Two novel AGXT mutations identified in primary hyperoxaluria type-1 and distinct morphological and structural difference in kidney stones

Cui Wang, Jingru Lu, Yanhua Lang, Ting Liu, Xiaoling Wang, Xiangzhong Zhao, Leping Shao, Cui Wang, Jingru Lu, Yanhua Lang, Ting Liu, Xiaoling Wang, Xiangzhong Zhao, Leping Shao

Abstract

Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive oxalate accumulation in plasma and urine, resulting in various phenotypes because of allelic and clinical heterogeneity. This study aimed to detect disease-associated genetic mutations in three PH1 patients in a Chinese family. All AGXT exons and 3 common polymorphisms which might synergistically interact with mutations, including P11L, I340 M and IVSI+74 bp were analyzed by direct sequencing in all family members. It demonstrated that in each of three patients, a previously reported nonsense mutation p.R333(*) was in cis with a novel missense mutation p.M49L in the minor allele characterized by the polymorphism of 74-bp duplication in intron 1, while the other novel missense mutation p.N72I was in trans with both p.R333(*) and P.M49L in the major allele. Kidney stones from two sibling patients were also observed though stereomicroscopic examination and scanning electron microscopy. Distinct morphological and inner-structure differences in calculi were noticed, suggesting clinical heterozygosity of PH1 to a certain extent. In brief, two novel missense mutations were identified probably in association with PH1, a finding which should provide an accurate tool for prenatal diagnosis, genetic counseling and screening for potential presymptomatic individuals.

Figures

Figure 1. Pedigree of the Chinese family…
Figure 1. Pedigree of the Chinese family with Primary hyperoxaluria type 1.
□, male; ○, female; ↗, proband.
Figure 2. CT scanning at different stages…
Figure 2. CT scanning at different stages of three Chinese siblings of IIa, IIe and IIf with Primary Hyperoxaluria Type 1.
(A–C) CT scanning of bilateral kidneys of proband IIa; (D–H) CT scanning of bilateral kidneys of sibling IIe; (I) CT scanning of bilateral kidneys of sibling IIf.
Figure 3. Three AGXT mutations identified in…
Figure 3. Three AGXT mutations identified in the Chinese family with Primary Hyperoxaluria Type 1.
(A) wild type(left panel) and heterozygous mutant type (right panel) of p.M49L; (B) wild type(left panel) and heterozygous mutant type (right panel) of p.N72I; (C) wild type(left panel) and heterozygous mutant type (right panel) of p.R333*. Mutation naming and description rules refer to the latest guideline published by Human Genome Variation Society (http://www.hgvs.org/mutnomen/recs.html). AGXT-mRNA (NM_000030) starts from the first base of the first codon.
Figure 4. Morphologic characteristics of Calcium Oxalate…
Figure 4. Morphologic characteristics of Calcium Oxalate Monohydrate stones from two Chinese siblings with Primary Hyperoxaluria Type 1.
Panels (A,B) show stone surfaces on stereomicroscopic examination (×10), and Panels (C,D) show the sections on scanning electron microscopy. The stones of both siblings had light-brown surfaces. Stones from sibling IIa showed irregular in shape, ununiformity in size, and inhomogeneous internal structures with the aggregations of various sizes and dimensions plate-like crystals (A,C); In contrast, the stones from IIf had smooth surface, regular shape, well-organized geometric cross sections with more compact and radiating inner structure (B,D).

