Mice homozygous for big giant head mutation (bgh; Spef2bgh) have several abnormalities commonly associated with primary ciliary dyskinesia (PCD; including hydrocephalus, sinusitis and male infertility), as well as reduced respiratory ciliary motility. These C57BL/6J-congenic bgh mice (B6J.bgh) may be useful in studying PCD, as well as the role of mucociliary clearance in host defense.
Lance Lee, Sanford Children’s Health Research Center (Sanford Research Center)
Mice homozygous for the "big giant head" mutation (bgh/bgh; Spef2bgh/bgh) have several abnormalities commonly associated with primary ciliary dyskinesia (PCD); including hydrocephalus, sinusitis and male infertility. Homozygous mice do not exhibit situs inversus. Heterozygous mice are viable and fertile with no abnormal phenotype. The absence of full-length protein was confirmed by western blot analysis on testis extracts from homozygotes.
The donating investigator has assessed homozygous phenotype on three different backgrounds: C57BL/6J-congenic (B6J.bgh/bgh), 129S6/SvEvTac-congenic (129S6.bgh/bgh) and an F1 cross of these two backgrounds ((B6x129)F1.bgh/bgh). Overall, the severity of morphological brain damage is background strain-dependent. Alterations in astrocytosis, microglial activation, myelination, and the neuronal population were identified and are generally more severe on the C57BL/6J background. Specific details follow.
B6J.bgh/bgh mice exhibit lethal hydrocephalus (average death ~ 1 month of age) with damage to multiple cell types, as well as cilia-driven cerebrospinal fluid flow deficit, sinusitis and male infertility. B6J.bgh/bgh also exhibit upper airway abnormalities (reduced respiratory ciliary motility, but no ultrastructural defects); although no major cellular, developmental or inflammatory abnormalities in the lower airway are reported. The donating investigator reports that B6J.bgh/bgh mice do not exhibit situs inversus. Heterozygous mice (B6J.bgh/+) are viable and fertile with no abnormal phenotype.
129S6.bgh/bgh mice do not develop gross hydrocephalus or exhibit early mortality, although they have cilia-driven cerebrospinal fluid flow deficits and variable levels of ventricular enlargement and brain damage. The sinusitis phenotype and male fertility phenotype for 129S6.bgh/bgh mice has not been characterized to date (although the donating investigator expects it to be similar to B6J.bgh/bgh animals). The specific upper airway vs. lower airway phenotype described for B6J.bgh/bgh has not been tested in 129S6.bgh/bgh to date (July 2015). The donating investigator reports that 129S6.bgh/bgh mice do not exhibit situs inversus. Heterozygous mice (129S6.bgh/+) are viable and fertile with no abnormal phenotype.
(B6x129)F1.bgh/bgh mice exhibit sinusitis and male infertility, but no evidence of gross hydrocephalus or early mortality. (B6x129)F1.bgh/bgh also exhibit upper airway abnormalities (reduced respiratory ciliary motility, but no ultrastructural defects); although no major cellular, developmental or inflammatory abnormalities in the lower airway are reported. The infertility in (B6x129)F1.bgh/bgh males results from reduction in the number of elongating spermatids during spermiogenesis and structural defects in sperm flagella (this could not be tested directly in B6J.bgh/bgh males because they die before sexual maturity). The donating investigator reports that (B6x129)F1.bgh/bgh mice do not exhibit situs inversus. Heterozygous mice ((B6x129)F1.bgh/+) are viable and fertile with no abnormal phenotype. Compared to similarly treated (B6x129)F1 wildtype mice, the (B6x129)F1.bgh/bgh mice show increased lymphocytic response when challenged with Streptococcus pneumonia infection.
Dr. Richard J. Cornall (Oxford University) used N-ethyl-N-nitrosourea (ENU) mutagenesis in C57BL/6J mice to generate the fragile red (fred) mutant mice (Steap3Y288H or Steap3fred). The fred mice were next sent to Dr. Mark Fleming (Boston Children's Hospital). While maintaining them on a mixed C57BL/6J;C57BL/10J (B6;B10) background, some of offspring were found to spontaneously develop severe hydrocephalus. This resulting autosomal recessive "big giant head" mutation (bgh) was linked to two point mutations in the sperm flagellar 2 locus (Spef2) on chromosome 15: exon 3 has a T-to-A transversion (T835A) encoding a lysine-to-glutamine missense mutation (K412Q) in the DUF domain, and exon 28 has a C-to-G transversion (C8765G) encoding a lysine-to-nonsense codon mutation (K1320X). Both mutations are inherited in cis, and it is not known which mutation is causative in protein absence.
The Spef2bgh mice were then backcrossed several generations with C57BL/6J inbred mice and 129S6/SvEvTac inbred mice; creating the individual B6J-congenic Spef2bgh colony (B6J.bgh) and 129S6-congenic Spef2bgh colony (129S6.bgh), respectively. In 2010, the B6J.bgh mice (backcrossed six generations onto C57BL/6J) were sent to Dr. Lance Lee (Sanford Research Center) for further analysis. There, Dr. Lee backcrossed the B6J.bgh colony six more generations onto C57BL/6J before sending black male mice to The Jackson Laboratory Repository in 2015.
Upon arrival, males were used to cryopreserve sperm. To establish our living B6J-congenic Spef2bgh mouse colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6J inbred females (Stock No. 000664).
|Allele Name||big giant head|
|Allele Type||Chemically induced (ENU) (Null/Knockout)|
|Gene Symbol and Name||Spef2, sperm flagellar 2|
|Strain of Origin||C57BL/6J|
|Molecular Note||ENU induced a missense mutation in exon 3 that results in the amino acid substitution of lysine for glutamine in the DUF domain. An additional nonsense mutation in exon 28 results in a protein truncation after amino acid 1320. The absence of full-length protein was confirmed by western blot analysis on testis extracts.|
Homozygous mice on the C57BL/6J genetic background (B6J.bgh/bgh) exhibit lethal hydrocephalus (average death ~ 1 month of age) and male infertility. Therefore, when maintaining a live colony, heterozygous mice may be bred together, to wildtype mice from the colony or to C57BL/6J inbred mice (Stock No. 000664).
When using the big giant head (bgh) mouse strain in a publication, please cite the originating article(s) and include JAX stock #027799 in your Materials and Methods section.
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