Homologues to the First Gene for Autosomal Dominant Polycystic Kidney Disease Are Pseudogenes

doi:10.1006/geno.2001.6568

Genomics

Volume 74, Issue 3, 15 June 2001, Pages 333-341

https://doi.org/10.1006/geno.2001.6568 Get rights and content

Abstract

PKD1 is the first gene identified to be causative for the condition of autosomal dominant polycystic kidney disease. There are several genes homologous to PKD1 that are located proximal to the master gene on the same chromosome. Two of these genes have been recently covered in a large sequencing work on chromosome 16, and their structure has been broadly analyzed. However, the major question whether homologous genes (HG) code for functionally active polypeptides has not been resolved so far. The current study identifies and partially characterizes four more homologues of PKD1, different from the previously published sequence, two of which were found by screening of a BAC library and the other two contained in available databases. Analysis of HG transcripts shows that they are not translated in the model cell line T98G. Taken together, these findings suggest that homologues to PKD1 form a family of pseudogenes.

References (28)

J. Brosius
RNAs from all categories generate retrosequences that may be exapted as novel genes or regulatory elements
Gene
(1999)
M.C. Daoust et al.
Evidence for a third genetic locus for autosomal dominant polycystic kidney disease
Genomics
(1995)
J. Jurka
Repeats in genomic DNA: Mining and meaning
Curr. Opin. Struct. Biol.
(1998)
M. Kozak
Initiation of translation in prokaryotes and eukaryotes
Gene
(1999)
B.J. Loftus et al.
Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q
Genomics
(1999)
B.M. Mechler
Isolation of messenger RNA from membrane-bound polysomes
Methods Enzymol.
(1987)
P.G. Olsson et al.
The mouse homologue of the polycystic kidney disease gene (Pkd1) is a single-copy gene
Genomics
(1996)
F. Qian et al.
The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I
Cell
(1996)
T.J. Watnick et al.
Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease
Mol. Cell
(1998)
Hum. Mol. Genet.
(1995)

N. Bogdanova et al.

Genetic heterogeneity of polycystic kidney disease in Bulgaria

Hum. Genet.

(1995)

J. Cavaille et al.

From the cover: Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Proc. Natl. Acad. Sci. USA

(2000)

O.Z. Dalgard

Bilateral polycystic kidney disease of the kidneys: A follow-up of two hundred and eighty-four patients and their families

Acta Med. Scand.

(1957)

Cited by (73)

