| WDR62 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | WDR62 , C19orf14, MCPH2, WD repeat domain 62 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613583 MGI: 1923696 HomoloGene: 15927 GeneCards: WDR62 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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WD repeat-containing protein 62 is a protein that in humans is encoded by the WDR62 gene. [5] [6]
WDR62 is a scaffold protein and interacts with different kinases. WDR62 plays a role in mediating activation of the JNK pathway in response to TNFα. This finding might have implications in the research of TNFα related diseases such as autoimmune diseases and cancer. [7] It has been also shown that WDR62 upregulation can lead to overproliferation of glia cells and potentially glioma and this is coupled with an upregulation in AURKA, AKT, MYC and PI3K signalling. [8]
WDR62 effect on neurogenesis is regulated by MEKK3 in coordination with FBW7 (F-box and WD repeat domain-containing protein 7). [9]
WDR62 has been shown to have a regulatory role on hippocampus development and neurogenesis. [10]
WDR62 is also involved in male spermatogenesis with an essential role in centriole duplication and manchette removal during the spermatogenesis process. The deficiency of WDR62 results in low sperm counts with defected motility, and abnormal morphology. [11]
Mutations in the WDR62 gene cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, [12] pachygyria with cortical thickening, hypoplasia of the corpus callosum, [5] polymicrogyria as well as microlissencephaly. [13]
Cortical malformation, associated with WDR62 point mutations occurring in humans (V65M and R438H) has been linked to ciliopathies. These WDR62 point mutations drive ciliary disruption in Radial glial cell via disrupting the cilia and centrosome localization of CENPJ and the Intraflagellar transport protein 88 (IFT88), which are required for tubulin requitment to centrosome and transport of tubulin to the cilia tip, respectively. [14]
Abnormal spindle-like microcephaly-associated protein, also known as abnormal spindle protein homolog or Asp homolog, is a protein that in humans is encoded by the ASPM gene. ASPM is located on chromosome 1, band q31 (1q31). The ASPM gene contains 28 exons and codes for a 3477 amino‐acid‐long protein. The ASPM protein is conserved across species including human, mouse, Drosophila, and C. elegans. Defective forms of the ASPM gene are associated with autosomal recessive primary microcephaly.
Polymicrogyria (PMG) is a condition that affects the development of the human brain by multiple small gyri (microgyri) creating excessive folding of the brain leading to an abnormally thick cortex. This abnormality can affect either one region of the brain or multiple regions.
Bilateral frontoparietal polymicrogyria is a genetic disorder with autosomal recessive inheritance that causes a cortical malformation. Our brain has folds in the cortex to increase surface area called gyri and patients with polymicrogyria have an increase number of folds and smaller folds than usual. Polymicrogyria is defined as a cerebral malformation of cortical development in which the normal gyral pattern of the surface of the brain is replaced by an excessive number of small, fused gyri separated by shallow sulci and abnormal cortical lamination. From ongoing research, mutation in GPR56, a member of the adhesion G protein-coupled receptor (GPCR) family, results in BFPP. These mutations are located in different regions of the protein without any evidence of a relationship between the position of the mutation and phenotypic severity. It is also found that GPR56 plays a role in cortical pattering.
Intraflagellar transport (IFT) is a bidirectional motility along axoneme microtubules that is essential for the formation (ciliogenesis) and maintenance of most eukaryotic cilia and flagella. It is thought to be required to build all cilia that assemble within a membrane projection from the cell surface. Plasmodium falciparum cilia and the sperm flagella of Drosophila are examples of cilia that assemble in the cytoplasm and do not require IFT. The process of IFT involves movement of large protein complexes called IFT particles or trains from the cell body to the ciliary tip and followed by their return to the cell body. The outward or anterograde movement is powered by kinesin-2 while the inward or retrograde movement is powered by cytoplasmic dynein 2/1b. The IFT particles are composed of about 20 proteins organized in two subcomplexes called complex A and B.
Pachygyria is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy.
The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. It docks to the intracellular part of the Reelin very low density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation. In mice, Dab1 mutation results in the scrambler mouse phenotype.
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.
Nuclear receptor TLX also known as NR2E1 is a protein that in humans is encoded by the NR2E1 gene. TLX is a member of the nuclear receptor family of intracellular transcription factors.
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Centromere protein F is a protein that in humans is encoded by the CENPF gene. It is involved in chromosome segregation during cell division. It also has a role in the orientation of microtubules to form cellular cilia.
Centrin-2 is a protein that in humans is encoded by the CETN2 gene. It belongs to the centrin family of proteins.
SCL-interrupting locus protein is a protein that in humans is encoded by the STIL gene. STIL is present in many different cell types and is essential for centriole biogenesis. This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint.
Centromere protein J is a protein that in humans is encoded by the CENPJ gene. It is also known as centrosomal P4.1-associated protein (CPAP). During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein.
Zinc finger protein 238 is a zinc finger containing transcription factor that in humans is encoded by the ZNF238 gene.
Uncharacterized protein KIAA1377 is a protein that in humans is encoded by the KIAA1377 gene. Also known as Cep126, the protein has been shown to localize to the centrosome. Furthermore, it is found at pericentriolar satellites and the base of the primary cilium. Depleting Cep126 leads to dispersion of pericentriolar satellites, in turn disrupting microtubule organization at the mitotic spindle.
Sperm flagellar protein 2 is a protein that in humans is encoded by the SPEF2 gene.
Spindle assembly abnormal protein 6 homolog (SAS-6) is a protein that in humans is encoded by the SASS6 gene.
Microlissencephaly (MLIS) is a rare congenital brain disorder that combines severe microcephaly with lissencephaly. Microlissencephaly is a heterogeneous disorder, i.e. it has many different causes and a variable clinical course. Microlissencephaly is a malformation of cortical development (MCD) that occurs due to failure of neuronal migration between the third and fifth month of gestation as well as stem cell population abnormalities. Numerous genes have been found to be associated with microlissencephaly, however, the pathophysiology is still not completely understood.
Strømme syndrome is a very rare autosomal recessive genetic condition characterised by intestinal atresia, eye abnormalities and microcephaly. The intestinal atresia is of the "apple-peel" type, in which the remaining intestine is twisted around its main artery. The front third of the eye is typically underdeveloped, and there is usually moderate developmental delay. Less common features include an atrial septal defect, increased muscle tone or skeletal abnormalities. Physical features may include short stature, large, low-set ears, a small jaw, a large mouth, epicanthic folds, or fine, sparse hair.
Rotatin is a protein that in humans is encoded by the RTTN gene. It is involved in the maintenance of cellular cilia and the radial migration of neurons in the cerebral cortex.
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