Alternative titles; symbols
HGNC Approved Gene Symbol: DOLK
SNOMEDCT: 718712005;
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38) : 9:128,945,530-128,947,603 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Congenital disorder of glycosylation, type Im | 610768 | Autosomal recessive | 3 |
Dolichyl monophosphate is an essential glycosyl carrier lipid for C- and O-mannosylation and N-glycosylation of proteins and for biosynthesis of glycosyl phosphatidylinositol anchors in endoplasmic reticulum (ER). DOLK catalyzes CTP-mediated phosphorylation of dolichol, the terminal step in de novo dolichyl monophosphate biosynthesis (Fernandez et al., 2002).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Kikuno et al. (1999) cloned DOLK, which they designated KIAA1094. The deduced protein contains 538 amino acids. RT-PCR ELISA detected low to moderate expression in all adult and fetal tissues examined, with highest expression in liver.
Fernandez et al. (2002) determined that the 538-amino acid DK1 protein has a predicted molecular mass of 59.3 kD. It has 13 transmembrane (TM) domains and shares 30% amino acid identity with yeast Sec59. DK1 expressed in insect cells had an apparent molecular mass of 59 to 60 kD by SDS-PAGE.
Using immunofluorescence localization of tagged DK1, Shridas and Waechter (2006) showed that the N terminus of DK1 is on the luminal side of the ER and the C terminus is cytoplasmic.
Lefeber et al. (2011) observed highest expression levels of DOLK mRNA in fetal and adult brain, followed by fetal skeletal muscle and heart and adult heart tissue.
Fernandez et al. (2002) found that overexpression of DK1 complemented the growth deficiency and hypoglycosylation phenotypes of Sec59-deficient yeast. Overexpression of DK1 in Sec59-deficient yeast increased the cellular pool of dolichol phosphate. Crude microsomes from DK1-transfected insect cells showed a 15-fold increase in DK activity compared with controls.
Using site-directed mutagenesis, Shridas and Waechter (2006) showed that asp451, thr472, and the combination of lys470 and lys471, all of which are located in a conserved cytoplasmic motif between TM11 and TM12, were critical for DK1 kinase activity. Mutation of lys470, lys471, and thr472 altered the affinity of DK1 for CTP, but not dolichol. Mutation of gly443 within TM11 also abolished DK1 activity.
By radiation hybrid analysis, Kikuno et al. (1999) mapped the DOLK gene to chromosome 9.
Kranz et al. (2007) described 2 consanguineous families, one German and one Turkish, each with 2 infants with congenital disorder of glycosylation type Im (CDG1M; 610768), previously designated dolichol kinase deficiency. In each patient they found homozygosity for 1 of 2 mutations in the DOLK gene (610746.0001; 610746.0002). Affected individuals presented with a severe phenotype, including muscular hypotonia and dilated cardiomyopathy (CMD), and died in early infancy. Dolichol phosphate is involved in several glycosylation reactions, such as N-glycosylation, glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and C- and O-mannosylation. All 4 patients reported by Kranz et al. (2007) showed a remarkable loss of oligosaccharide structures on serum transferrin, as shown by isoelectric focusing (IEF) and immunoprecipitation of the protein, thus implicating a disorder affecting N-glycosylation. This finding prompted Kranz et al. (2007) to analyze the biosynthetic pathway of dolichol phosphate. Kranz et al. (2007) stated that this was the first defect in humans that affects the biosynthesis of dolichol phosphate by the disturbance of the final phosphorylation step.
In affected children from 4 unrelated consanguineous families with dolichol kinase deficiency and CMD mapping to chromosome 9q33.1-q34.11, Lefeber et al. (2011) identified homozygosity for 3 missense mutations in the DOLK gene (610746.0003-610746.0005). Unlike the patients described previously by Kranz et al. (2007), who died in early infancy with a severe congenital multisystem phenotype, these children presented primarily with nonsyndromic dilated cardiomyopathy at 5 to 13 years of age, and additional clinical symptoms in some of the patients, including ichthyosiform dermatitis, failure to thrive, and neurologic involvement, were mild.
In 2 affected first cousins in a consanguineous German family, Kranz et al. (2007) demonstrated that congenital disorder of glycosylation type Im (610768) was caused by homozygosity for a 295T-A transversion in the DOLK gene, resulting in a cys99-to-ser (C99S) substitution.
In 2 affected sibs in a consanguineous Turkish family, Kranz et al. (2007) demonstrated that congenital disorder of glycosylation type Im (CDG1M; 610768) was caused by homozygosity for a 1322A-C transversion in the DOLK gene, resulting in a tyr441-to-ser (Y441S) substitution.
In affected children from 2 consanguineous Israeli Druze families with congenital disorder of glycosylation type Im (CDG1M; 610768), Lefeber et al. (2011) identified homozygosity for a 1222C-G transversion in the DOLK gene, resulting in a his408-to-asp (H408D) substitution at a highly conserved residue. The mutation was not found in more than 1,000 Caucasian controls or in the 1000 Genomes Project. Although the families resided in 2 different villages in northern Israel and were believed to be unrelated, the presence of an identical 5-Mb haplotype and mutation suggested a founder event among these Druze kindreds. Functional analysis in temperature-sensitive underglycosylated sec59 yeast cells demonstrated that the mutant protein failed to restore glycosylation to the same extent as wildtype. Cardiac tissue from a patient's explanted heart showed reduced O-mannosylation of alpha dystroglycan (128239) with concomitant functional loss of its laminin (see 150320)-binding capacity.
