| KCTD7 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | KCTD7 , CLN14, EPM3, potassium channel tetramerization domain containing 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 611725 MGI: 2442265 HomoloGene: 17687 GeneCards: KCTD7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Potassium channel tetramerisation domain containing 7 is a protein in humans that is encoded by the KCTD7 gene. [4] Alternative splicing results in multiple transcript variants.
The KCTD7 gene encodes a member of the potassium channel tetramerisation domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. [4] KCTD7 displays a primary sequence and hydropathy profile indicating intracytoplasmic localization. EST database analysis showed that KCTD7 is expressed in human and mouse brain. [5]
KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. [6] KCTD7 mRNA and protein are expressed in hippocampal neurons, deep layers of the cerebral cortex and Purkinje cells of the murine brain as shown by in situ hybridization and immunohistochemistry experiments. Immunoprecipitation assays demonstrates that KCTD7 is able to prudhommerie and directly interacts with cullin-3 (CUL3), a component of the ubiquitin ligase complex. These interactions are thought to be mediated via the BTB/POZ domain of KCTD7. However, KCTD7 does not show any interaction cullin-1 (CUL1). Immunoprecipitation assays also shows that KCTD7 does not interact with Ubiquitin-flag, suggesting a potential role of KCTD7 in the ubiquitin ligase complex without being itself subject to ubiquitination. Immunofluorescence microscopy shows a cytosolic expression of the recombinant GFP-KCTD7 protein in transfected COS-7 cells.
One possible hypothesis is that KCTD7 regulates indirectly the membrane expression level of a potassium channel. By conjugating with cullin-3 ubiquitin ligase complex, KCTD7 may modulate the expression level of a negative regulator of potassium channel. Therefore, the overexpression of KCTD7 in neurons would increase the degradation of that regulatory molecule leading to the increase of potassium current through the cell membrane as observed in patch clamp experiments.
In cultured mouse hippocampal cells, expression is found in the cell soma, in neuritic varicosities along the developing neuronal extensions, and in neurite growth cones, but not in the nucleus. [7] Kctd7 is widely expressed in neurons throughout the intact mouse brain, including in cortical neurons, in granular and pyramidal cell layers of the hippocampus, and in cerebellar Purkinje cells. However, not all neuronal cells are immunopositive for Kctd7, and expression is not seen in astrocytes or microglial cells. Expression is constant from P5 to 2 months in cerebellar lysates. Overexpression of KCTD7 in HeLa and COS-1 cells, which do not express endogenous KCTD7, shows diffuse cytosolic localization, with no colocalization with markers for endosomes, ER, Golgi, lysosomes, or the cytoskeleton.
Beside the BTB/POZ domain of KCTD7, other residues are critical for its proper interaction with cullin-3. [8] Furthermore, a full-length 31-kD Kctd7 isoform is expressed in mouse brain. Other major immunoreactive bands included a 28-kD species in the spleen, liver, and kidneys, a 37-kD species in the kidneys, and a 62-kD form most likely corresponding to a stable dimer. The presence of multiple bands was consistent with alternative splicing and tissue-specific regulation.
In 3 affected members of a large consanguineous Moroccan family with progressive myoclonic epilepsy-3, a homozygous nonsense mutation in the KCTD7 gene (R99X) has been identified. [5]
In 2 Mexican siblings with infantile onset of progressive myoclonic epilepsy and pathologic findings of neuronal ceroid lipofuscinosis in multiple cell types, a homozygous mutation in the KCTD7 gene (R184C) has been identified. [8] The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. This phenotype has been identified as CLN14. KCTD7 mutations were not found in 32 additional CLN samples. [8]
Ubiquitin carboxy-terminal hydrolase L1 is a deubiquitinating enzyme.
Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.
Myoclonic epilepsy refers to a family of epilepsies that present with myoclonus. When myoclonic jerks are occasionally associated with abnormal brain wave activity, it can be categorized as myoclonic seizure. If the abnormal brain wave activity is persistent and results from ongoing seizures, then a diagnosis of myoclonic epilepsy may be considered.
