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Nine novel HOGA1 gene mutations identified in primary hyperoxaluria type 3 and distinct clinical and biochemical characteristics in Chinese children

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Abstract

Background

Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 patients are thought to present with a less severe phenotype than PH1 and PH2 patients. However, the clinical characteristics of PH3 patients have yet to be defined in sufficient detail. The aims of this study were to report HOGA1 mutations of PH3 in Chinese children, and to analyze the genotype and clinical characteristics of these PH3 patients.

Methods

Genetic analysis (targeted gene panel-based and/or whole-exome sequencing) of HOGA1 was performed in 52 patients with a high suspicion of PH3, and DNA was obtained from the patient and both the parents. The clinical, biochemical, and genetic data of these 12 patients identified with HOGA1 mutations were subsequently retrospectively reviewed.

Results

These 12 patients were identified with HOGA1 mutation. The median onset of clinical symptoms was 18.25 (range 5–38) months. In total, 14 different mutations were identified including 9 novel mutations in these 12 patients with PH3. All of these 12 patients initially presented with urolithiasis, and 3 patients among them comorbid urinary tract infection (UTI) as another initial symptom. Ten patients experienced hyperoxaluria (average oxalate 0.77 mmol/1.73 m2/24h). In contrast, urine calcium excretion was normal in 8 patients and 2 patients with hypercalciuria (urine calcium > 4 mg/kg/24 h). At the time of diagnosis, estimated GFR was 155.6 ml/min per 1.73 m2, and at last follow-up time (17.3 months later from diagnosis on average), estimated GFR was 157.5 ml/min per 1.73 m2. To date, none of the patients has impaired renal function based on and progressed to ESRD.

Conclusions

We found that PH3 was significantly diagnosed in our urolithiasis patients during childhood. Nine novel HOGA1 mutations were identified in association with PH3, which provide a first-line investigation in Chinese PH3 patients. The eGFR was normal in all children with PH3. This finding is in contrast to the early impairment of renal function in PH1 and PH2.

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Abbreviations

PH:

Primary hyperoxaluria

AGXT:

Alanine–glyoxylate aminotransferase

ESRD:

End-stage renal disease

GRHPR:

Glyoxylate reductase–hydroxypyruvate reductase

HOGA1:

4-Hydroxy-2-oxoglutarate aldolase

eGFR:

Estimated glomerular filtration rate

UTI:

Urinary tract infection

CaOx:

Calcium oxalate

CaPhos:

Calcium phosphate

References

  1. Harambat J, Fargue S, Bacchetta J, Acquaviva C, Cochat P (2011) Primary hyperoxaluria. Int J Nephrol 2011:864580

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 369:649–658

    Article  CAS  PubMed  Google Scholar 

  3. Hoppe B (2012) An update on primary hyperoxaluria. Nat Rev Nephrol 8:467–475

    Article  CAS  PubMed  Google Scholar 

  4. Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP (1999) The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet 8:2063–2069

    Article  CAS  PubMed  Google Scholar 

  5. Beck BB, Baasner A, Buescher A, Habbig S, Reintjes N, Kemper MJ, Sikora P, Mache C, Pohl M, Stahl M, Toenshoff B, Pape L, Fehrenbach H, Jacob DE, Grohe B, WolfMT NG, Yigit G, Salido EC, Hoppe B (2013) Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 21:162–172

    Article  CAS  PubMed  Google Scholar 

  6. Belostotsky R, Seboun E, Idelson GH, Milliner DS, Becker-Cohen R, Rinat C, Monico CG, Feinstein S, Ben-Shalom E, Magen D, Weissman I, Charon C, Frishberg Y (2010) Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet 87:392–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  8. Cochat P, Hulton S-A, Acquaviva C, Danpure CJ, Daudon M, Demarchi M, Fargue S, Groothoff J, Harambat J, Hoppe B, Jamieson NV, Kemper MJ, Mandrile G, Marangella M, Picca S, Rumsby G, Salido E, Straub M, van Woerden CS, OxalEurope: Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant 2012; 27:1729–1736

  9. Danpure CJ, Jennings PR (1986) Peroxisomal alanine: glyoxylate aminotransferase deficiency in primary hyperoxaluria type I. FEBS Lett 201:20–24

    Article  CAS  PubMed  Google Scholar 

  10. M'dimegh S, Aquaviva-Bourdain C, Omezzine A, Souche G, M'barek I, Abidi K, Gargah T, Abroug S, Bouslama A (2017) HOGA1 gene mutations of primary hyperoxaluria type 3 in Tunisian patients. J Clin Lab Anal 31(3):1–5. https://doi.org/10.1002/jcla.22053

    Article  CAS  Google Scholar 

  11. Williams EL, Bockenhauer D, van’t Hoff WG, Johri N, Laing C, Sinha MD, Unwin R, Viljoen A, Rumsby G (2012) The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. Nephrol Dial Transplant 27:3191–3195

