Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.

Autor:	Akinyele O; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Munir A; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA., Johnson MA; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Perez MS; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA., Gao Y; Children's Neuroscience Institute, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Foley JR; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA., Nwafor A; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA., Wu Y; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Murray-Stewart T; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA., Casero RA Jr; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA., Bayir H; Children's Neuroscience Institute, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA., Kemaladewi DU; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.; Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.; Children's Neuroscience Institute, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2024 Jun 01; Vol. 17 (6). Date of Electronic Publication: 2024 May 09.
DOI:	10.1242/dmm.050639
Abstrakt:	Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene, which encodes spermine synthase, and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human gene variants and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model, which carries a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts and Sms-null hippocampal cells, indicating that SMS may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2024. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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