Blind sterile 2 (bs2), a hypomorphic mutation in Agps, results in cataracts and male sterility in mice
Open accessAbstract
Blind sterile 2 (bs2) is a spontaneous autosomal recessive mouse mutation exhibiting cataracts and male sterility. Detailed clinical and histological evaluation revealed that bs2 mice have cataracts resulting from severely disrupted lens fiber cells. Analysis of bs2 testes revealed the absence of mature sperm and the presence of large multinucleate cells within the lumens of seminiferous tubules. Linkage analysis mapped the bs2 locus to mouse chromosome 2, approximately 45cM distal from the centromere. Fine mapping established a 3.1Mb bs2 critical region containing 19 candidate genes. Sequence analysis of alkylglycerone-phosphate synthase (Agps), a gene within the bs2 critical region, revealed a G to A substitution at the +5 position of intron 14. This mutation results in two abundantly expressed aberrantly spliced Agps transcripts: Agps(∆exon14) lacking exon 14 or Agps(exon∆13-14) lacking both exons 13 and 14 as well as full-length Agps transcript. Agps is a peroxisomal enzyme which catalyzes the formation of the ether bond during the synthesis of ether lipids. Both aberrantly spliced Agps(∆exon14) and Agps(exon∆13-14) transcripts led to a frame shift, premature stop and putative proteins lacking the enzymatic FAD domain. We present evidence that bs2 mice have significantly decreased levels of ether lipids. Human mutations in Agps result in rhizomelic chondrodysplasia punctata type 3 (RCDP3), a disease for which bs2 is the only genetic model. Thus, bs2 is a hypomorphic mutation in Agps, and represents a useful model for investigation of the tissue specificity of ether lipid requirements which will be particularly valuable for elucidating the mechanism of disease phenotypes resulting from ether lipid depletion.
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Hypomorphic mouse models with residual Pex7 or Agps transcript and residual ether lipids mimic milder human RCDP.
“Furthermore, hypomorphic mouse models with residual transcript levels of the Pex7 [215] or the Agps [216] gene and, consequently, residual levels of ether lipids have been described, which mimic the milder form of the human disease.”
From Peroxisomes in brain development and function (2016) · cites this paper as [216]
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Peroxisomes in brain development and function
Berger, J., Dorninger, F., Forss-Petter, S., & Kunze, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.005 · Cited by 194 · see citing works
The neurology of rhizomelic chondrodysplasia punctata
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- Authors
- Liegel, R., Chang, B., Dubielzig, R., & Sidjanin, D. J.
- Affiliations
- Medical College of Wisconsin (US)
- Jackson Laboratory (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Sidjanin, D.J.
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 103
- Issue
- 1
- Pages
- 51-59
- ISSN
- 1096-7192 (ISSN-L)
- PMC
- PMC3081956
- OpenAlex
- W2038764117
- Cited by
- 38
- References
- 47
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 4 · 2021: 2 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 6 · 2012: 5
- FWCI
- 3.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health (5r01ey019943-13)
- National Eye Institute (EY19943, P30EY001931, R01-EY019943, EY15173, R01EY018872, R01EY015173)
- National Center for Research Resources (P20RR016475)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- aerosol-generating procedures, cataract, male sterility, lens fiber cells, peroxisomes, ether lipids, aberrant splicing, hypomorphic mutation, mouse chromosome 2, fine mapping, seminiferous tubules
- MeSH terms
- Animals, Base Sequence, Brain, Cataract, Cloning, Molecular, Female, Infertility, Male, Male, Mice, Inbred C57BL, Mutation, Phenotype, Testis, Transcription, Genetic, Alternative Splicing, Alkyl and Aryl Transferases, Peroxisomes, Protein Transport, Gene Order, Mice, Genetic Loci
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