PKHD1 Geni Yanlış Anlam Mutasyonları Kedilerde Sebebi Bilinmeyen Böbrek Hastalıkları İçin Önemli Olabilir mi?

Year 2021, Volume: 10 Issue: 2, 168 - 171, 12.12.2021

Nüket Bilgen

https://doi.org/10.31196/huvfd.983895

Abstract

Polikistik böbrek hastalığı (PKD), insanlarda otozomal resesif ve otozomal dominant olarak görülen heterojenik arka planı olan genetik bir hastalıktır. Kedilerde otozomal dominant PKD sıklıkla rapor edilirken, otozomal resesif PKD bildirilmemiştir. Tüm genom dizilemesi yapılmış olan siyam ırkı bir erkek kedide biyoinformatik analizler sonucunda PKHD1 geninde çeşitli yanlış anlam mutasyonları tespit edilmiştir. Bu Siyam ırkı kedinin kastrasyon için özel bir veteriner kliniğine getirilmesinin ardından böbrek ve karaciğeri izlemek için geniş kan paneli yapıldı ve yüksek BUN ve kreatinin değerleri gözlendi. Ayrıca GPT değerinin de 2,5 kat olduğu belirlendi. Kedilerde nadiren PKD1 mutasyonundan bağımsız kistik böbrek vakaları bildirilmektedir. Ancak otozomal çekinik polikistik böbrek hastalığına neden olan genler için kedi genomları daha önce incelenmemiştir. Bu çalışmada kedi genom verilerinde (n=100) otozomal resesif PKD’ye neden olan PKHD1 geni incelenmiştir. İnceleme sonucunda SIFT skoru yüksek 4 farklı mutasyon belirlenmiş ve bu mutasyonların PKHD1 geninden üretilen 7 transkriptte dur kodonu oluşumu ve dur kodonu kaybı ile sonuçlandığı ortaya konmuştur. Nadir hastalık olmasını destekler nitelikte, belirlenen mutasyonların frekanslarının 0.003, 0.001, 0.001 ve 0.003 olduğu hesaplanmıştır.

Keywords

Böbrek, Kedi, genom, PKHD1 geni

Thanks

99 Kedi Genom konsorsiyumuna veri paylaşımı için teşekkür ederiz.

Could PKHD1 Gene Missense Mutations Be İmportant for İdiopathic Kidney Disease in Cats?

Abstract

Polycystic kidney disease (PKD) is a genetic disease with a heterogeneous background seen in humans as autosomal recessive and autosomal dominant. While autosomal dominant PKD is frequently reported in cats, autosomal recessive PKD has not been reported. Various missense mutations in the PKHD1 gene were detected as a result of bioinformatic analyzes in a male cat whose whole genome was sequenced. After this Siamese cat was brought to a private veterinary clinic for castration, a broad blood panel was performed to monitor kidney and liver, and elevated BUN and creatinine values were observed. In addition, the GPT value was determined to be 2.5 times higher. Cases of cystic kidney independent of PKD1 mutation have been reported rarely in cats. However, cat genomes have not been previously
examined for genes that cause autosomal recessive polycystic kidney disease. In this study, the PKHD1 gene, which causes autosomal recessive PKD, was examined in cat genome data (n=100). As a result of the examination, four different mutations with high SIFT scores were identified. These mutations resulted in stop codon formation and loss of stop codons in 7 transcripts produced from the PKHD1 gene. The frequencies of the determined mutations were calculated to be 0.003, 0.001, 0.001, and 0.003, which supports the fact that it is a rare disease.

Keywords

Cat, Genome, Kidney, PKHD1 gene

References

• Bilgen N, Bişkin Türkmen M, Çınar Kul B, Isparta S, Şen Y, Akkurt MY, Çıldır Ö Ş, Bars Z, 2020: Prevalence of PKD1 gene mutation in cats in Turkey and pathogenesis of feline polycystic kidney disease. J of Vet Diagn, 32(4), 549–555.
• Buckley RM, Gandolfi B, Creighton EK, Pyne CA, Bouhan DM, LeRoy ML, Senter DA, Gobble JR, Abitbol M, Lyons LA, 99 Lives Consortium, 2020a: Werewolf, There Wolf: Variants in Hairless Associated with Hypotrichia and Roaning in the Lykoi Cat Breed. Genes (Basel) 11 (6), 682.
• Buckley RM, Davis BW, Brashear WA, Farias FHG, Kuroki K, Graves T, Hiller WL, Kremitzki M, Li G, Middleton RP, Minx P, Tomlinson C, Lyons LA, Murphy WJ, Warren WC:2020b A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism. PLoS Genet, 16(10).
• Chen H, Dunaevich A, Apfelbaum N, Kuzi S, Mazaki‐Tovi M, Aroch I, Segev G, 2020: Acute on chronic kidney disease in cats: Etiology, clinical and clinicopathologic findings, prognostic markers, and outcome. J Vet Inter Med, 34(4), 1496-1506.
• Cogne B, Latypova X, Senaratne LDS, Martin L, Koboldt DC, Kellaris G, Fievet L, Le Meur G, Caldari D, Debray D, Nizon M, Frengen E, Bowne S, 2020: Mutations in the kinesin-2 motor kif3b cause an autosomal-dominant ciliopathy. Am J Hum Genet, 106(6), 893-904.
• Guerra JM, Daniel AGT, Cardoso NC, Grandi F, Queiroga F, Cogliati B, 2015: Congenital hepatic fibrosis and polycystic kidney disease not linked to C> A mutation in exon 29 of PKD1 in a Persian cat. JFMS open reports, 1(2), 2055116915619191.
• Hunt SE, McLaren W, Gil L, Thormann A, Schuilenburg H, Sheppard D, Parton A, Armean IM, Trevanion SJ, Flicek P, Cunningham F, 2018: Ensembl variation resources. Database, 2018(2018) bay119.
• Lee YJ, Chen HY, Hsu WL, Ou CM, Wong ML, 2010: Diagnosis of feline polycystic kidney disease by a combination of ultrasonographic examination and PKD1 gene analysis. Veterinary record, 167(16), 614-618.
• Lyons LA, Fox DB, Chesney KL, Britt LG, Buckley RM, Coates JR, Gandolfi B, Grahn RA, Hamilton MJ, Middleton JR, Sellers ST, Villani NA, Pfleuger S, 99 Lives Consortium, 2019: Localization of a feline autosomal dominant dwarfism locus: A novel model of chondrodysplasia. bioRxiv. 687210.
• Lyons LA, Biller DS, Erdman CA, Lipinski MJ, Young AE, Roe BA, Qin B, Grahn RA, 2004: Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol, 15(10), 2548-2555.
• McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, Flicek P, Cunningham F, 2016: The Ensembl Variant Effect Predictor. Genome Biol, 6, 17(1), 122.
• Ontiveros ES, Ueda Y, Harris SP, Stern JA, 99 Lives Consortium, 2019: Precision medicine validation: Identifying the mybpc3 a31p variant with whole-genome sequencing in two maine coon cats with hypertrophic cardiomyopathy. J Feline Med Surg 21(12), 1086-1093.
• Yu Y, Creighton EK, Buckley RM, Lyons LA, 99 Lives Consortium, 2020: A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats. Genes (Basel), 11(6), 672.