    Article  CAS  PubMed  Google Scholar 

  12. Monico CG, Rossetti S, Belostotsky R, Cogal AG, Herges RM, Seide BM, Olson JB, Bergstrahl EJ, Williams HJ, Haley WE, Frishberg Y, Milliner DS (2011) Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. Clin J Am Soc Nephrol 6:2289–2295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jacob DE, Grohe B, Gessner M, Beck BB, Hoppe B (2013) Kidney stones in primary hyperoxaluria: new lessons learnt. PLoS One 8:e70617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Allard L, Cochat P, Leclerc AL, Cachat F, Fichtner C, De Souza VC, Garcia CD, Camoin-Schweitzer MC, Macher MA, Acquaviva-Bourdain C, Bacchetta J (2015) Renal function can be impaired in children with primary hyperoxaluria type 3. Pediatr Nephrol 30(10):1807–1813. https://doi.org/10.1007/s00467-015-3090-x

    Article  PubMed  Google Scholar 

  15. Xinsheng Wang, Xiangzhong Zhao, Xiaoling Wang, Jian Yao, Feifei Zhang, Yanhua Lang, Sylvie Tuffery-Giraud, Irene Bottillo, Leping Shao: Two novel HOGA1 splicing mutations identified in a Chinese patient with primary hyperoxaluria type 3. Am J Nephrol 2015;42:78–84.DOI: https://doi.org/10.1159/000439232

  16. Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, Lieske JC, Milliner DS, Harris PC (2015) Rare kidney stone consortium: phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 10:2559–2570

    Article  Google Scholar 

  17. Jiang D, Geng H (2017) Primary hyperoxaluria. N Engl J Med 376:e33. https://doi.org/10.1056/NEJMicm1609986

    Article  PubMed  Google Scholar 

  18. Greed L, Willis F, Johnstone L, Teo S, Belostotsky R, Frishberg Y, Pitt J (2018) Metabolite diagnosis of primary hyperoxaluria type 3. Pediatr Nephrol 33(8):1443–1446. https://doi.org/10.1007/s00467-018-3967-6

    Article  PubMed  Google Scholar 

  19. Richard E, Blouin JM, Harambat J, Llanas B, Bouchet S, Acquaviva C, de la Faille R (2017) Late diagnosis of primary hyperoxaluria type III. Ann Clin Biochem 54(3):406–411. https://doi.org/10.1177/0004563216677101

    Article  CAS  PubMed  Google Scholar 

  20. Pitt JJ, Willis F, Tzanakos N, Belostotsky R, Frishberg Y (2015) 4-Hydroxyglutamate is a biomarker for primary hyperoxaluria type 3. JIMD Rep 15:1–6

    PubMed  Google Scholar 

  21. Riedel TJ, Knight J, Murray MS, Milliner DS, Holmes RP, Lowther WT (2012) 4-Hydroxy-2-oxoglutarate aldolase inactivity in primary hyperoxaluria type 3 and glyoxylate reductase inhibition. Biochim Biophys Acta 1822:1544–1552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aronson LD, Rosso R, GAdams E. A constitutive aldolase for 4-hydroxy-2-ketoglutarate in soil bacteria. Biochim Biophys Acta 1967;132:200–203

    Article  CAS  Google Scholar 

  23. Ventzke A, Feldkötter M, Wei A, Becker J, Beck BB, Hoppe B (2017) Systematic assessment of urinary hydroxy-oxo-glutarate for diagnosis and follow-up of primary hyperoxaluria type III. Pediatr Nephrol 32(12):2263–2271. https://doi.org/10.1007/s00467-017-3731-3

    Article  PubMed  Google Scholar 

  24. Zhao F, Bergstralh EJ, Mehta RA, Vaughan LE, Olson JB, Seide BM, Meek AM, Cogal AG, Lieske JC, Milliner DS (2016) Predictors of incident ESRD among patients with primary hyperoxaluria presenting prior to kidney failure. Clin J Am Soc Nephrol 11(1):119–126

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We acknowledge the efforts of the entire clinical and non-clinical staff of the Department of Pediatric Urology, Xinhua Hospital, in identifying potential patients, and procuring and transporting the blood samples. We thank Dr. Yu Yongguo and his study group, Shanghai Institute for Pediatric Research, whose research has benefitted our patients and their families to a great extent.

Financial support and sponsorship

This study was supported by grants from the National Natural Scientific Foundation of China (81770702).

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Author notes

  1. Xiaoliang Fang and Lei He contributed equally to this work and should be regarded as joint first authors.

Authors and Affiliations

  1. Department of Pediatric Urology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 KongJiang Road, Shanghai, 200092, China

    Xiaoliang Fang, Lei He, Guofeng Xu, Houwei Lin, Maosheng Xu & Hongquan Geng

  2. Children’s Stone Treatment Center of National Health and Family Planning Commission of the People’s Republic of China, 1665 KongJiang Road, Shanghai, 200092, China

    Xiaoliang Fang, Lei He, Guofeng Xu, Houwei Lin, Maosheng Xu & Hongquan Geng

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  1. Xiaoliang Fang
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Correspondence to Hongquan Geng.

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Fang, X., He, L., Xu, G. et al. Nine novel HOGA1 gene mutations identified in primary hyperoxaluria type 3 and distinct clinical and biochemical characteristics in Chinese children. Pediatr Nephrol 34, 1785–1790 (2019). https://doi.org/10.1007/s00467-019-04279-7

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