In 3 affected sibs from a consanguineous Bedouin family of northern Israel with congenital disorder of glycosylation type Im (CDG1M; 610768), Lefeber et al. (2011) identified homozygosity for a 912G-T transversion in the DOLK gene, resulting in a trp304-to-cys (W304C) substitution at a highly conserved residue. The mutation was not found in more than 1,000 Caucasian controls or in the 1000 Genomes Project. Functional analysis in temperature-sensitive underglycosylated sec59 yeast cells demonstrated that the mutant protein failed to restore glycosylation to the same extent as wildtype. The 13-year-old girl had asymptomatic dilated cardiomyopathy and her 2 asymptomatic younger brothers showed minimal evidence of CMD on echocardiography; all 3 sibs had ichthyosiform dermatitis. Their older brother had died at 9 years of age from end-stage CMD.
In an 11-year-old Indian girl with congenital disorder of glycosylation type Im (CDG1M; 610768), who died while awaiting cardiac transplant for dilated cardiomyopathy, Lefeber et al. (2011) identified homozygosity for a 3G-A transition in the DOLK gene, resulting in a met1-to-ile (M1I) substitution at the highly conserved initiator residue. Her affected younger brother, who had mild developmental delay and CMD but normal cardiac function, was also homozygous for the mutation, which was not found in more than 1,000 Caucasian controls or in the 1000 Genomes Project. Functional analysis in temperature-sensitive underglycosylated sec59 yeast cells demonstrated that the mutant protein failed to restore glycosylation to the same extent as wildtype.
In 2 sibs, born of consanguineous Syrian Turkish parents, with congenital disorder of glycosylation type Im (CDG1M; 610768), Helander et al. (2013) identified a homozygous c.2T-C transition in the DOLK gene, resulting in a change in the initiation methionine triplet. The authors referred to the mutation as M1?. The patients presented at age 4 months with severe intractable seizures and hypsarrhythmia, consistent with a clinical diagnosis of West syndrome (see 308350). Both had normal early development before the onset of seizures, but thereafter showed delayed psychomotor development with lack of speech. The seizures eventually remitted later in childhood in both patients after intense therapy. Neither patient had cardiac involvement. Serum transferrin analysis showed a CDG type 1 pattern, and lipid-linked oligosaccharides were normal, suggesting an early defect in glycan assembly. Helander et al. (2013) emphasized the purely neurologic presentation in these patients.
Fernandez, F., Shridas, P., Jiang, S., Aebi, M., Waechter, C. J. Expression and characterization of a human cDNA that complements the temperature-sensitive defect in dolichol kinase activity in the yeast sec59-1 mutant: the enzymatic phosphorylation of dolichol and diacylglycerol are catalyzed by separate CTP-mediated kinase activities in Saccharomyces cerevisiae. Glycobiology 12: 555-562, 2002. [PubMed: 12213788] [Full Text: https://doi.org/10.1093/glycob/cwf068]
Helander, A., Stodberg, T., Jaeken, J., Matthijs, G., Eriksson, M., Eggertsen, G. Dolichol kinase deficiency (DOLK-CDG) with a purely neurological presentation caused by a novel mutation. Molec. Genet. Metab. 110: 342-344, 2013. [PubMed: 23890587] [Full Text: https://doi.org/10.1016/j.ymgme.2013.07.002]
Kikuno, R., Nagase, T., Ishikawa, K., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 197-205, 1999. [PubMed: 10470851] [Full Text: https://doi.org/10.1093/dnares/6.3.197]
Kranz, C., Jungeblut, C., Denecke, J., Erlekotte, A., Sohlbach, C., Debus, V., Kehl, H. G., Harms, E., Reith, A., Reichel, S., Grobe, H., Hammersen, G., Schwarzer, U., Marquardt, T. A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy. Am. J. Hum. Genet. 80: 433-440, 2007. [PubMed: 17273964] [Full Text: https://doi.org/10.1086/512130]
Lefeber, D. J., de Brouwer, A. P. M., Morava, E., Riemersma, M., Schuurs-Hoeijmakers, J. H. M., Absmanner, B., Verrijp, K., van den Akker, W. M. R., Huijben, K., Steenbergen, G., van Reeuwijk, J., Jozwiak, A., and 10 others. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation. PLoS Genet. 7: e1002427, 2011. Note: Electronic Article. [PubMed: 22242004] [Full Text: https://doi.org/10.1371/journal.pgen.1002427]
Shridas, P., Waechter, C. J. Human dolichol kinase, a polytopic endoplasmic reticulum membrane protein with a cytoplasmically oriented CTP-binding site. J. Biol. Chem. 281: 31696-31704, 2006. [PubMed: 16923818] [Full Text: https://doi.org/10.1074/jbc.M604087200]