|Coordinate||19,957,043 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||Valine changed to Aspartic acid|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000053023] [ENSMUSP00000130755]|
AA Change: V255D
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.555 (Sensitivity: 0.88; Specificity: 0.91)
|Predicted Effect||noncoding transcript|
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-01-30 8:07 AM by Diantha La Vine|
|Record Created||2018-12-09 12:50 PM by Bruce Beutler|
The Parula phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1871, some of which showed increased frequencies of T cells (Figure 1), CD4+ T cells (Figure 2), CD8+ T cells (Figure 3), and B1a cells (Figure 4) in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 81 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Klhl6: a T to A transversion at base pair 19,957,043 (v38) on chromosome 16, or base pair 26,007 in the GenBank genomic region NC_000082 encoding Klhl6. The strongest association was found with an additive model of inheritance to the normalized frequency of T cells, wherein four variant homozygotes and seven heterozygous mice departed phenotypically from nine homozygous reference mice with a P value of 7.53 x 10-7 (Figure 5).
The mutation corresponds to residue 810 in the mRNA sequence NM_183390 within exon 3 of 7 total exons.
The mutated nucleotide is indicated in red. The mutation results in a valine to aspartic acid substitution at position 255 (V255D) in the KLHL6 protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 0.555).
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) (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 Parula mutation results in a valine to aspartic acid substitution at position 255 (V255D); amino acid 255 is within the BACK 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) .
Parula(F):5'- AGAGTCCCTGGATAATGCCTTAC -3'
Parula(R):5'- GGACAGTTTAAAGATGCAAGTCC -3'
Parula_seq(F):5'- TGGATAATGCCTTACATTCCCAAC -3'
Parula_seq(R):5'- AGATGCAAGTCCAAAGTTACATC -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|