Alkylglycerone phosphate synthase (AGPS) deficient mice: Models for rhizomelic chondrodysplasia punctata type 3 (RCDP3) malformation syndrome
| Autor: | Ryan Liegel, Duska J. Sidjanin, Adam Ronchetti |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty RCDP rhizomelic chondrodysplasia punctata AGPS Mouse Transgene GNPAT glyceronephosphate O-acyltransferase Male infertility Andrology Endocrinology Cataracts Genetics medicine Alkylglycerone-phosphate synthase Molecular Biology lcsh:QH301-705.5 lcsh:R5-920 Rhizomelic chondrodysplasia punctata biology business.industry medicine.disease Phenotype PTS peroxisomal targeting signal 3. Good health lcsh:Biology (General) PEX7 peroxisomal biogenesis factor 7 Knockout mouse Mutation Congenital cataracts Hypomorphic KOMP Knockout Mouse Project biology.gene business RCDP3 lcsh:Medicine (General) AGPS alkylglycerone phosphate synthase Research Paper |
| Zdroj: | Molecular Genetics and Metabolism Reports, Vol 1, Iss C, Pp 299-311 (2014) Molecular Genetics and Metabolism Reports |
| ISSN: | 2214-4269 |
| DOI: | 10.1016/j.ymgmr.2014.06.003 |
| Popis: | 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 in blind sterile 2 (bs2) mice are caused by a spontaneous hypomorphic mutation in Agps. As a part of this study, we set out to further explore the bs2 phenotypes and how they correlate to the clinical presentations of RCDP3 patients. Our results show that ~ 50% bs2 mice die embryonically and surviving bs2 mice exhibit growth delays that they overcome by adulthood. The X-ray analysis of adult bs2 mice revealed significant humeral, but not femoral shortening. Clinical and histological eye evaluations revealed that bs2 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 bs2 mice is due to the aberrant formation of multicellular cellular clusters that undergo apoptosis. Given that the bs2 locus is a hypomorphic Agps mutation, we set out to generate Agps knockout mice utilizing the Knockout Mouse Project (KOMP) resource. Our results showed that ~ 85% of Agps knock-out mice die embryonically whereas surviving adult Agps knock-out mice phenotypically exhibit cataracts and testicular abnormalities similar to those observed in bs2 mice. Given that the majority of Agps knock-out mice die embryonically, this presented a challenge for further analyses of Agps deficiency in mouse models. Although not done as a part of this study, Agps-KOMP mice or ES cells can be further modified with FLP recombinase to generate mice suitable for subsequent matings with a transgenic Cre strain of choice, thereby providing an opportunity to study conditional Agps deficiency in a specific tissue or desired developmental time points without Agps deficiency-mediated embryonic lethality. |
| Databáze: | OpenAIRE |
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