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The G209R mutant mouse as a model for human PCSK1 polyendocrinopathy.
Shakya, Manita; Gahlot, Surbhi; Martin, Nicolle K; Arunagiri, Anoop; Martin, Martin G; Arvan, Peter; Low, Malcolm J; Lindberg, Iris.
Afiliación
  • Shakya M; Dept. of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD.
  • Gahlot S; Dept. Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI.
  • Martin NK; Dept. of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
  • Arunagiri A; Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI.
  • Martin MG; Dept. of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
  • Arvan P; Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI.
  • Low MJ; Dept. Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI.
  • Lindberg I; Dept. of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, MD.
Endocrinology ; 2022 Mar 04.
Article en En | MEDLINE | ID: mdl-35245347
PCSK1 encodes an enzyme required for prohormone maturation into bioactive peptides. A striking number of SNPs and rare mutations in PCSK1 are associated with a range of clinical phenotypes. Infants bearing two copies of a catalytically inactivating mutation, such as G209R, exhibit life-threatening chronic diarrhea and subsequently develop systemic endocrinopathies. Using CRISPR/Cas9 technology, we have engineered a mouse model bearing a G209R missense mutation in exon 6 of the murine Pcsk1 locus. Most pups homozygous for the G209R mutation succumbed by day 2, and surviving pups were severely dwarfed. In homozygous (but not heterozygous) pups, blood glucose levels were significantly lower, accompanied by elevated plasma insulin-like immunoreactivity and accumulation of large quantities of unprocessed proinsulin in the pancreas. Peptide hormone processing was also aberrant in G209R mouse pituitary, with mature ACTH levels markedly reduced in homozygotes, accompanied by a significant accumulation of POMC. We also observed a significant reduction in PC1/3 protein in the brains of G209R homozygous mice by Western blotting, while PC2 levels remained unaffected. Most likely due to the continued presence of PC2, pituitary and brain levels of α-MSH were not impaired. Analysis of intestinal cell types indicated a modest reduction of enteroendocrine cells in G209R homozygotes. We suggest that the G209R Pcsk1 mouse model recapitulates many of the dramatic neonatal deficiencies of human patients with this homozygous mutation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Endocrinology Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Endocrinology Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos