Blind sterile 2 (bs2), a hypomorphic mutation in Agps, results in cataracts and male sterility in mice

Abstract

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 45 cM distal from the centromere. Fine mapping established a 3.1 Mb 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.