Table of Contents - *610345
External Links:
Genome
DNA
Protein
Gene Info
Variation
Animal Models
Cellular Pathways
| *610345 | |||||||||
| ACYLGLYCEROL KINASE; AGK | |||||||||
| Alternative titles; symbols | |||||||||
| MULTISUBSTRATE LIPID KINASE; MULK | |||||||||
| HGNC Approved Gene Symbol: AGK | |||||||||
| Cytogenetic location: 7q34 Genomic coordinates (GRCh37): 7:141,251,077 - 141,354,208 (from NCBI) | |||||||||
| Gene Phenotype Relationships | |||||||||
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| TEXT | |||||||||
| Cloning | |||||||||
| Using BLAST analysis with the sequence of sphingosine kinase-2 (SPHK2; 607092) as query, Waggoner et al. (2004) identified a sequence which they named multisubstrate lipid kinase (MULK). MULK contains an N-terminal diacylglycerol (DG) kinase domain, a putative nuclear localization signal, and a region with 44% homology to SPHK2. Comparison of putative vertebrate MULK orthologs showed strong conservation of amino acid sequences, and phylogenetic analysis of lipid kinases demonstrated that human and mouse Mulk together form a distinct lipid kinase family. Expression of a MULK-EGFP fusion protein in 293T cells and CHO cells showed that MULK fractionates with membranes and localizes to internal membrane compartments. RT-PCR analysis showed MULK is ubiquitously expressed, with highest expression in pancreas and brain. Bektas et al. (2005) identified and cloned MULK as acylglycerol kinase (AGK) based upon its homology to SPHK1 (603730). They reported that the MULK gene encodes a 422-amino acid protein with 1 predicted transmembrane domain. Immunofluorescence showed that MULK localizes to mitochondria in a variety of cell lines, and cellular fractionation experiments showed that MULK is enriched in mitochondrial fractions. Northern blot analysis showed expression of a 2.6-kb MULK transcript in a variety of tissues, with the highest expression in heart, kidney, muscle, and brain. Northern dot-blot analysis showed that MULK expression is upregulated in prostate cancer, and also expressed in many cancer cell lines including prostate cancer cells. | |||||||||
| Gene Function | |||||||||
| Using an in vitro lipid phosphorylation assay, Waggoner et al. (2004) showed that recombinant MULK phosphorylates diacylglycerol, ceramide, and 1-acylglycerol. MULK exhibits a higher Vmax toward diacylglycerol in vitro, and MULK activity is enhanced by cardiolipin and inhibited by sphingosine. In vitro assays demonstrated that MULK activity is stimulated by calcium when magnesium concentrations are low, and inhibited by calcium when magnesium concentrations are high. Using phosphorylation assays, Bektas et al. (2005) showed that MULK phosphorylates acylglycerols to form phosphatidic acid and lysophosphatidic acid (LPA). Site-directed mutagenesis showed that the conserved GDG sequence in the putative ATP-binding region is required for MULK phosphorylating activity. Using a variety of transfection experiments, the authors showed that expression of MULK in the prostate cancer cell line PC-3 increased formation and secretion of LPA, and that this increase transactivated EGFR (131550) and activated ERK1/2 (601795; 176948), resulting in enhanced cellular proliferation. MULK expression also increased cell migration, as measured by the Boyden chamber cell migration assay. | |||||||||
| Gene Structure | |||||||||
| Waggoner et al. (2004) determined that the MULK gene comprises 15 exons. | |||||||||
| Mapping | |||||||||
| Waggoner et al. (2004) mapped the MULK gene to chromosome 7q34 by genomic sequence analysis. | |||||||||
| Molecular Genetics | |||||||||
| In 2 unrelated patients with myopathic mtDNA depletion syndrome-10 (MTDPS10; 614467), Calvo et al. (2012) identified homozygous or compound heterozygous mutations in the AGK gene (610345.0001-610345.0003). | |||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||
| Table View | |||||||||
| .0001 MITOCHONDRIAL DNA DEPLETION SYNDROME 10 (MYOPATHIC TYPE) | |||||||||
| AGK, IVS3DS, T-C, +2 | |||||||||
| In a patient with mitochondrial DNA depletion syndrome-10 (MTDPS10; 614467), manifest primarily as a myopathy, Calvo et al. (2012) identified compound heterozygosity for 2 mutations in the AGK gene: a T-to-C transition in intron 3 (297+2T-C), resulting in a shortened transcript with a premature termination codon, and a 1170T-A transversion resulting in a tyr390-to-ter (Y390X; 610345.0002) substitution. Each unaffected parent was heterozygous for 1 of the mutations. Both mutations would cause deletion of a highly conserved C-terminal region. The patient presented at age 9 months with hypertrophic obstructive cardiomyopathy and cardiac failure associated with metabolic lactic acidosis. She later had generalized muscle weakness and delayed motor development. At age 11 years, she became wheelchair-bound due to muscle weakness, and later showed some cognitive decline. She died of sudden cardiac arrest during a viral illness at age 18 years. Skeletal muscle biopsy showed mtDNA depletion and a deficiency of mitochondrial respiratory complex activity. | |||||||||
| .0002 MITOCHONDRIAL DNA DEPLETION SYNDROME 10 (MYOPATHIC TYPE) | |||||||||
| AGK, TYR390TER | |||||||||
| See 610345.0001 and Calvo et al. (2012). | |||||||||
| .0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 10 (MYOPATHIC TYPE) | |||||||||
| AGK, IVS13DS, G-T, +1 | |||||||||
| In a neonate, born of consanguineous Pakistani parents, with mitochondrial DNA depletion syndrome-10 (MTDPS10; 614467), manifest primarily as a myopathy, Calvo et al. (2012) identified a homozygous G-to-T transversion in intron 13 of the AGK gene (1131+1G-T), resulting in a shortened transcript with a premature termination codon. The mutation would cause deletion of a highly conserved C-terminal region. The patient developed respiratory distress and circulatory failure in the first hour of life, associated with severe metabolic lactic acidosis. Studies suggested persistent pulmonary hypertension. Other features included bilateral cataracts and thrombocytopenia. She died at age 3 days. Skeletal muscle biopsy showed mtDNA depletion and a deficiency of mitochondrial respiratory complex activity. | |||||||||
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