Phenotypic Mutation 'marine_blue'

• Allele: marine_blue
• Mutation Type: missense
• Chromosome: 6
• Coordinate: 125,289,771 bp (GRCm39)
• Base Change: T ⇒ C (forward strand)
• Gene: Ltbr
• Gene Name: lymphotoxin B receptor
• Synonym(s): Ltar, TNF-R-III, Tnfrsf3, TNFR2-RP, LT-beta receptor, LT beta-R, TNF receptor-related protein, Tnfbr, LTbetaR, TNFCR, TNFRrp
• Chromosomal Location: 125,283,534-125,290,848 bp (-) (GRCm39)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the tumor necrosis factor receptor superfamily. The major ligands of this receptor include lymphotoxin alpha/beta and tumor necrosis factor ligand superfamily member 14. The encoded protein plays a role in signalling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Activity of this receptor has also been linked to carcinogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012] ; PHENOTYPE: Homozygotes for a targeted null mutation lack Peyer's patches, colon-associated lymphoid tissues, and lymph nodes. Mutants also exhibit severely reduced numbers of NK cells and increased susceptibility to Theiler's murine encephalomyelitis virus. [provided by MGI curators]
• Mapped: Yes
• Amino Acid Change: Histidine changed to Arginine
• Institutional Source: Beutler Lab
• Gene Model: predicted gene model for protein(s): [ENSMUSP00000032489]
• AlphaFold: P50284
• SMART Domains: Protein: ENSMUSP00000032489; Gene: ENSMUSG00000030339; AA Change: H141R

Domain	Start	End	E-Value	Type
signal peptide	1	27	N/A	INTRINSIC
TNFR	43	80	5.73e-5	SMART
TNFR	83	124	3.96e-8	SMART
Blast:TNFR	126	169	3e-7	BLAST
TNFR	172	212	1.95e-7	SMART
transmembrane domain	222	244	N/A	INTRINSIC
low complexity region	294	305	N/A	INTRINSIC
low complexity region	362	388	N/A	INTRINSIC

• Predicted Effect: probably damaging ; PolyPhen 2 Score 0.983 (Sensitivity: 0.75; Specificity: 0.96)
  (Using ENSMUST00000032489)
• Meta Mutation Damage Score: 0.2372
• Is this an essential gene?: Non Essential (E-score: 0.000)
• Phenotypic Category: Unknown
• Mode of Inheritance: Unknown
• Last Updated: 2019-09-04 9:37 PM by Diantha La Vine
• Record Created: 2018-03-29 1:49 PM by Xue Zhong
• Record Posted: 2018-04-04
• Science Writers: Anne Murray
• Illustrators: Diantha La Vine
• Authors: Jin Huk Choi, Xue Zhong, Evan Nair-Gill, and Bruce Beutler

Accession Number

NCBI RefSeq: NM_010736; MGI:104875

Alleles Listed at MGI

NCBI RefSeq: NM_010736; MGI:104875

Phenotypic Description

Figure 1. Marine_blue mice exhibit increased B to T cell ratios. Flow cytometric analysis of peripheral blood was utilized to determine B and T cell frequencies. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 2. Marine_blue mice exhibit increased frequencies of peripheral B cells. Flow cytometric analysis of peripheral blood was utilized to determine B cell frequency. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 3. Marine_blue mice exhibit increased frequencies of peripheral B1 cells. Flow cytometric analysis of peripheral blood was utilized to determine B1 cell frequency. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 4. Marine_blue mice exhibit reduced frequencies of peripheral CD8+ T cells. Flow cytometric analysis of peripheral blood was utilized to determine T cell frequency. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 5. Marine_blue mice exhibit reduced frequencies of peripheral CD44+ T cells. Flow cytometric analysis of peripheral blood was utilized to determine T cell frequency. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 6. Marine_blue mice exhibit reduced frequencies of peripheral CD44 CD4 T cells. Flow cytometric analysis of peripheral blood was utilized to determine T cell frequency. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 7. Marine_blue mice exhibit reduced frequencies of peripheral NK cells. Flow cytometric analysis of peripheral blood was utilized to determine NK cell frequency. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 8. Marine_blue mice exhibit reduced B220 expression on peripheral blood B cells. Flow cytometric analysis of peripheral blood was utilized to determine B220 MFI. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 9. Marine_blue mice exhibit reduced CD44 expression on peripheral blood T cells. Flow cytometric analysis of peripheral blood was utilized to determine CD44 MFI. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 10. Marine_blue mice exhibit reduced CD44 expression on peripheral blood CD4+ T cells. Flow cytometric analysis of peripheral blood was utilized to determine CD44 MFI. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

