title: Alkylglycerone phosphate synthase (AGPS) deficient mice: models for rhizomelic chondrodysplasia punctate type 3 (RCDP3) malformation syndrome.
abstract: 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 (AGPS) cause RCDP type 3 (RCDP3). We've previously established that cataracts and male infertility inblind sterile 2 (bs2)mice are caused by a spontaneous hypomorphic mutation inAgps. As a part of this study, we set out to further explore thebs2phenotypes and how they correlate to the clinical presentations of RCDP3 patients. Our results show that ∼50%bs2mice die embryonically and survivingbs2mice exhibit growth delays that they overcome by adulthood. The X-ray analysis of adultbs2mice revealed significant humeral, but not femoral shortening. Clinical and histological eye evaluations revealed thatbs2lenses undergo normal development with first opacities developing at P21 that by P28 rapidly progress to mature cataracts. Evaluation of testes determined that infertility inbs2mice is due to the aberrant formation of multicellular cellular clusters that undergo apoptosis. Given that thebs2locus is a hypomorphicAgpsmutation, we set out to generateAgpsknockout mice utilizing Knockout Mouse Project (KOMP) resource. Our results showed that ∼85% ofAgpsknock-out mice die embryonically whereas surviving adultAgpsknock-out mice phenotypically exhibit cataracts and testicular abnormalities similar to those observed inbs2mice. Given that the majority ofAgpsknock-out mice die embryonically presented a challenge for further analyses ofAgpsdeficiency in mouse models. Although not done as a part of this study,Agps-KOMPmice or ES cells can be further modified with FLP recombinase to generate mice suitable for subsequent matings with a transgenicCrestrain of choice, thereby providing an opportunity to study conditionalAgpsdeficiency in a specific tissue or desired developmental time points withoutAgpsdeficiency-mediated embryonic lethality.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Liegel
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Adam
authors.initials: A
authors.lastname: Ronchetti
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI ; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI.
authors.forename: D J
authors.initials: DJ
authors.lastname: Sidjanin
keywords: AGPS; RCDP3; hypomorphic; mouse; mutation; phenotype