References

    1. Kanoun H. et al.. A double mutation in AGXT gene in families with primary hyperoxaluria type 1. Gene. 531, 451–456 (2013).
    1. Hoppe B., Beck B. B. & Milliner D. S. The primary hyperoxalurias. Kidney Int. 75, 1264–1271 (2009).
    1. Oppici E. et al.. Biochemical analyses are instrumental in identifying the impact of mutations on holo and/or apo-forms and on the region(s) of alanine: glyoxylate aminotransferase variants associated with Primary Hyperoxaluria Type I. Mol Genet Metab. 105, 132–140 (2012).
    1. Cregeen D. P., Williams E. L., Hulton S. & Rumsby G. Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. Hum Mutat. 22, 497–506 (2003).
    1. Hopp K. et al.. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol. 26, 2559–2570 (2015).
    1. Wang X. et al.. Two Novel HOGA1 Splicing Mutations Identified in a Chinese Patient with Primary Hyperoxaluria Type 3. Am J Nephrol. 42, 78–84 (2015).
    1. Purdue P. E. et al.. Characterization and chromosomal mapping of a genomic clone encoding human alanine: glyoxylate aminotransferase. Genomics. 10, 34–42 (1991).
    1. Nagara M. et al.. Mutation spectrum of primary hyperoxaluria type 1 in Tunisia: implication for diagnosis in North Africa. Gene. 15, 527 (2013).
    1. Pierre C. et al.. Primary hyperoxaluria. Nephrol Ther. 7(4), 249–259 (2011).
    1. Fargue S., Lewin J., Rumsby G., Danpure C. J. Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele. J Biol Chem. 288(4), 2475–2484 (2013).
    1. Danpure C. J., Cooper P. J., Wise P. J. & Jennings P. R. An enzyme trafficking defect in two patients with primary hyperoxaluria type 1: peroxisomal alanine/glyoxylate aminotransferase rerouted to mitochondria. J Cell Biol. 108(4), 1345–1352 (1989).
    1. Danpure C. J., Jennings P. R., Fryer P., Purdue P. E. & Allsop J. Primary hyperoxaluria type1: genotypic and phenotypic heterogeneity. J Inherit Metab Dis. 17, 487–499 (1994).
    1. Lumb M. J. & Danpure C. J. Functional synergism between the most common polymorphism in human alanine: glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 275, 36415–36422 (2000).
    1. Alfadhel M., Alhasan K. A., Alotaibi M. & Al Fakeeh K. Extreme intrafamilial variability of Saudi brothers with primary hyperoxaluria type 1. The Clin Risk Manag. 8, 373–376 (2012).
    1. Williams E. L. et al.. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum Mutat. 30, 910–917 (2009).
    1. Daudon M., Jungers P. & Bazin D. Peculiar morphology of stones in primary hyperoxaluria. N Engl J Med. 359, 100–102 (2008).
    1. Al Riyami M. S., Al Ghaithi B., Al Hashmi N. & Al Kalbani N. Primary hyperoxaluria type 1 in 18 children: genotyping and outcome. Int J Nephrol. (2015).
    1. Mandrile G. et al.. Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int. 86(6), 1197–1204 (2014).
    1. Rumsby G. Primary Hyperoxaluria Mutation Database. Accessed July 23, 2016. (2013).
    1. Grases F., Söhnel O., García-Ferragut L. & Costa-Bauzá A. A study on calcium oxalate monohydrate renal uroliths. II. Fine inner structure. Scand J Urol Nephrol. 29, 421–428 (1995).
    1. Zhang X. et al.. Crystal structure of alanine: glyoxylate aminotransferase and the relationship between genotype and enzymatic phenotype in Primary Hyperoxaluria Type 1. J Mol Biol. 331, 643–652 (2003).
    1. Montioli R. et al.. Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine: glyoxylate aminotransferase and chaperoning activity of pyridoxine. Biochim Biophys Acta. 1854(10)Pt A, 1280–1289 (2015).
    1. Lage M. D., Pittman A. M., Roncador A., Cellini B. & Tucker C. L. Allele-specific Characterization of Alanine: Glyoxylate Aminotransferase Variants Associated with Primary Hyperoxaluria. PLoS One. 9(4), e94338 (2014).
    1. Ségurel L., Lafosse S., Heyer E. & Vitalis R. Frequency of the AGT Pro11Leu polymorphism in humans: Does diet matter? Ann Hum Genet. 74, 57–64 (2010).
    1. Boualla L. et al.. AGXT Gene Mutations and Prevalence of Primary Hyperoxaluria Type 1 in Moroccan Population. Genet Test Mol Biomarkers. 19(11), 623–628 (2015).
    1. Coulter-Mackie M. B., Tung A., Henderson H. E., Toone J. R. & Applegarth D. A. The AGXT gene in Africa: a distinctive minor allele haplotype, a polymorphism (V326I), and a novel PH1 mutation (A112D) in Black Africans. Mol Genet Metab. 78(1), 44–50 (2003).
    1. Purdue P. E., Lumb M. J., Allsop J. & Danpure C. J. An intronic duplication in the alanine: glyoxylate aminotransferase gene facilitates identification of mutations in compound heterozygote patients with primary hyperoxaluria type 1. Hum Genet. 87(4), 394–396 (1991).
    1. Cellinni B. et al.. Molecular defects of the glycine 41 variants of alanine glyoxylate aminotransferase associated with primary hyperoxaluria type 1. Proc Natl Acad Sci USA 107(7), 2896–2901 (2010).
    1. Fargue S., Rumsby G. & Danpure C. J. Multiple mechanisms of action of pyridoxine in Primary Hyperoxaluria Type 1. Biochim Biophys Acta. 1832, 1776–1783 (2013).
    1. Cellini B., Montioli R. & Voltattorni C. B. Human liver peroxisomal alanine: glyoxylate aminotransferase: Characterization of the two allelic forms and their pathogenic variants. Biochim Biophys Acta. 1814, 1577–1584 (2011).
    1. Kurt-Sukur E. D. et al.. Primary Hyperoxaluria Type 1: A Cause for Infantile Renal Failure and Massive Nephrocalcinosis. Klin Padiatr. 227(5), 293–295 (2015).
    1. Chutipongtanate S., Sutthimethakorn S., Chiangjong W. & Thongboonkerd V. Bacteria can promote calcium oxalate crystal growth and aggregation. Biol Inorg Chem. 18, 299–308 (2013).
    1. Monico C. G., Rossetti S., Olson J. B. & Milliner D. S. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int. 67, 1704–1709 (2005).
    1. Cellini B. et al.. The chaperone role of the pyridoxal 5′-phosphate and its implications for rare diseases involving B6-dependent enzymes. Clin Biochem. 47, 158–165 (2014).
    1. Clayton P. T B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis. 29, 317–326 (2014).
    1. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol. 8, 467–475 (2012).
    1. Narasimhan G. et al.. Preserving double equipoise in living donor liver-kidney transplantation for primary hyperoxaluria type 1. Liver Transpl. 21(10), 1324–1326 (2015).
    1. Monico C. G. et al.. Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J Am Soc Nephrol. 18, 1905–1914 (2007).
    1. Grantham R. Amino acid difference formula to help explain protein evolution. Science. 185, 862–864 (1974).
    1. Abkevich V. et al.. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 41, 492–507 (2004).

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