Auxiliary genetic analysis in a Chinese adolescent NPH family by single nucleotide polymorphism screening

Tang,Chunrong; Zhou,Daoyuan; Tan,Rongshao; Zhong,Xiaoshi; Xiao,Xiao; Qin,Danping; Liu,Yun; Hu,Jianguang; Liu,Yan

doi:10.3892/mmr.2020.10917

Auxiliary genetic analysis in a Chinese adolescent NPH family by single nucleotide polymorphism screening

Authors:
- Chunrong Tang
- Daoyuan Zhou
- Rongshao Tan
- Xiaoshi Zhong
- Xiao Xiao
- Danping Qin
- Yun Liu
- Jianguang Hu
- Yan Liu
View Affiliations

Affiliations: Department of Nephrology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
Published online on: January 8, 2020 https://doi.org/10.3892/mmr.2020.10917
Pages: 1115-1124
Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hereditary nephropathy is a progressive fatal renal disease caused by genetic changes. In this study, genetic screening was used to reveal mutations in a family in Southern China, in which there are two patients with confirmed hereditary nephropathy, who are alive at the time of publication. Imaging tests, including color Doppler ultrasonography and magnetic resonance imaging (MRI), as well as pathological examinations, including hematoxylin‑eosin staining, electron microscopy and immunohistochemistry were performed. Target sequencing of nephrosis 2 (NPHS2), wilms tumor 1 (WT1), phospholipase C ε 1 (PLCE1), actinin α 4 (ACTN4), angiotensin I converting enzyme (ACE), uromodulin (UMOD) and nephrocystin 1 (NPHP1) was also carried out. This study indicated that heterozygous genetic variants of NPHS2, WT1, ACTN4, PLCE1 and UMOD found in the patients were gene polymorphisms. A renal biopsy showed sclerosing glomerulonephritis, dilated tubules and lymphocyte/monocyte infiltration in the interstitium of the index patients. Genetic analysis showed vertical transmission of the disease‑causing mutations, including a homozygous deletion in NPHP1 and a nonsense mutation in ACE found via PCR‑based single nucleotide polymorphism screening. Further network analysis identified direct and indirect co‑location genes between NPHP1 and ACE. To conclude, familial adolescent nephronophthisis was diagnosed in two index patients in this study. It is recommended that comprehensive gene mutation screening is used in the diagnosis of complex hereditary diseases.