Mechanisms of Cyst Development in Polycystic Kidney Disease
2023, Advances in Kidney Disease and Health
Autosomal dominant polycystic kidney disease is the most common inherited cause of end-stage kidney disease worldwide. Most cases result from mutation of either of 2 genes, PKD1 and PKD2, which encode proteins that form a probable receptor/channel complex. Studies suggest that a loss of function of the complex below an indeterminate threshold triggers cyst initiation, which ultimately results in dysregulation of multiple metabolic processes and downstream pathways and subsequent cyst growth. Noncell autonomous factors may also promote cyst growth. In this report, we focus primarily on the process of early cyst formation and factors that contribute to its variability with brief consideration of how new studies suggest this process may be reversible.
A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery
2022, Cell Stem Cell
Human pluripotent stem-cell-derived organoids are models for human development and disease. We report a modified human kidney organoid system that generates thousands of similar organoids, each consisting of 1–2 nephron-like structures. Single-cell transcriptomic profiling and immunofluorescence validation highlighted patterned nephron-like structures utilizing similar pathways, with distinct morphogenesis, to human nephrogenesis. To examine this platform for therapeutic screening, the polycystic kidney disease genes PKD1 and PKD2 were inactivated by gene editing. PKD1 and PKD2 mutant models exhibited efficient and reproducible cyst formation. Cystic outgrowths could be propagated for months to centimeter-sized cysts. To shed new light on cystogenesis, 247 protein kinase inhibitors (PKIs) were screened in a live imaging assay identifying compounds blocking cyst formation but not overall organoid growth. Scaling and further development of the organoid platform will enable a broader capability for kidney disease modeling and high-throughput drug screens.
CRISPR-Directed Therapeutic Correction at the NCF1 Locus Is Challenged by Frequent Incidence of Chromosomal Deletions
2020, Molecular Therapy Methods and Clinical Development
Resurrection of non-processed pseudogenes may increase the efficacy of therapeutic gene editing, upon simultaneous targeting of a mutated gene and its highly homologous pseudogenes. To investigate the potency of this approach for clinical gene therapy of human diseases, we corrected a pseudogene-associated disorder, the immunodeficiency p47^phox-deficient chronic granulomatous disease (p47^phox CGD), using clustered regularly interspaced short palindromic repeats-associated nuclease Cas9 (CRISPR-Cas9) to target mutated neutrophil cytosolic factor 1 (NCF1). Being separated by less than two million base pairs, NCF1 and two pseudogenes are closely co-localized on chromosome 7. In healthy people, a two-nucleotide GT deletion (ΔGT) is present in the NCF1B and NCF1C pseudogenes only. In the majority of patients with p47^phox CGD, the NCF1 gene is inactivated due to a ΔGT transfer from one of the two non-processed pseudogenes. Here we demonstrate that concurrent targeting and correction of mutated NCF1 and its pseudogenes results in therapeutic CGD phenotype correction, but also causes potentially harmful chromosomal deletions between the targeted loci in a p47^phox-deficient CGD cell line model. Therefore, development of genome-editing-based treatment of pseudogene-related disorders mandates thorough safety examination, as well as technological advances, limiting concurrent induction of multiple double-strand breaks on a single chromosome.
Update and review of adult polycystic kidney disease
2020, Disease-a-Month
Citation Excerpt :
Additionally, it was identified that a region the gene (exon 1–33) was duplicated at a few other sites on the same chromosome.6 Since these genes do not undergo translation, they were labelled as “pseudogenes”.7 This designation may be diagnostically important since it may be difficult to distinguish the mutation in the pseudogenes from those in the PKD1.
Autosomal dominant polycystic kidney disease is a common cause of end stage kidney disease. It is a progressive and unfortunately incurable condition that can lead to significant morbidity and kidney failure. Many more patients are diagnosed with this disease without any symptoms as the population is increasingly undergoing imaging for other problems and diagnostic workup. Our understanding of the genetic variants has increased in recent years as research continues to improve. As well, therapeutic options have developed with the FDA approval of a new treatment medication, with many others underway. This review updates the clinician on the pathophysiology, clinical aspects, and therapeutic options for patients the is form of kidney disease.
Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease
2018, American Journal of Kidney Diseases
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling.
Genetic testing and prenatal diagnosis of 64 pedigrees with autosomal dominant polycystic kidney disease
2023, Chinese Journal of Nephrology

View all citing articles on Scopus

^☆: Sequence data from this article have been deposited with the GenBank Data Library under Accession Nos. AF320593 and AF320594.

¹: Both first authors contributed equally to this work.

²: To whom correspondence should be addressed at the Institut für Humangenetik, WWU Münster, Vesalliusweg 12-14, D-48149 Münster, Germany. Telephone: +49 251 835-5401. Fax: +49 251 835-5431. E-mail: [email protected].

View full text

Regular ArticleHomologues to the First Gene for Autosomal Dominant Polycystic Kidney Disease Are Pseudogenes☆

Abstract

Gene

Genomics

Curr. Opin. Struct. Biol.

Gene

Genomics

Methods Enzymol.

Genomics

Cell

Mol. Cell

Hum. Mol. Genet.

Genetic heterogeneity of polycystic kidney disease in Bulgaria

Hum. Genet.

From the cover: Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Proc. Natl. Acad. Sci. USA

Bilateral polycystic kidney disease of the kidneys: A follow-up of two hundred and eighty-four patients and their families

Acta Med. Scand.

Regular Article
Homologues to the First Gene for Autosomal Dominant Polycystic Kidney Disease Are Pseudogenes☆