Phenotypic Mutation 'primurus' (pdf version)
Alleleprimurus
Mutation Type missense
Chromosome19
Coordinate25,160,973 bp (GRCm39)
Base Change T ⇒ C (forward strand)
Gene Dock8
Gene Name dedicator of cytokinesis 8
Synonym(s) 1200017A24Rik, 5830472H07Rik, A130095G14Rik
Chromosomal Location 24,976,898-25,179,796 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 DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]
PHENOTYPE: Mice homozygous for inactivating mutations of this gene exhibit loss of marginal zone B cells, decrease in peritoneal B1 cells and peripheral naive T cells, failure of sustained antibody response after immunization, failure of germinal center persistence, and failure of B cell affinity maturation. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_033374; Ensembl: ENSMUST00000025831; MGI: 2149010

MappedYes 
Amino Acid Change Serine changed to Proline
Institutional SourceAustralian Phenomics Network
Gene Model not available
AlphaFold Q8C147
PDB Structure Crystal structure of the DHR-2 domain of DOCK8 in complex with Cdc42 (T17N mutant) [X-RAY DIFFRACTION]
SMART Domains Protein: ENSMUSP00000025831
Gene: ENSMUSG00000052085
AA Change: S1827P

DomainStartEndE-ValueType
Pfam:DUF3398 71 164 3.9e-25 PFAM
Pfam:DOCK-C2 557 739 6.7e-49 PFAM
low complexity region 786 803 N/A INTRINSIC
low complexity region 1003 1020 N/A INTRINSIC
low complexity region 1123 1138 N/A INTRINSIC
low complexity region 1236 1246 N/A INTRINSIC
low complexity region 1371 1383 N/A INTRINSIC
Pfam:DHR-2 1534 2060 5e-210 PFAM
Predicted Effect probably damaging

PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
(Using ENSMUST00000025831)
Meta Mutation Damage Score Not available question?
Is this an essential gene? Probably nonessential (E-score: 0.083) question?
Phenotypic Category Autosomal Recessive
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance 100% 
Alleles Listed at MGI

