Mujgan Ozdemir Erdogan¹*, Başak Gogus¹, Handan Yildiz¹, Sinan Kazan², Serdar Ceylaner³, Alper Emre Kurt⁴, Sena Ulu⁵ and Muhsin Elmas¹

¹Medical Genetics Department, Afyonkarahisar Health Sciences University, Faculty of Medicine, Afyonkarahisar, Turkey
²Internal Medicine and Nephrology Department, Afyonkarahisar Health Sciences University, Faculty of Medicine, Afyonkarahisar, Turkey
³Medical Genetics Department, Lokman Hekim University, Faculty of Medicine, Ankara, Turkey
⁴Internal Medicine Department, Afyonkarahisar Public Hospital, Afyonkarahisar, Turkey
⁵Internal Medicine and Nephrology Department, Bahcesehir University, Faculty of Medicine, Istanbul, Turkey

*Corresponding Author: Mujgan Ozdemir Erdogan, Medical Genetics Department, Afyonkarahisar Health Sciences University, Faculty of Medicine, Afyonkarahisar, Turkey.

Received: October 21, 2022; Published: January 05, 2023

Abstract

Objectıve: Mutational screening of the PKD1 and PKD2 genes, which are known to be associated with the severity of the disease, and the GANAB gene, which is a strong candidate gene, which is thought to be involved in the genetic basis of ADPKD, were performed in 16 cases admitted with the indication of autosomal dominant polycystic kidney disease (ADPKD).

Materıals and Methods: A total of 16 cases who were diagnosed with ADPKD and met the criteria were evaluated. After DNA isolation from peripheral blood samples of the case group, PCR was performed with primers designed specifically for PKD1, PKD2 and GANAB genes. In this study, targeted resequencing method was applied by using MiSeq (Illumina, San Diego, CA) system for mutation screening of the aforementioned genes. In the analysis of detected variants, in silico analyzes, database searches and literature reviews were performed. For this, Varsome, Polyphen2, HGMD-Public, PubMed, Google search, Clinvar, EXAC and 1,000 Genomes studies were used.

Results: As a result of the sequence analysis of PKD1, PKD2 and GANAB genes from 16 cases diagnosed with ADPKD, at least one of the 3 genes analyzed for all patients and at least one disease-related variant was detected. The changes found are all heterozygous changes.

Six PKD1 polymorphism were found in 4 patients. In 11 of 16 patients, 14 different variants for the PKD1 gene (2 frameshifts, 5 missense, 3 nonsense, 1spilice region and 3 synonyms) were detected. In 6 of 16 patients, 6 different variants (3 nonsense, 1 missense, 2 synonyms) were detected for the PKD2 gene with a pathogenic effect. As a result of the GANAB gene sequence analysis, 6 different variants (1 missense, 3 synonyms and 2 noncoding) were determined for 5 patients. Of the 27 non-polymorphic variants detected for these 3 genes, 5 are novel mutations that have not been reported before. Of these 5 mutations, 3 were found in the PKD1 gene, and 1 in each of the PKD2 and GANAB genes. While 6 of these mutations in 16 patients are de novo (fresh mutation), 10 of them have autosomal dominant inheritance.

Conclusıon: Our study results shed light on the genotype-phenotype correlation, the effect of genotype on clinical progression, and mutations not previously reported in the literature. In addition, our study results support that the GANAB gene is a strong candidate gene that plays a role in the genetic basis of ADPKD. It is recommended that similar studies be conducted with patient groups with a higher number of patients.

Keywords: Autosomal Dominant Polycystic Kidney Disease; PKD1 Gene; PKD2 Gene; GANAB Gene

