Scholar
  2. 2.
    Hopp K, Cogal AG, Bergstralh EJ, et al. Phenotypegenotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol, 2015,26(10):2559–2570CrossRefGoogle Scholar
  3. 3.
    Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med, 2013,369(7):649–658CrossRefGoogle Scholar
  4. 4.
    Purdue PE, Lumb MJ, Fox M, et al. Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase. Genomics, 1991,10(1):34–42CrossRefGoogle Scholar
  5. 5.
    Pelle A, Cuccurullo A, Mancini C, et al. Updated genetic testing of Italian patients referred with a clinical diagnosis of primary hyperoxaluria. J Nephrol, 2017,30(2):219–225CrossRefGoogle Scholar
  6. 6.
    Toussaint C. Pyridoxine-responsive PH1: treatment. J Nephrol, 1998, 11(Suppl):49–50Google Scholar
  7. 7.
    van Woerden CS, Groothoff JW, Wijburg FA, et al. Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int, 2004,66(2):746–752CrossRefGoogle Scholar
  8. 8.
    Monico CG, Rossetti S, Olson JB, et al. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int, 2005,67(5):1704–1709CrossRefGoogle Scholar
  9. 9.
    Fargue S, Rumsby G, Danpure CJ. Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1. Biochim Biophys Acta, 2013, 1832(10):1776–1783CrossRefGoogle Scholar
  10. 10.
    Cochat P, Hulton SA, Acquaviva C, et al. Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant, 2012,27(5):1729–1736CrossRefGoogle Scholar
  11. 11.
    Beck BB, Hoyer-Kuhn H, Gobel H, et al. Hyperoxaluria and systemic oxalosis: an update on current therapy and future directions. Expert Opin Investig Drugs, 2013,22(1):117–129CrossRefGoogle Scholar
  12. 12.
    Hoppe B. Evidence of true genotype-phenotype correlation in primary hyperoxaluria type 1. Kidney Int, 2010,77(5):383–385CrossRefGoogle Scholar
  13. 13.
    Wang F, Xu CQ, He Q, et al. Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nat Genet, 2011,43(4):345–349CrossRefGoogle Scholar
  14. 14.
    Michele Petrarulo SP, Marangella M, Cosseddu D, et al. High-performance liquid chromatographic microassay for L-alanine: glyoxylate aminotransferase activity in human liver. Clin Chim Acta, 1992, 208(3) 183–192CrossRefGoogle Scholar
  15. 15.
    Barbara Cellini MB, Montioli R, Paiardini A, et al. Human wild-type alanine:glyoxylate aminotransferase and its naturally occurring G82E variant: functional properties and physiological implications. Biochem J, 2007,408(1):39–50CrossRefGoogle Scholar
  16. 16.
    Williams E, Rumsby G. Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1. Clin Chem, 2007,53(7):1216–1221CrossRefGoogle Scholar
  17. 17.
    Rumsby G, Williams E, Coulter-Mackie M. Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int, 2004, 66(3):959–963CrossRefGoogle Scholar
  18. 18.
    Monico CG, Rossetti S, Schwanz HA, et al. Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J Am Soc Nephrol, 2007,18(6):1905–1914CrossRefGoogle Scholar
  19. 19.
    Takada Y, Kaneko N, Esumi H, et al. Human peroxisomal L-alanine: glyoxylate aminotransferase. Evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon. Biochem J, 1990,268(2):517–520CrossRefGoogle Scholar
  20. 20.
    Robbiano A, Frecer V, Miertus J, et al. Modeling the effect of 3 missense AGXT mutations on dimerization of the AGT enzyme in primary hyperoxaluria type 1. J Nephrol, 2010,23(6):667–676Google Scholar
  21. 21.
    Jagadeesh KA, Wenger AM, Berger MJ, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet, 2016,48(12):1581–1586CrossRefGoogle Scholar

Copyright information

© Huazhong University of Science and Technology 2018

Authors and Affiliations

  • Dun-feng Du
    • 1
    • 2
  • Qian-qian Li
    • 3
  • Chen Chen
    • 4
  • Shu-mei Shi
    • 3
  • Yuan-yuan Zhao
    • 1
    • 2
  • Ji-pin Jiang
    • 1
    • 2
  • Dao-wen Wang
    • 4
  • Hui Guo
    • 1
    • 2
  • Wei-jie Zhang
    • 1
    • 2
    Email author
  • Zhi-shui Chen
    • 1
    • 2
    Email author
  1. 1.Institute of Organ TransplantationHuazhong University of Science and TechnologyWuhanChina
  2. 2.Key Laboratory of Organ TransplantationMinistry of Health/EducationWuhanChina
  3. 3.Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome ResearchHuazhong University of Science and TechnologyWuhanChina
  4. 4.Institute of Hypertension, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations