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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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HGNC Approved Gene Symbol: CLK2Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,262,867-155,273,503 (from NCBI)▼ Cloning and ExpressionThe prot...

HGNC Approved Gene Symbol: CLK2

Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,262,867-155,273,503 (from NCBI)

▼ Cloning and Expression
The protein kinases are a family of enzymes that catalyze the phosphorylation of proteins and are classified according to the amino acid that acts as the phosphate acceptor. Hanes et al. (1994) cloned human ovarian follicle cDNAs encoding the novel serine/threonine kinase CLK2 based on their high sequence identity to human and mouse protein kinase CLK1 (CLK; 601951) cDNAs. The authors identified 2 alternative CLK2 cDNAs of different lengths that represent differentially spliced CLK2 transcripts; these mRNAs coexist at varying ratios in human prostate, testis, leukocytes, and muscle. The longer CLK2 cDNA encodes a predicted 499-amino acid protein that has a nonconserved N-terminal domain, a highly conserved C-terminal kinase domain, and multiple potential phosphorylation sites. This CLK2 isoform has 61% and 56% sequence identity with the CLK3 (602990) and CLK1 proteins, respectively. The shorter cDNA contains an internal deletion corresponding to an 88-bp exon, resulting in a predicted 139-amino acid protein that lacks the kinase domain. Southern blot analysis of human genomic DNA suggested that CLK2 is a single-copy gene.

▼ Mapping
By PCR analysis of a human-rodent somatic cell hybrid panel, Hanes et al. (1994) mapped the human CLK2 gene to chromosome 1.

Tsujikawa et al. (1998) determined that CLK2 and the gene for AMP-activated protein kinase, alpha-2 (PRKAA2; 600497) are located in the same interval of approximately 2.6 cM between D1S2890 and D1S2801. The PRKAA2 gene is located at 1p31.

Talmadge et al. (1998) mapped the CLK2 gene to chromosome 1q21 by fluorescence in situ hybridization.

▼ Gene Function
Haploinsufficiency of SHANK3 (606230) causes neurologic features of Phelan-McDermid syndrome (PHMDS; 606232), including risk of autism spectrum disorder (see 209850). Using cultured rat and mouse neurons, Bidinosti et al. (2016) showed that knockdown of Shank3 resulted in reduced ubiquitination-dependent degradation of Clk2. Elevated Clk2 levels caused increased phosphorylation and activation of B56-beta (PPP2R5B; 601644), a regulatory subunit of protein phosphatase-2A (PP2A). Activation of PP2A led to excessive dephosphorylation and deactivation of Akt (see 164730) and proteins in the mTORC1 pathway (see 601231). Knockdown of Shank3 also reduced miniature excitatory postsynaptic current frequency in cultured rodent neurons. Human neurons from induced pluripotent stem cells of 2 unrelated PMDS patients showed reduced AKT phosphorylation and reduced frequency of spontaneous excitatory postsynaptic currents compared with controls. Pharmacologic activation of AKT or inhibition of CLK2 restored AKT phosphorylation and synaptic activity in SHANK3-deficient rodent and human neurons. IGF1 treatment also restored normal dendritic spine density to Shank3-knockdown neurons in an Akt-dependent manner. Neurons from mice lacking expression of major Shank3 isoforms had excessive Clk2 protein and activity and reduced Akt phosphorylation in synaptosomal fractions. Pharmacologic inhibition of Clk2 significantly decreased self-grooming and increased normal social behavior in mutant mice and increased Akt phosphorylation in mutant synaptosomal fractions.

▼ Cytogenetics
Nothwang et al. (2001) reported a translocation t(1;19)(q21.3;q13.2) in a female with mental retardation, ataxia, and atrophy of the brain. Sequence analysis of the breakpoints revealed an Alu repeat-mediated mechanism of recombination that led to truncation of CLK2 and PAFAH1B3 (603074), the gene product of which interacts with LIS1 (601545) as part of the heterotrimeric G protein complex PAFAH1B. One expressed fusion gene encoded the first 136 amino acids of PAFAH1B3, followed by the complete CLK2 protein. Truncated PAFAH1B3 protein lost its potential to interact with LIS1, whereas CLK2 activity was conserved within the fusion protein. These data emphasized the importance of PAFAH1B in brain development and function.

Tags: 1q22