All alleles(6) : Gene trapped(4) Chemically induced(2)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
captain_morgan APN 19 25105076 critical splice donor site probably benign
IGL00737:Dock8 APN 19 25160340 missense probably benign 0.00
IGL00755:Dock8 APN 19 25028873 missense probably benign 0.09
IGL00822:Dock8 APN 19 25165773 nonsense probably null
IGL00838:Dock8 APN 19 25152823 nonsense probably null
IGL01419:Dock8 APN 19 25096816 missense probably benign 0.08
IGL01456:Dock8 APN 19 25096863 missense possibly damaging 0.95
IGL01532:Dock8 APN 19 25146805 missense probably damaging 0.99
IGL01602:Dock8 APN 19 25067252 splice site probably benign
IGL01605:Dock8 APN 19 25067252 splice site probably benign
IGL01753:Dock8 APN 19 25038656 splice site probably benign
IGL01843:Dock8 APN 19 25067292 missense probably benign 0.02
IGL02032:Dock8 APN 19 25107769 missense probably damaging 0.99
IGL02073:Dock8 APN 19 25178350 critical splice acceptor site probably null
IGL02192:Dock8 APN 19 25055569 critical splice donor site probably null
IGL02402:Dock8 APN 19 25055509 missense probably benign 0.25
IGL02529:Dock8 APN 19 25078290 nonsense probably null
IGL02728:Dock8 APN 19 25109584 missense probably benign
IGL02739:Dock8 APN 19 25165852 missense probably damaging 1.00
IGL03037:Dock8 APN 19 25063545 missense probably benign 0.02
IGL03104:Dock8 APN 19 25178384 nonsense probably null
IGL03137:Dock8 APN 19 25133312 missense probably benign 0.19
IGL03365:Dock8 APN 19 25077048 missense possibly damaging 0.70
Defenseless UTSW 19 25028927 missense probably benign 0.00
Guardate UTSW 19 25127195 missense probably benign
hillock UTSW 19 25151697 critical splice donor site probably null
Molehill UTSW 19 25107825 missense probably damaging 1.00
Pap UTSW 19 25099805 missense probably benign 0.31
Papilla UTSW 19 25055448 nonsense probably null
snowdrop UTSW 19 25162305 critical splice donor site probably null
warts_and_all UTSW 19 25146865 critical splice donor site probably null
R0021:Dock8 UTSW 19 25140411 missense probably benign 0.01
R0147:Dock8 UTSW 19 25096823 missense probably benign 0.00
R0148:Dock8 UTSW 19 25096823 missense probably benign 0.00
R0294:Dock8 UTSW 19 25165714 missense probably damaging 1.00
R0537:Dock8 UTSW 19 25148941 missense probably benign 0.08
R0630:Dock8 UTSW 19 25038524 missense probably benign 0.10
R1163:Dock8 UTSW 19 25028867 missense probably benign
R1164:Dock8 UTSW 19 25067391 missense probably benign 0.44
R1471:Dock8 UTSW 19 25178400 missense possibly damaging 0.74
R1477:Dock8 UTSW 19 25072914 missense possibly damaging 0.95
R1633:Dock8 UTSW 19 25028927 missense probably benign 0.00
R1803:Dock8 UTSW 19 25109599 missense probably benign 0.00
R1822:Dock8 UTSW 19 25138422 missense probably benign 0.31
R1852:Dock8 UTSW 19 25104492 missense probably benign 0.45
R1916:Dock8 UTSW 19 25038521 missense probably benign 0.02
R1984:Dock8 UTSW 19 25098545 missense probably null
R2311:Dock8 UTSW 19 25160368 missense possibly damaging 0.93
R2341:Dock8 UTSW 19 25177757 missense probably damaging 0.99
R2483:Dock8 UTSW 19 25057241 missense probably benign
R3116:Dock8 UTSW 19 25165858 missense probably benign 0.00
R3157:Dock8 UTSW 19 25127195 missense probably benign
R3623:Dock8 UTSW 19 25057241 missense probably benign
R3624:Dock8 UTSW 19 25057241 missense probably benign
R3800:Dock8 UTSW 19 25141716 missense probably benign 0.08
R3844:Dock8 UTSW 19 25042794 nonsense probably null
R3895:Dock8 UTSW 19 25028865 missense probably benign 0.31
R3901:Dock8 UTSW 19 25078269 missense possibly damaging 0.69
R3959:Dock8 UTSW 19 25162305 critical splice donor site probably null
R4428:Dock8 UTSW 19 25042754 missense probably benign 0.00
R4428:Dock8 UTSW 19 25177863 missense probably damaging 0.98
R4429:Dock8 UTSW 19 25042754 missense probably benign 0.00
R4431:Dock8 UTSW 19 25042754 missense probably benign 0.00
R4545:Dock8 UTSW 19 25165722 missense probably damaging 1.00
R4839:Dock8 UTSW 19 25146858 missense probably benign 0.00
R4897:Dock8 UTSW 19 25159001 missense probably benign 0.00
R4939:Dock8 UTSW 19 25099764 missense probably damaging 1.00
R4995:Dock8 UTSW 19 25135747 missense probably benign 0.02
R5035:Dock8 UTSW 19 25063571 missense probably damaging 0.99
R5294:Dock8 UTSW 19 25038517 missense probably benign 0.01
R5324:Dock8 UTSW 19 25140458 missense probably benign 0.17
R5478:Dock8 UTSW 19 25057186 missense probably benign
R5704:Dock8 UTSW 19 25151586 missense probably damaging 1.00
R5724:Dock8 UTSW 19 25099785 missense probably damaging 1.00
R5745:Dock8 UTSW 19 25107761 missense probably benign 0.02
R5864:Dock8 UTSW 19 25038584 missense probably damaging 0.99
R5870:Dock8 UTSW 19 25109490 missense probably benign
R5893:Dock8 UTSW 19 25099811 missense probably damaging 1.00
R5954:Dock8 UTSW 19 25148983 missense probably damaging 1.00
R6087:Dock8 UTSW 19 25138438 missense probably benign 0.00
R6223:Dock8 UTSW 19 25138416 missense probably benign 0.00
R6391:Dock8 UTSW 19 25072914 missense possibly damaging 0.95
R6759:Dock8 UTSW 19 25104848 missense probably damaging 0.99
R6786:Dock8 UTSW 19 25160386 missense possibly damaging 0.49
R6794:Dock8 UTSW 19 25099805 missense probably benign 0.31
R6818:Dock8 UTSW 19 25146865 critical splice donor site probably null
R6885:Dock8 UTSW 19 25124742 missense possibly damaging 0.95
R6908:Dock8 UTSW 19 25165746 missense probably damaging 1.00
R6923:Dock8 UTSW 19 25072970 missense probably benign
R7001:Dock8 UTSW 19 25077041 missense probably benign
R7141:Dock8 UTSW 19 25158984 missense probably null 0.75
R7203:Dock8 UTSW 19 25158927 missense probably damaging 1.00
R7257:Dock8 UTSW 19 25104449 missense probably benign 0.08
R7296:Dock8 UTSW 19 25162245 missense probably benign 0.00
R7538:Dock8 UTSW 19 25135782 missense probably damaging 1.00
R7555:Dock8 UTSW 19 25152764 missense probably damaging 0.99
R7641:Dock8 UTSW 19 25151697 critical splice donor site probably null
R7764:Dock8 UTSW 19 25074899 missense probably benign
R7859:Dock8 UTSW 19 25160934 missense probably damaging 1.00
R7864:Dock8 UTSW 19 25140864 missense possibly damaging 0.95
R8090:Dock8 UTSW 19 25131606 missense probably damaging 1.00
R8160:Dock8 UTSW 19 25124711 missense probably damaging 1.00
R8287:Dock8 UTSW 19 25107825 missense probably damaging 1.00
R8295:Dock8 UTSW 19 25100600 missense probably benign 0.04
R8443:Dock8 UTSW 19 25133281 missense probably benign 0.04
R8537:Dock8 UTSW 19 25107870 missense probably benign 0.00
R8673:Dock8 UTSW 19 25160867 missense probably damaging 0.96
R8709:Dock8 UTSW 19 25055448 nonsense probably null
R8834:Dock8 UTSW 19 25140834 missense probably benign 0.16
R8991:Dock8 UTSW 19 25165731 missense possibly damaging 0.82
R9292:Dock8 UTSW 19 25160995 splice site probably benign
R9509:Dock8 UTSW 19 25072985 missense probably benign 0.00
R9526:Dock8 UTSW 19 25165739 missense probably benign 0.10
R9622:Dock8 UTSW 19 25098545 missense probably null
R9634:Dock8 UTSW 19 25169585 missense probably damaging 1.00
R9654:Dock8 UTSW 19 25124710 missense probably damaging 1.00
R9670:Dock8 UTSW 19 25148926 missense probably null 0.01
R9699:Dock8 UTSW 19 25133388 critical splice donor site probably null
R9726:Dock8 UTSW 19 25154374 missense probably damaging 0.97
R9765:Dock8 UTSW 19 25146832 missense possibly damaging 0.94
X0027:Dock8 UTSW 19 25138493 missense probably benign
Z1177:Dock8 UTSW 19 25133336 missense probably benign 0.16
Z1177:Dock8 UTSW 19 25109487 missense probably benign 0.05
Mode of Inheritance Autosomal Recessive
Local Stock None
Repository