Prickle is also known as REST/NRSF-interacting LIM domain protein, which is a putative nuclear translocation receptor. Prickle is part of the non-canonical Wnt signaling pathway that establishes planar cell polarity. A gain or loss of function of Prickle1 causes defects in the convergent extension movements of gastrulation. In epithelial cells, Prickle2 establishes and maintains cell apical/basal polarity. Prickle1 plays an important role in the development of the nervous system by regulating the movement of nerve cells.
Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and seizures through antiepileptic medication (AED).
Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino-acid-long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.
Sodium channel protein type 1 subunit alpha (SCN1A), is a protein which in humans is encoded by the SCN1A gene.
Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late infantile neuronal ceroid lipofuscinosis.
WNK , also known as WNK1, is an enzyme that is encoded by the WNK1 gene. WNK1 is serine-threonine protein kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney. CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell. WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).
Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.
POU domain, class 4, transcription factor 1 (POU4F1) also known as brain-specific homeobox/POU domain protein 3A (BRN3A), homeobox/POU domain protein RDC-1 or Oct-T1 is a protein that in humans is encoded by the POU4F1 gene.
ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.
DnaJ homolog subfamily C member 5, also known as cysteine string protein or CSP is a protein, that in humans encoded by the DNAJC5 gene. It was first described in 1990.
Ceroid-lipofuscinosis neuronal protein 5 is a protein that in humans is encoded by the CLN5 gene.
Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.
Jansky–Bielschowsky disease is an extremely rare autosomal recessive genetic disorder that is part of the neuronal ceroid lipofuscinosis (NCL) family of neurodegenerative disorders. It is caused by the accumulation of lipopigments in the body due to a deficiency in tripeptidyl peptidase I as a result of a mutation in the TPP1 gene. Symptoms appear between ages 2 and 4 and consist of typical neurodegenerative complications: loss of muscle function (ataxia), drug resistant seizures (epilepsy), apraxia, development of muscle twitches (myoclonus), and vision impairment. This late-infantile form of the disease progresses rapidly once symptoms are onset and ends in death between age 8 and teens. The prevalence of Jansky–Bielschowsky disease is unknown; however, NCL collectively affects an estimated 1 in 100,000 individuals worldwide. Jansky–Bielschowsky disease is related to late-infantile Batten disease and LINCL, and is under the umbrella of neuronal ceroid lipofuscinosis.
Northern epilepsy syndrome (NE), or progressive epilepsy with mental retardation (EPMR), is a subtype of neuronal ceroid lipofuscinosis and a rare disease that is regarded as a Finnish heritage disease. Unlike most Finnish heritage diseases, this syndrome has been reported only in Finland. The disease is characterized by seizures in early childhood that progressively get worse until after puberty. Once the onset of seizures occurs, mental degradation is seen. This continues into adulthood, even after seizure frequency has decreased. The cause of the disease is a missense mutation on chromosome 8. The creation of a new protein occurs, and the lipid content of the brain is altered because of it. The ratio of the mutation carriers is 1:135. There is nothing that has been found to stop the progression of the disease, but symptomatic approaches, such as the use of benzodiazepines, have helped control seizures.
Major facilitator superfamily domain containing 8 also called MFSD8 is a protein that in humans is encoded by the MFSD8 gene. MFSD8 is an atypical SLC, thus a predicted SLC transporter. It clusters phylogenetically to the Atypical MFS Transporter family 2 (AMTF2).
Kufs disease is one of many diseases categorized under a disorder known as neuronal ceroid lipofuscinosis (NCLs) or Batten disease. NCLs are broadly described to create problems with vision, movement and cognitive function. Among all NCLs diseases, Kufs is the only one that does not affect vision, and although this is a distinguishing factor of Kufs, NCLs are typically differentiated by the age at which they appear in a patient
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