Figure 11. Marine_blue mice exhibit reduced CD44 expression on peripheral blood CD8+ T cells. Flow cytometric analysis of peripheral blood was utilized to determine CD44 MFI. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

The marine_blue phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5859, some of which showed increased B to T cell ratios (Figure 1), increased frequencies of B cells (Figure 2) and B1 cells (Figure 3) with concomitant reduced frequencies of CD8+ T cells (Figure 4), CD44+ T cells (Figure 5), CD44+ CD4 T cells (Figure 6), and NK cells (Figure 7), all in the peripheral blood. Some mice showed reduced B220 expression on peripheral blood B cells (Figure 8) as well as reduced CD44 expression on peripheral blood T cells (Figure 9), CD4+ T cells (Figure 10), and CD8+ T cells (Figure 11).

Nature of Mutation

Figure 12. Linkage mapping of the reduced B220 expression using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 64 mutations (X-axis) identified in the G1 male of pedigree R5859. Normalized phenotype data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.

Whole exome HiSeq sequencing of the G1 grandsire identified 64 mutations. All of the above anomalies were linked by continuous variable mapping to mutations in two genes on chromosome 6: Vmn2r27 and Ltbr. The mutation in Ltbr was presumed causative because the marine­­_ blue phenotype mimics that of other Ltbr alleles (see MGI). The mutation in Ltbr is an A to G transition at base pair 125,312,808 on chromosome 6, corresponding to base pair 1,063 in GenBank genomic region NC_000072. The strongest association was found with a recessive model of inheritance to the B220 expression on peripheral blood B cells phenotype, wherein eight variant homozygotes departed phenotypically from 19 homozygous reference mice and 27 heterozygous mice with a P value of 4.874 x 10^-18 (Figure 12). 

The mutation corresponds to residue 622 in the mRNA sequence NM_010736 within exon 4 of 10 total exons.

606 GACAATGAGTGTGTGCACTGTGAGGAGGAGCGG 136 -D--N--E--C--V--H--C--E--E--E--R-

The mutated nucleotide is indicated in red.  The mutation results in a histidine to arginine substitution at position 141 (H141R) in the LTβR protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 0.983).

Protein Prediction

Figure 13. Domain structure of LTβR. The marine_blue mutation within CRD3 is shown. Abbreviations: SP, signal peptide; CRD, cysteine-rich domain; TMD, transmembrane domain; SAD, self-association domain; TRAF, tumor necrosis factor receptor-associated factor; ECD, extracellular domain; ICD, intracellular domain. really interesting new gene; ZINC, zinc finger motifs; CC, coiled coil; MATH, meprin and TRAF homology. This image is interactive. Other mutations found in LTβR are noted in red. Click on the mutations for more information.

Ltbr encodes the lymphotoxin β receptor (LTβR), a member of the tumor necrosis factor receptor (TNFR) superfamily (1). Similar to other members of the TNFR family, LTβR has an extracellular domain (ECD; amino acids 28-221; SMART), a transmembrane domain (TMD; amino acids 222-244), and an intracellular domain (ICD; amino acids 245-415) [(2); reviewed in (3)]. Amino acids 1-27 of LTβR comprise a signal peptide (2). LTβR has two conserved putative Asn-linked glycosylation sites at Asn40 and Asn179 (2). Within the ECD, LTβR has four cysteine-rich domains (CRDs; amino acids 43-80, 83-124, 126-169, and 172-212) [(4); reviewed in (3)]. The CRDs mediate ligand (i.e., LTα₁β₂ and LIGHT) specificity and affinity [(5;6); reviewed in (3)]. The second and third CRDs (i.e., amino acids 83-124 and 126-169) mediate most receptor-ligand interactions (6). The self-association domain (SAD; amino acids 324-377) within the ICD is required for LTβR-associated apoptotic signaling as well as for the association of LTβR with the serine/threonine kinases p50 and p80 (1;7).

The marine_blue mutation results in a histidine to arginine substitution at position 141 (H141R) in the LTβR protein; amino acid 141 is within the third CRD within the ECD.

See the record for kama for more information about Ltbr.

Putative Mechanism

LTα₁β₂ and LIGHT (alternatively, TNF superfamily (TNFSF)14) are the known ligands of LTβR; both LTα₁β₂ and LIGHT are members of the TNF superfamily [4;8-12); see the record PanR1 (Tnf) and walla (Cd40lg)]. LTα₁β₂ is expressed on activated T and B lymphocytes as well as natural killer (NK) cells, a subset of follicular B cells, and lymphoid tissue inducer (LTi) cells (CD4⁺IL-7R⁺CD3⁻ CD45⁺RORγt⁺; see the record for chestnut) (9;13;14). LIGHT is a homotrimer expressed on T lymphocytes, monocytes, granulocytes, and immature dendritic cells (13).