References

1. Grantham JJ. “The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: recent advances”. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation6 (1996): 788-803.
2. Gabow PA., et al. “The clinical utility of renal concentrating capacity in polycystic kidney disease”. Kidney International2 (1989): 675-680.
3. Chapman AB., et al. “Overt proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease”. Journal of the American Society of Nephrology6 (1994): 1349-1354.
4. Torres VE., et al. “Renal Stone Disease in Autosomal Dominant Polycystic Kidney Disease”. American Journal of Kidney Diseases4 (1993): 513-519.
5. Zerres K and Rudnik-Schöneborn S. “On genetic heterogeneity, anticipation, and imprinting in polycystic kidney diseases”. Nephrology Dialysis Transplantation1 (1995): 7-9.
6. Hogan MC., et al. “Liver Involvement in Early Autosomal-Dominant Polycystic Kidney Disease”. Clinical Gastroenterology and Hepatology 1 (2015): 155-164.e6.
7. Kim JA., et al. “Pancreatic Cysts in Autosomal Dominant Polycystic Kidney Disease: Prevalence and Association with PKD2 Gene Mutations”. Radiology 3 (2016): 762-770.
8. Butler WE., et al. “Patients with Polycystic Kidney Disease Would Benefit from Routine Magnetic Resonance Angiographic Screening for Intracerebral Aneurysms: A Decision Analysis”. Neurosurgery 3 (1996): 506-516.
9. Hossack KF., et al. “Echocardiographic Findings in Autosomal Dominant Polycystic Kidney Disease”. New England Journal of Medicine14 (1988): 907-912.
10. “The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16”. The European Polycystic Kidney Disease Consortium. Cell 6 (1994): 881-894.
11. Hwang YH., et al. “Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease”. Journal of the American Society of Nephrology 6 (2016): 1861-1868.
12. Ong ACM and Harris PC. “A polycystin-centric view of cyst formation and disease: the polycystins revisited”. Kidney International4 (2015): 699-710.
13. Cornec-Le Gall E., et al. “Genetics and pathogenesis of autosomal dominant polycystic kidney disease: 20 years on”. Human Mutation12 (2014): 1393-1406.
14. Mochizuki T., et al. PKD2, a Gene for Polycystic Kidney Disease That Encodes an Integral Membrane Protein Published by: American Association for the Advancement of Science Stable (2016).
15. Liu X., et al. “Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium”. Elife (2018).
16. Treml K., et al. “The alpha- and beta-subunits are required for expression of catalytic activity in the hetero-dimeric glucosidase II complex from human liver”. Glycobiology 5 (2000): 493-502.
17. Besse W., et al. “A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family”. Human Mutation3 (2018): 378-382.
18. Xu C and Ng DTW. “Glycosylation-directed quality control of protein folding”. Nature Reviews Molecular Cell Biology 12 (2015): 742-752.
19. Pei Y and Watnick T. “Diagnosis and Screening of Autosomal Dominant Polycystic Kidney Disease”. Advances in Chronic Kidney Disease2 (2010): 140-152.
20. Harris PC., et al. “Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease”. Journal of the American Society of Nephrology11 (2006): 3013-3019.
21. Parfrey PS., et al. “The diagnosis and prognosis of autosomal dominant polycystic kidney disease”. The New England Journal of Medicine 16 (1990): 1085-1090.
22. Spithoven EM., et al. “Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease”. Kidney International6 (2014): 1244-1252.
23. Willey C., et al. “Analysis of Nationwide Data to Determine the Incidence and Diagnosed Prevalence of Autosomal Dominant Polycystic Kidney Disease in the USA: 2013-2015”. Kidney Diseases2 (2019): 107-117.
24. Torres VE and Harris PC. “Autosomal dominant polycystic kidney disease: The last 3 years”. Kidney International 76 (2009): 149-168.
25. Torres VE., et al. “Autosomal dominant polycystic kidney disease”. The Lancet9569 (2007): 1287-1301.
26. Demetriou K., et al. “Autosomal dominant polycystic kidney disease—type 2. Ultrasound, genetic and clinical correlations”. Nephrology Dialysis Transplantation2 (2000): 205-211.
27. Bergmann C., et al. “Polycystic kidney disease”. Nature Reviews Disease Primers1 (2018): 50.
28. Spithoven EM., et al. “Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival-an analysis of data from the ERA-EDTA Registry on behalf of the ERA-EDTA Registry **, the”. Nephrology Dialysis Transplantation 29 (2014): 15-25.
29. Jiang T., et al. “Application of next-generation sequencing technologies in Neurology”. Annals of Translational Medicine's 12 (2014): 125.

Citation

Citation: Mujgan Ozdemir Erdogan., et al. “Investigation of Distribution of PKD1, PKD2 and GANAB Genes in Autosomal Dominant Polycystic Kidney Patients in Turkish Population”.Acta Scientific Medical Sciences 7.2 (2023): 10-25.

Copyright

Copyright: © 2022 Mujgan Ozdemir Erdogan., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.