Australian PhenomeBank: 4498

Last Updated 2019-05-26 8:06 AM by Diantha La Vine
Record Created 2011-01-12 2:36 PM by Nora G. Smart
Record Posted 2011-01-12
Phenotypic Description

The primurus mutation was identified while screening N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice for a failure to mount long-lived, high-affinity antibody responses despite a relatively normal initial wave of antibody production.  Primurus is allelic to captain morgan.

For more information on the phenotype of primurus mice, please see the record for captain morgan.

Nature of Mutation

The primurus mutation was mapped to Chromosome 19.  Sequencing B cell–expressed transcripts in the minimal 4.5 Mb interval identified a T to C transition at position 5601 of the Dock8 transcript using Genbank record NM_028785.3, in exon 43 of 48 total exons.

5586 AAGCTCCCGGAGATCTCACATAGACTAGAGGGA
1822 -K--L--P--E--I--S--H--R--L--E--G-

The mutated nucleotide is indicated in red lettering and causes a serine to proline change at amino acid 1827 of the encoded protein.

Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 1. Domain structure of DOCK8, a member of the DOCKC subfamily. DHR-1 domain shares a weak homology to the C2 domain. The large DHR-2 domain interacts with the nucleotide-free form of Rac and/or Cdc42. The primurus mutation causes a serine to proline change at amino acid 1827 of the encoded protein. This image is interactive. Other mutations found in DOCK8 are noted in red. Click on each mutation for more specific information.

The primurus mutation alters a highly conserved amino acid in the DHR-2 domain (Figure 1).  In the structure of DOCK9 in complex with Cdc42 (1), this conserved serine lies in the DHR-2 lobe B α-helix 6, which forms part of the Cdc42-binding site and provides four Cdc42 contact residues.  The pri substitution of Ser1827 to Pro1827 would be expected to break this α-helical structure and interfere with the guanine-exchange factor activity of the DHR-2 domain.

Putative Mechanism

The phenotypes of primurus animals are identical to those found in captain morgan mice, suggesting that primurus is a strong loss of function allele.  

For more information on Dock8, please see the record for captain morgan.

Primers Primers cannot be located by automatic search.
Genotyping

Genotyping protocols are from the Australian PhenomeBank. 

Primurus

References

1. Yang, J., Zhang, Z., Roe, S. M., Marshall, C. J., and Barford, D. (2009) Activation of Rho GTPases by DOCK Exchange Factors is Mediated by a Nucleotide Sensor. Science. 325, 1398-1402.

Science Writers Nora G. Smart
Illustrators Diantha La Vine
AuthorsKatrina L Randall, Teresa Lambe, Andy L Johnson, Bebhinn Treanor, Edyta Kucharska, Heather Domaschenz, Belinda Whittle, Lina E Tze, Anselm Enders, Tanya L Crockford, Tiphaine Bouriez-Jones, Duncan Alston, Jason G Cyster, Michael J Lenardo, Fabienne Mackay, Elissa K Deenick, Stuart G Tangye, Tyani D Chan, Tahra Camidge, Robert Brink, Carola G Vinuesa, Facundo D Batista, Richard J Cornall, Christopher C Goodnow
Edit History
2011-05-25 10:55 AM (current)
2011-01-14 11:51 AM
2011-01-13 10:11 AM
2011-01-13 10:11 AM
2011-01-12 5:12 PM
2011-01-12 3:33 PM
2011-01-12 3:27 PM