LTβR signals through both the canonical (classical; see the record for finlay) and non-canonical (alternative; see the record for xander) nuclear factor κB (NF-κB) signaling pathways [(15-17); reviewed in (18)]. LTβR-mediated activation of the NF-κB signaling pathways results in the expression of genes that encode adhesion molecules, chemokines (e.g., CCL21 and CXCL13), and lymphokines involved in inflammation and secondary lymphoid organogenesis and homeostasis [(16); reviewed in (3)]. For a detailed review on the NF-κB signaling pathways see the records for finlay and xander.

LTβR-associated signaling mediates several functions including lymphoid tissue development and maintenance (19-23), formation of germinal centers (24), dendritic cell-mediated immune function (25;26), apoptosis (27), chemokine secretion, maintenance of splenic architecture, maintenance of T and B cell segregation into discrete compartments, protection against autoimmune diseases, regulation of lipid metabolism (28), homeostasis of the intestinal immune system (16) including protection against Citrobacter rodentium-induced colitis (10;29) and DSS-induced colitis (30) as well as protection against Mycbacterium bovis bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis, Listeria monocytogenes, and cytomegalovirus infections (31-33).

LTβR-associated signaling has been linked to several human conditions including autoimmunity, atherosclerosis, and cancer (see descriptions, above). Mutations in LTBR have been linked to increased risk for IgA nephropathy (OMIM: %161950), a form of glomerulonephritis that leads to end-stage renal disease, in Korean children (34).

Ltbr knockout (Ltbr^-/-; Ltbr^tm1Kpf, MGI:2384140) mice appear healthy, are born at the expected Menelian frequency, and are fertile (22). Ltbr^-/- mice exhibited defects in secondary lymphoid organogenesis including the absence of cervical, axillary, inguinal, paraaortic/sacral, popliteal, and mesenteric lymph nodes, Peyer’s patches, and germinal centers, disorganization of the splenic architecture (i.e., disturbed microarchitecture of the white pulp, no separate B- and T-cell areas, no follicles, and disruptions to the marginal zone), and disruption of the thymic stroma architecture (21;22;35;36). All of the Ltbr^-/- mice had a spleen and a thymus; the spleens of the Ltbr^-/- mice were 1.5 to 2 times bigger than those in wild-type mice (22). Thymocyte maturation was normal in the Ltbr^-/- mice (22). Within the spleen, the marginal zone B cell population (B220⁺, IgM^high, IgD^dull), MOMA-1⁺ metallophilic macrophages, sialoadhesin⁺ MZ macrophages, and MAdCAM-1⁺ sinus lining cells were completely undetectable (22). Flow cytometric analysis of lymphocytes from lungs and spleens of the Ltbr^-/- mice determined that α_Eβ₇^high integrin⁺ T cells were absent (22). The phenotypes observed in the marine_blue mice indicate loss of LTβR^marine_blue function.

Primers

PCR Primer
marine_blue_pcr_F: CATACCAGTTCATGTCTTGGCAG
marine_blue_pcr_R: GGATCTGCATGATGGGTACG

Sequencing Primer
marine_blue_seq_F: TTCTCCCAGTGGGCAGAG
marine_blue_seq_R: ATCTGCATGATGGGTACGACTGG

Genotyping

PCR program

1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40x
6) 72°C 10:00
7) 4°C hold

The following sequence of 419 nucleotides is amplified (chromosome 6, - strand):

1   ggatctgcat gatgggtacg actgggaggg ccagctcctc tctgactctt ccctctccct
61  gacagtgctg ggctttgagg aggttgcccc ttgcaccagc gatcggaaag ccgagtgccg
121 ctgtcagccg gggatgtcct gtgtgtatct ggacaatgag tgtgtgcact gtgaggagga
181 gcggcttgta ctctgccagc ctggcacaga agccgaggtc acaggtcaga ggtcactgag
241 ggcagccagt aaagggaggc tgggcatcaa gggcaaggaa cgtgatactg tgcgcatggt
301 gcttctcccc actggtactg tgagtgtggt acctctgccc actgggagaa ccataaagaa
361 tctatcagtc cttgaaaaag gctcacagga gggggtctgc caagacatga actggtatg

Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.

References

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