Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction

Abstract

BackgroundAutosomal dominant polycystic kidney disease (ADPKD), the commonest inherited kidney disease, is generally caused by heterozygous mutations in PKD1, PKD2, or GANAB (PKD3).MethodsWe performed mutational analyses of PKD genes to identify causative mutations. A set of 90 unrelated families with ADPKD were subjected to mutational analyses of PKD genes. Genes were analysed using long-range PCR (LR-PCR), direct PCR sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) or screening of GANAB for some patients. Semen quality was assessed for 46 male patients, and the correlation between mutations and male infertility was analysed.ResultsA total of 76 mutations, including 38 novel mutations, were identified in 77 families, comprising 72 mutations in PKD1 and 4 in PKD2, with a positive detection rate of 85.6%. No pathogenic mutations of GANAB were detected. Thirty-seven patients had low semen quality and were likely to be infertile. No association was detected between PKD1 mutation type and semen quality. However, male patients carrying a pathogenic mutation in the Ig-like repeat domain of PKD1 had a high risk of infertility.ConclusionOur study identified a group of novel mutations in PKD genes, which enrich the PKD mutation spectrum and might help clinicians to make precise diagnoses, thereby allowing better family planning and genetic counselling. Men with ADPKD accompanied by infertility should consider intracytoplasmic sperm injection combined with preimplantation genetic diagnosis to achieve paternity and obtain healthy progeny.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0693-7) contains supplementary material, which is available to authorized users.

Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives

“…PKD1 also harbors a G protein-coupled receptor autoproteolysis-inducing (GAIN) domain that may be responsible for its activation [ 81 , 82 ]. The role of the PKD gene in male fertility was investigated by a correlational study on patients suffering from autosomal dominant polycystic kidney disease (ADPKD) [ 49 ]. The authors analyzed a set of 90 unrelated families with ADPKD and identified predicted pathogenic variants in PKD1 and PKD2 associated with low sperm quality, mainly asthenozoospermia or oligo-astheno-zoospermia [ 49 ].…”

“…The role of the PKD gene in male fertility was investigated by a correlational study on patients suffering from autosomal dominant polycystic kidney disease (ADPKD) [ 49 ]. The authors analyzed a set of 90 unrelated families with ADPKD and identified predicted pathogenic variants in PKD1 and PKD2 associated with low sperm quality, mainly asthenozoospermia or oligo-astheno-zoospermia [ 49 ]. Although no further exploration of the impact of the identified PKD variants on protein functionality was performed [ 49 ], additional findings supporting an essential role of PKD genes for sperm motility were obtained in the Drosophila model.…”

“…The authors analyzed a set of 90 unrelated families with ADPKD and identified predicted pathogenic variants in PKD1 and PKD2 associated with low sperm quality, mainly asthenozoospermia or oligo-astheno-zoospermia [ 49 ]. Although no further exploration of the impact of the identified PKD variants on protein functionality was performed [ 49 ], additional findings supporting an essential role of PKD genes for sperm motility were obtained in the Drosophila model. Hence, silencing of the PKD2 ortholog, of which the expression is enriched in male reproductive organs, was shown to induce male infertility due to the inability of the spermatozoa to correctly find their way through the female genital tract and reach the sperm storage organs of the female flies [ 83 , 84 , 85 ].…”

Analysis of partial Y chromosome microdeletions and NGS data in Lithuanian infertile men

“…Also, for a patient with the already discussed BRCA2 gene variant (a case of severe oligoasthenospermia), a variant of uncertain clinical signi cance was identi ed in the PKD1 gene, which may be associated with male infertility. Variants of this gene are not only associated with polycystic kidney disease, but also with asthenospermia and azoospermia (He et al 2018). Furthermore, this gene is also associated with prostate cancer (https://varsome.com/).…”

Reduction in Heart Rate Variability in Autosomal Dominant Polycystic Kidney Disease

“…By the age of 50-60 years [1,2], 50% of patients undergo a gradual subversion of the renal parenchyma with an enlargement in the total kidney volume and eventually reach end-stage renal disease. Cardiovascular complications are the major cause of morbidity and mortality, with a cardiacrelated death that is estimated to be 1.6-to 3.2-fold higher in these patients than in the general population [3,4]. Hypertension, endothelial dysfunction, systemic inflammation, and accelerated atherosclerosis are alterations found at a very early stage of the disease and are responsible for increasing both cardiovascular risks and progression towards end-stage renal disease.…”