|Coordinate||96,140,656 bp (GRCm38)|
|Base Change||C ⇒ T (forward strand)|
|Gene Name||glycerol kinase 5 (putative)|
|Chromosomal Location||96,119,362-96,184,608 bp (+)|
|MGI Phenotype||PHENOTYPE: Homozygous knockout does not result in an obvious skin phenotype and does not lead to alopecia. [provided by MGI curators]|
|Amino Acid Change||Glutamine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000082313] [ENSMUSP00000112717] [ENSMUSP00000123594]|
AA Change: Q182*
|Predicted Effect||probably null|
AA Change: Q182*
|Predicted Effect||probably null|
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.608|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: excellent candidate; human score: 0.5; ML prob: 0.806|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Local Stock||Live Mice|
|Last Updated||2019-09-04 9:38 PM by Anne Murray|
|Record Created||2018-01-09 1:07 PM by Jamie Russell|
The homer phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5643, some of which showed hair loss (Figure 1). Some mice also showed increased frequencies of CD44+ CD8 T cells (Figure 2), and central memory CD8 T cells in CD8 T cells (Figure 3) in the peripheral blood as well as increased expression of CD44 on peripheral blood CD8 T cells (Figure 4).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 111 mutations. All of the above anomalies were linked to a mutation in Gk5: a C to T transition at base pair 96,140,656 (v38) on chromosome 9, or base pair 21,313 in the GenBank genomic region NC_000075. The strongest association was found with a recessive model of inheritance to the hair loss phenotype (P = 5.939 x 10-9), wherein 10 affected mice were homozygous (N = 9) for the variant allele (genotyping failed for one affected mouse at all sites tested), and 34 unaffected mice were either heterozygous (N = 13) or homozygous for the reference allele (N = 21) (Figure 5).
The mutation corresponds to residue 566 in the mRNA sequence NM_177352.4 within exon 5 of 17 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of glutamine 182 for a premature stop codon (Q182*) in the GK5 protein.
The glycerol kinase 5 (putative) (Gk5) gene encodes the 534 amino acid (aa) GK5 protein. The protein domains and function of GK5 have not been documented. SMART predicts that this uncharacterized protein contains two domains that are found in the FGGY family of carbohydrate kinases. The FGGY kinases contain conserved motifs at both the N- and C-termini (Figure 6; aa 25-287 and aa 396-416 in GK5, respectively; SMART). The FGGY_N and FGGY_C termini are structurally similar and adopt a ribonuclease H-like fold (1;2). Between the FGGY_N and FGGY_C domains is a catalytic cleft where the sugar substrate and ATP bind (3). The mutation results in substitution of glutamine 182 for a premature stop codon (Q182*) in the GK5 protein; amino acid 182 is within the FGGY_N domain.
For more information about Gk5, please see the entry for toku.
The over 4,000 members of the FGGY family phosphorylate sugar substrates in an ATP-dependent manner (3). Similar to glycerol kinase, GK5 is proposed to be involved in ATP binding, phosphotransferase activity, and glycerol kinase activity. GK5 is necessary for hair growth, and functions in the regulation of SREBP-1/-2-mediated cholesterol production in the skin (4). The buildup of sterol precursors in the sebocytes results in defects in hair follicle development and homeostasis as observed in the homer mice (4).
1) 94°C 2:00
The following sequence of 400 nucleotides is amplified (chromosome 9, + strand):
1 cccaagtgcc cttaaatgta tttccttaaa gatctctttt gtttttaaaa cagctattgc
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Hurley, J. H., Faber, H. R., Worthylake, D., Meadow, N. D., Roseman, S., Pettigrew, D. W., and Remington, S. J. (1993) Structure of the Regulatory Complex of Escherichia Coli IIIGlc with Glycerol Kinase. Science. 259, 673-677.
2. Ormo, M., Bystrom, C. E., and Remington, S. J. (1998) Crystal Structure of a Complex of Escherichia Coli Glycerol Kinase and an Allosteric Effector Fructose 1,6-Bisphosphate. Biochemistry. 37, 16565-16572.
3. Zhang, Y., Zagnitko, O., Rodionova, I., Osterman, A., and Godzik, A. (2011) The FGGY Carbohydrate Kinase Family: Insights into the Evolution of Functional Specificities. PLoS Comput Biol. 7, e1002318.
4. 1. Zhang, D., Tomisato, W., Su, L., Sun, L., Choi, J. H., Zhang, Z., Wang, K., Zhan, X., Choi, M., Li, X., Castro-Perez, J. M., Hildebrand, S., Murray, A. R., Moresco, E. M. Y., and Beutler, B. (2017) Skin-Specific Regulation of SREBP Processing and Lipid Biosynthesis by Glycerol Kinase 5. Proc Natl Acad Sci USA. 114, E5197-E5206.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Lauren Prince, Duanwu Zhang, Jamie Russell, Xue Zhong, and Bruce Beutler|