|Coordinate||19,948,127 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||kelch-like 6|
|Chromosomal Location||19,946,496-19,983,037 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the kelch-like (KLHL) family of proteins, which is involved in B-lymphocyte antigen receptor signaling and germinal-center B-cell maturation. The encoded protein contains an N-terminal broad-complex, tramtrack and bric a brac (BTB) domain that facilitates protein binding and dimerization, a BTB and C-terminal kelch (BACK) domain, and six C-terminal kelch repeat domains. Naturally occurring mutations in this gene are associated with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]
PHENOTYPE: Mice homozygous for a knock-out allele exhibit spleen hypoplasia, defects in mature B-cell subsets with normal pro- and pre-B-cell development, severely impaired antigen-dependent germinal center formation, and reduced memory IgG response. [provided by MGI curators]
|Amino Acid Change||Cysteine changed to Serine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000053023]|
AA Change: C506S
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Meta Mutation Damage Score||0.312|
|Is this an essential gene?||Probably nonessential (E-score: 0.074)|
|Candidate Explorer Status||CE: not good candidate; human score: -4.5; ML prob: 0.34|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-05-24 4:38 PM by Diantha La Vine|
|Record Created||2019-01-22 12:33 PM by Bruce Beutler|
The torres_del_paine phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5475, some of which showed increased frequencies of B1 cells in the peripheral blood (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 61 mutations. The B1 cell phenotype was linked by continuous variable mapping to a mutation in Klhl6: a T to A transversion at base pair 19,948,127 (v38) on chromosome 16, or base pair 34,923 in the GenBank genomic region NC_000082 encoding Klhl6. Linkage was found with a recessive model of inheritance, wherein four variant homozygotes departed phenotypically from 17 homozygous reference mice and 13 heterozygous mice with a P value of 0.000797 (Figure 2).
The mutation corresponds to residue 1,562 in the mRNA sequence NM_183390 within exon 6 of 7 total exons.
The mutated nucleotide is indicated in red. The mutation results in a cysteine to serine substitution at position 506 (C506S) in the KLHL6 protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 1.000).
KLHL6 is a member of the Kelch-like family (see the record for teeny for information about KBTBD2, another Kelch-like family member). Similar to other Kelch-like family members, KLHL6 has a Bric-a-brac, Tramtrack, Broad-complex (BTB) domain at the N-terminus, a BACK domain, and a kelch repeat region at the C-terminus (KLHL6 has five or six kelch repeats) (Figure 3) (1). BTB domains facilitate protein-protein interactions, the BACK domain has no known function, and Kelch domains form a tertiary structure of β-propellers that have a role in extracellular functions, morphology, and binding to other proteins.
The torres_del_paine mutation results in a cysteine to serine substitution at position 506 (C506S); amino acid 506 is within the fourth Kelch domain.
Please see the record cerulean for more information about Klhl6.
KLHL6 has putative functions in B cell receptor-associated signal transduction and germinal center responses (2). Loss of KLHL6 expression results in impaired transitional B cell survival and differentiation (3). Klhl6-deficient (Klhl6-/-) mice exhibited impaired B cell development past the immature stage, reduced numbers of B220+ and CD3- B cells in the spleen and peripheral blood, reduced numbers of follicular B cells in the lymph nodes, reduced spleen weight, spleen hypoplasia, impaired germinal center formation, and impaired memory IgG responses (2). Mice homozygous for an ENU-induced Klhl6 mutation (W267*) exhibited increased numbers of immature B cells, but reduced numbers of mature B cells (MGI).
Putative functions for KLHL6 in T cells has not been described. The role of KLHL6 in B cells is unknown, but it may contribute to cell proliferation and cell survival through interactions with proteins (e.g., HBXIP and Cul3) (3). The phenotype observed in the torres_del_paine mice indicate loss of KLHL6-associated function in B cells.
torres_del_paine(F):5'- TCTCCAGGACTTCTAGGGAAATC -3'
torres_del_paine(R):5'- GCACATTGACTTCTTGTGCC -3'
torres_del_paine_seq(F):5'- GGAAATCCCACCAAGGCCTAGG -3'
torres_del_paine_seq(R):5'- GTGCCCTCTGCCTCCACAG -3'
1. Gupta-Rossi, N., Storck, S., Griebel, P. J., Reynaud, C. A., Weill, J. C., and Dahan, A. (2003) Specific Over-Expression of Deltex and a New Kelch-Like Protein in Human Germinal Center B Cells. Mol Immunol. 39, 791-799.
2. Kroll, J., Shi, X., Caprioli, A., Liu, H. H., Waskow, C., Lin, K. M., Miyazaki, T., Rodewald, H. R., and Sato, T. N. (2005) The BTB-Kelch Protein KLHL6 is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation. Mol Cell Biol. 25, 8531-8540.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Xue Zhong, Jin Huk Choi, and Bruce Beutler|