View Figures

View References

1	Tianjun G, Zhihong L, Zhaohong C, Wweixin H, XIiaodan Y and Zheng T: Association studies of gene polymorphism in lupus nephritis. Chin J Nephrol Dial Transplant. 5–10. 100:1997.
2	Sharif B and Barua M: Advances in molecular diagnosis and therapeutics in nephrotic syndrome and focal and segmental glomerulosclerosis. Curr Opin Nephrol Hypertens. 27:194–200. 2018. View Article : Google Scholar : PubMed/NCBI
3	Hou JH, Zhu HX, Zhou ML, Le WB, Zeng CH, Liang SS, Xu F, Liang DD, Shao SJ, Liu Y and Liu ZH: Changes in the spectrum of kidney diseases: An analysis of 40,759 biopsy-proven cases from 2003 to 2014 in China. Kidney Dis (Basel). 4:10–19. 2018. View Article : Google Scholar : PubMed/NCBI
4	Sperry ZJ, Na K, Parizi SS, Chiel HJ, Seymour J, Yoon E and Bruns TM: Flexible microelectrode array for interfacing with the surface of neural ganglia. J Neural Eng. 15:0360272018. View Article : Google Scholar : PubMed/NCBI
5	Rosenberg AZ and Kopp JB: Focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 12:502–517. 2017. View Article : Google Scholar : PubMed/NCBI
6	Wolf MTF and Hildebrandt F: Nephronophthisis. Pediatr Nephrol. 26:181–194. 2011. View Article : Google Scholar : PubMed/NCBI
7	Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloğlu A, Ozen S, Sanjad S, et al: Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA. 106:19096–19101. 2009. View Article : Google Scholar : PubMed/NCBI
8	McInerney-Leo AM, Marshall MS, Gardiner B, Benn DE, McFarlane J, Robinson BG, Brown MA, Leo PJ, Clifton-Bligh RJ and Duncan EL: Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. Clin Endocrinol (Oxf). 80:25–33. 2014. View Article : Google Scholar : PubMed/NCBI
9	Clifford RJ, Edmonson MN, Nguyen C, Scherpbier T, Hu Y and Buetow KH: Bioinformatics tools for single nucleotide polymorphism discovery and analysis. Ann N Y Acad Sci. 1020:101–109. 2004. View Article : Google Scholar : PubMed/NCBI
10	Benetti E, Caridi G, Malaventura C, Dagnino M, Leonardi E, Artifoni L, Ghiggeri GM, Tosatto SC and Murer L: A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 5:698–702. 2010. View Article : Google Scholar : PubMed/NCBI
11	Dhandapani MC, Venkatesan V, Rengaswamy NB, Gowrishankar K, Nageswaran P and Perumal V: Association of ACE and MDR1 gene polymorphisms with steroid resistance in children with idiopathic nephrotic syndrome. Genet Test Mol Biomarkers. 19:454–456. 2015. View Article : Google Scholar : PubMed/NCBI
12	Sako M, Nakanishi K, Obana M, Yata N, Hoshii S, Takahashi S, Wada N, Takahashi Y, Kaku Y, Satomura K, et al: Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Kidney Int. 67:1248–1255. 2005. View Article : Google Scholar : PubMed/NCBI
13	Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, Allen SJ, Soliman NA, Hildebrandt F and Otto EA; GPN Study Group, : Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 132:865–884. 2013. View Article : Google Scholar : PubMed/NCBI
14	Kang HG, Lee HK, Ahn YH, Joung JG, Nam J, Kim NK, Ko JM, Cho MH, Shin JI, Kim J, et al: Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. Exp Mol Med. 48:e2512016. View Article : Google Scholar : PubMed/NCBI
15	Wolf MTF, Lee J, Panther F, Otto EA, Guan KL and Hildebrandt F: Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans. J Am Soc Nephrol. 16:676–687. 2005. View Article : Google Scholar : PubMed/NCBI
16	Waldherr R, Lennert T, Weber HP, Födisch HJ and Schärer K: The nephronophthisis complex-A clinicopathologic study in children. Virchows Arch A Pathol Anat Histol. 394:235–254. 1982. View Article : Google Scholar : PubMed/NCBI
17	Chaki M, Hoefele J, Allen SJ, Ramaswami G, Janssen S, Bergmann C, Heckenlively JR, Otto EA and Hildebrandt F: Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Kidney Int. 80:1239–1245. 2011. View Article : Google Scholar : PubMed/NCBI
18	Wolf MTF, Mucha BE, Attanasio M, Zalewski I, Karle SM, Neumann HP, Rahman N, Bader B, Baldamus CA, Otto E, et al: Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains. Kidney Int. 64:1580–1587. 2003. View Article : Google Scholar : PubMed/NCBI
19	Rinschen MM, Schermer B and Benzing T: Vasopressin-2 receptor signaling and autosomal dominant polycystic kidney disease: From bench to bedside and back again. J Am Soc Nephrol. 25:1140–1147. 2014. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar : PubMed/NCBI
