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]
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.
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
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.
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 cannot be located by automatic search.
Genotyping protocols are from the Australian PhenomeBank.
Katrina 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