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The G209R mutant mouse as a model for human PCSK1 polyendocrinopathy.
Manita Shakya1, Surbhi Gahlot2, Nicolle K Martin3
1Dept. of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD.
Endocrinology
|March 4, 2022
Summary
Proprotein convertase 1 (PCSK1) mutations cause severe infant disease. A new G209R Pcsk1 mouse model shows dwarfism and hormone processing defects, mirroring human conditions.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- PCSK1 mutations are linked to severe human phenotypes, including chronic diarrhea and endocrinopathies.
- The enzyme PCSK1 is crucial for processing prohormones into bioactive peptides.
Purpose of the Study:
- To create and characterize a mouse model for the PCSK1 G209R mutation.
- To investigate the physiological consequences of this mutation in vivo.
Main Methods:
- CRISPR/Cas9 gene editing was used to introduce the G209R mutation into the murine Pcsk1 locus.
- Phenotypic analysis included survival rates, growth, blood glucose, hormone levels, and protein expression via Western blotting.
Main Results:
- Homozygous G209R Pcsk1 mice exhibited high mortality, severe dwarfism, hypoglycemia, and pancreatic proinsulin accumulation.
- Pituitary POMC processing was impaired, reducing mature ACTH levels, while PC1/3 protein was reduced in the brain.
- Enteroendocrine cell numbers were modestly reduced in homozygous mice.
Conclusions:
- The G209R Pcsk1 mouse model effectively recapitulates key neonatal deficiencies observed in human patients with PCSK1 mutations.
- This model provides a valuable tool for studying PCSK1-related disorders and potential therapeutic strategies.