22	Montojo J, Zuberi K, Rodriguez H, Kazi F, Wright G, Donaldson SL, Morris Q and Bader GD: GeneMANIA cytoscape plugin: Fast gene function predictions on the desktop. Bioinformatics. 26:2927–2928. 2010. View Article : Google Scholar : PubMed/NCBI
23	Angioi A and Pani A: FSGS: From pathogenesis to the histological lesion. J Nephrol. 29:517–523. 2016. View Article : Google Scholar : PubMed/NCBI
24	Soliman NA, Hildebrandt F, Allen SJ, Otto EA, Nabhan MM and Badr AM: Homozygous NPHP1 deletions in Egyptian children with nephronophthisis including an infantile onset patient. Pediatr Nephrol. 25:2193–2194. 2010. View Article : Google Scholar : PubMed/NCBI
25	Yang X, Kanegane H, Nishida N, Imamura T, Hamamoto K, Miyashita R, Imai K, Nonoyama S, Sanayama K, Yamaide A, et al: Clinical and genetic characteristics of XIAP deficiency in Japan. J Clin Immunol. 32:411–420. 2012. View Article : Google Scholar : PubMed/NCBI
26	Gheissari A, Harandavar M, Hildebrandt F, Braun DA, Sedghi M, Parsi N, Merrikhi A, Madihi Y and Aghamohammadi F: Gene mutation analysis in Iranian children with nephronophthisis: A two-center study. Iran J Kidney Dis. 9:119–125. 2015.PubMed/NCBI
27	Hoefele J, Nayir A, Chaki M, Imm A, Allen SJ, Otto EA and Hildebrandt F: Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion. Pediatr Nephrol. 26:967–971. 2011. View Article : Google Scholar : PubMed/NCBI
28	Saunier S, Calado J, Benessy F, Silbermann F, Heilig R, Weissenbach J and Antignac C: Characterization of the NPHP1 locus: Mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am J Hum Genet. 66:778–789. 2000. View Article : Google Scholar : PubMed/NCBI
29	Caridi G, Dagnino M, Rossi A, Valente EM, Bertini E, Fazzi E, Emma F, Murer L, Verrina E and Ghiggeri GM: Nephronophthisis type 1 deletion syndrome with neurological symptoms: Prevalence and significance of the association. Kidney Int. 70:1342–1347. 2006. View Article : Google Scholar : PubMed/NCBI
30	Sugimoto K, Takemura Y, Yanagida H, Fujita S, Miyazawa T, Sakata N, Okada M and Takemura T: Renal tubular dysgenesis and tubulointerstitial nephritis antigen in juvenile nephronophthisis. Nephrology (Carlton). 16:495–501. 2011. View Article : Google Scholar : PubMed/NCBI
31	Salomon R, Saunier S and Niaudet P: Nephronophthisis. Pediatr Nephrol. 24:2333–2344. 2009. View Article : Google Scholar : PubMed/NCBI
32	Hildebrandt F, Strahm B, Nothwang HG, Gretz N, Schnieders B, Singh-Sawhney I, Kutt R, Vollmer M and Brandis M; Members of the APN Study Group, : Molecular genetic identification of families with juvenile nephronophthisis type 1: Rate of progression to renal failure. Kidney Int. 51:261–269. 1997. View Article : Google Scholar : PubMed/NCBI
33	Bleyer AJ, Woodard AS, Shihabi Z, Sandhu J, Zhu H, Satko SG, Weller N, Deterding E, McBride D, Gorry MC, et al: Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int. 64:36–42. 2003. View Article : Google Scholar : PubMed/NCBI
34	Krege JH, John SWM, Langenbach LL, Hodgin JB, Hagaman JR, Bachman ES, Jennette JC, O'Brien DA and Smithies O: Male-female differences in fertility and blood pressure in ACE-deficient mice. Nature. 375:146–148. 1995. View Article : Google Scholar : PubMed/NCBI
35	Esther CR Jr, Howard TE, Marino EM, Goddard JM, Capecchi MR and Bernstein KE: Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Investig. 74:953–965. 1996.PubMed/NCBI
36	Omran H, Häffner K, Vollmer M, Pigulla J, Wagner G, Caridi G and Hildebrandt F: Exclusion of the candidate genes ACE and Bcl-2 for six families with nephronophthisis not linked to the NPH1 locus. Nephrol Dial Transplant. 14:2328–2331. 1999. View Article : Google Scholar : PubMed/NCBI
37	Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M, et al: Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 145:513–528. 2011. View Article : Google Scholar : PubMed/NCBI
38	Tory K, Lacoste T, Burglen L, Morinière V, Boddaert N, Macher MA, Llanas B, Nivet H, Bensman A, Niaudet P, et al: High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: Potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J Am Soc Nephrol. 18:1566–1575. 2007. View Article : Google Scholar : PubMed/NCBI