Polycystic kidney disease 3 (autosomal dominant)

PKD3
Identifiers
Aliases	PKD3 , polycystic kidney disease 3 (autosomal dominant)
External IDs	GeneCards: PKD3; OMA:PKD3 - orthologs
Orthologs
	5312
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	n ; a
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	Wikidata
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Last updated October 14, 2024

Polycystic kidney disease 3 (autosomal dominant) is a protein that in humans is encoded by the PKD3 gene.^[2]

Polycystic kidney disease (ADPKD) is a life threatening hereditary disorder; it is characterized by the development of fluid-filled cyst formation and expansion of the kidney and other organs.^[3] It is an autosomal dominant disease, and it is the most common hereditary disorders with a rate of occurrence of approximately 1 in 1000.^[4]

Characteristics

ADPKD is an autosomal dominant disease, classified into three types, with the chromosomal location of the responsible gene in parenthesis: PKD1 (16 Chr), PKD2 (4 Chr) PKD3 (11 Chr, this gene). Mutations in the three different genes PKD1, PKD2 and PKD3 cause a very similar disorder of the autosomal dominant form of polycystic kidney disease (ADPKD).^[5] The PKD3 gene is located on chromosome number 11q12.3; the phenotype MIM number is 600666.

PKD3 it is the result of a mutation in the GANAB gene. The GANAB gene codes the catalytic alpha subunit of glucosidase II and noncatalytic beta subunit; the glycosyl hydrolase 31 families of proteins. The heterodimeric glucosidase II enzyme has an important function in protein folding and catalyzes the hydrolysis of glucose residues. In the endoplasmic reticulum, the quality control is done by cutting the residues of glucose from the immature glycoproteins. The rise in the expression of the protein leads to the lung tumor tissue. Also, any mutation in this gene causes autosomal dominant polycystic liver disease. [7]

PKD3 occurs in adults and it sometimes shows symptoms in children. It is known as 'polycystic kidneys'. Polycystic kidney disease (PKD3) is an autosomal dominant inheritance that leads to renal cysts. It is related to the liver cysts that sometimes causes organ dysfunction. It is usually detected in middle to late aged individuals developing severe cysts in kiddy and liver. However, the renal disease is mild and very few patients have hypertension, it does not happen regularly. Unlike the liver disease where it develops a wide spectrum of severity; some have no cyst, while others have severe liver involvement polycystic kidney disease.^[3]

Clinical features

In an analysis of 20 patients from nine unrelated families develop polycystic kidney disease with heterozygous mutations in the GANAB gene. Five of the mutations from the GANAB gene were predicted to result in a short protein (frameshift, nonsense, or splicing), and three missense mutations. Seven of the families had a diagnosis of PKD, while the other two families had a diagnosis of polycystic liver disease (PCLD). Most of the patients developed during adulthood, except one showed symptoms at the age of 9. The recordings indicate that the renal disease was insignificant. Also, very few of them had high blood pressure. Renal imaging has also been done, which present variable numbers of multiple cysts (from less than 10 to more than 40).Those suffering from PCLD, some had no cyst while others develop severe disease, requiring surgery. Therefore, this shows that GANAB-related PKD and PCLD are not necessarily separate diseases, but there was significant phenotypic overlap between the two, and that the PKD3 is responsible for this disease.^[4]

Treatment

There is no specific treatment for PKD3. However, a lot of research is going on to mimic the symptoms. Regular monitoring and following up on the complications can assist in maintaining the health and extend a person's life. Recent research shows that the treatment with protein kinase C (PKC) inhibitor may help to mimic the increase of PKD3, by RacV12 and aluminum fluoride.

Mechanism

Both Galpha (12/13) and Rac are important components in the signal transduction pathways that mediate bombesin receptor induced PKD3 activation.[6]
The addition aluminum fluoride to COS-7 cells cotransfected with PKD3 and Gapha (13/12) leads to PKD3 activation; also it is related with a transient plasma membrane translocation of cytosolic PKD3.^[6]
The catalytic domain of PKD3 can localize to the nucleus when expressed without the kinase domain.^[7] Moreover, the catalytic activation of PKD3 in response to RacV12, Galpha (13/12) signalling, bombesin correlated with Ser-731/735 phosphorylation in the activation loop of this enzyme.^[6]

Related Research Articles

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.

<span class="mw-page-title-main">Chromosome 4</span> Human chromosome

Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 190 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.

Cystic kidney disease refers to a wide range of hereditary, developmental, and acquired conditions and with the inclusion of neoplasms with cystic changes, over 40 classifications and subtypes have been identified. Depending on the disease classification, the presentation may be at birth, or much later into adult life. Cystic disease may involve one or both kidneys and may, or may not, occur in the presence of other anomalies. A higher incidence is found in males and prevalence increases with age. Renal cysts have been reported in more than 50% of patients over the age of 50. Typically, cysts grow up to 2.88 mm annually and may cause related pain and/or hemorrhage.

Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder characterized by tubulointerstitial sclerosis leading to end-stage renal disease. Because the presence of cysts is neither an early nor a typical diagnostic feature of the disease, and because at least four different gene mutations may give rise to the condition, the name autosomal dominant tubulointerstitial kidney disease (ADTKD) has been proposed, to be appended with the underlying genetic variant for a particular individual. Importantly, if cysts are found in the medullary collecting ducts they can result in a shrunken kidney, unlike that of polycystic kidney disease. There are two known forms of medullary cystic kidney disease, mucin-1 kidney disease 1 (MKD1) and mucin-2 kidney disease/uromodulin kidney disease (MKD2). A third form of the disease occurs due to mutations in the gene encoding renin (ADTKD-REN), and has formerly been known as familial juvenile hyperuricemic nephropathy type 2.

Polycystic liver disease (PLD) usually describes the presence of multiple cysts scattered throughout normal liver tissue. PLD is commonly seen in association with autosomal-dominant polycystic kidney disease, with a prevalence of 1 in 400 to 1000, and accounts for 8–10% of all cases of end-stage renal disease. The much rarer autosomal-dominant polycystic liver disease will progress without any kidney involvement.

Fibrocystin is a large, receptor-like protein that is thought to be involved in the tubulogenesis and/or maintenance of duct-lumen architecture of epithelium. FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway.

TRPP is a family of transient receptor potential ion channels which when mutated can cause polycystic kidney disease.

Polycystin 1 (PC1) is a protein that in humans is encoded by the PKD1 gene. Mutations of PKD1 are associated with most cases of autosomal dominant polycystic kidney disease, a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction.

<span class="mw-page-title-main">Polycystin 2</span> Protein and coding gene in humans

Polycystin-2(PC2) is a protein that in humans is encoded by the PKD2 gene.

Glucosidase 2 subunit beta is an enzyme that in humans is encoded by the PRKCSH gene.

Polycystic kidney disease 2-like 1 protein also known as transient receptor potential polycystic 2 is a protein that in humans is encoded by the PKD2L1 gene.

A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.

Polycystic kidney disease is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.

<span class="mw-page-title-main">Autosomal recessive polycystic kidney disease</span> Medical condition

Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 cause ARPKD.

Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. As of December 2021, lixivaptan is in Phase III clinical development for the treatment of Autosomal dominant polycystic kidney disease (ADPKD), the most common form of polycystic kidney disease. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to lixivaptan for the treatment of ADPKD.

The GAIN domain is a protein domain found in a number of cell surface receptors, including adhesion-GPCRs and polycystic kidney disease proteins PKD1 and PKD2. The domain is involved in the self-cleavage of these transmembrane receptors, and has been shown to be crucial for their function. Point mutations within the GAIN domain of PKD1 and GPR56 are known to cause polycystic kidney disease and polymicrogyria, respectively.

Glomerulocystic kidney disease (GCKD) is a cystic disorder of the kidneys. GCKD involves cystic dilation of Bowman's capsule. It can occur with or without congenital abnormality.

The Polycystin Cation Channel (PCC) Family consists of several transporters ranging in size from 500 to over 4000 amino acyl residues (aas) in length and exhibiting between 5 and 18 transmembrane segments (TMSs). This family is a constituent of the Voltage-Gated Ion Channel (VIC) Superfamily. These transporters generally catalyze the export of cations. A representative list of proteins belonging to the PCC family can be found in the Transporter Classification Database.

Shrawan Kumar, is an Indian-American geneticist, working in the fields of molecular and population genetics. He contributed to the discovery of two genes related to Branchio-oto-renal syndrome (BOR) and Autosomal Dominant Polycystic Kidney Disease (ADPKD2).

References

↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Entrez Gene: Polycystic kidney disease 3 (autosomal dominant)".
1 2 Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, et al. (2016). "Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease". American Journal of Human Genetics. 98 (6): 1193–207. doi:10.1016/j.ajhg.2016.05.004. PMC 4908191 . PMID 27259053.
1 2 Paul BM, Consugar MB, Ryan Lee M, Sundsbak JL, Heyer CM, Rossetti S, Kubly VJ, Hopp K, Torres VE, Coto E, Clementi M, Bogdanova N, de Almeida E, Bichet DG, Harris PC (2014). "Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families". Kidney International. 85 (2): 383–92. doi:10.1038/ki.2013.227. PMC 3883953 . PMID 23760289.
↑ Koptides M, Deltas CC (2000). "Autosomal dominant polycystic kidney disease: molecular genetics and molecular pathogenesis". Human Genetics. 107 (2): 115–26. doi:10.1007/s004390000347. PMID 11030408. S2CID 11284208.
1 2 3 Yuan J, Rey O, Rozengurt E (2006). "Activation of protein kinase D3 by signaling through Rac and the alpha subunits of the heterotrimeric G proteins G12 and G13". Cellular Signalling. 18 (7): 1051–62. doi:10.1016/j.cellsig.2005.08.017. PMID 16198087.
↑ Papazyan R, Rozengurt E, Rey O (2006). "The C-terminal tail of protein kinase D2 and protein kinase D3 regulates their intracellular distribution". Biochemical and Biophysical Research Communications. 342 (3): 685–9. doi:10.1016/j.bbrc.2006.02.013. PMID 16494840.

[7] GANAB glucosidase II alpha subunit Homo sapiens (human). Gene ID:23193, 2016.