Alkylglycerone phosphate synthase (AGPS) deficient mice: models for rhizomelic chondrodysplasia punctate type 3 (RCDP3) malformation syndrome.

Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous autosomal recessive syndrome characterized by congenital cataracts, shortening of the proximal limbs, neurological abnormalities, seizures, growth delays, and severe intellectual disability. Most RCDP children die in the first decade of life due to respiratory complications. Mutations in alkylglycerone phosphate synthase () cause RCDP type 3 (RCDP3). We've previously established that cataracts and male infertility in mice are caused by a spontaneous hypomorphic mutation in . As a part of this study, we set out to further explore the phenotypes and how they correlate to the clinical presentations of RCDP3 patients. Our results show that ∼50% mice die embryonically and surviving mice exhibit growth delays that they overcome by adulthood. The X-ray analysis of adult mice revealed significant humeral, but not femoral shortening. Clinical and histological eye evaluations revealed that lenses undergo normal development with first opacities developing at P21 that by P28 rapidly progress to mature cataracts. Evaluation of testes determined that infertility in mice is due to the aberrant formation of multicellular cellular clusters that undergo apoptosis. Given that the locus is a hypomorphic mutation, we set out to generate knockout mice utilizing Knockout Mouse Project (KOMP) resource. Our results showed that ∼85% of knock-out mice die embryonically whereas surviving adult knock-out mice phenotypically exhibit cataracts and testicular abnormalities similar to those observed in mice. Given that the majority of knock-out mice die embryonically presented a challenge for further analyses of deficiency in mouse models. Although not done as a part of this study, mice or ES cells can be further modified with FLP recombinase to generate mice suitable for subsequent matings with a transgenic strain of choice, thereby providing an opportunity to study conditional deficiency in a specific tissue or desired developmental time points without deficiency-mediated embryonic lethality.