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Ex vivo disease modelling of Rett syndrome: the transcriptomic and metabolomic implications of direct neuronal conversion.
Karaosmanoglu, Beren; Imren, Gozde; Ozisin, M Samil; Reçber, Tuba; Simsek Kiper, Pelin Ozlem; Haliloglu, Goknur; Alikasifoglu, Mehmet; Nemutlu, Emirhan; Taskiran, Ekim Z; Utine, Gulen Eda.
Afiliación
  • Karaosmanoglu B; Faculty of Medicine, Department of Medical Genetics, Hacettepe University, Ankara, Türkiye.
  • Imren G; Faculty of Medicine, Department of Medical Genetics, Hacettepe University, Ankara, Türkiye.
  • Ozisin MS; Institute of Health Sciences, Department of Medical and Surgical Research, Hacettepe University, Ankara, Türkiye.
  • Reçber T; Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Ankara, Türkiye.
  • Simsek Kiper PO; Faculty of Medicine, Department of Pediatric Genetics, Hacettepe University, Ankara, Türkiye.
  • Haliloglu G; Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Hacettepe University, Ankara, Türkiye.
  • Alikasifoglu M; Faculty of Medicine, Department of Medical Genetics, Hacettepe University, Ankara, Türkiye.
  • Nemutlu E; Faculty of Pharmacy, Department of Analytical Chemistry, Hacettepe University, Ankara, Türkiye.
  • Taskiran EZ; Faculty of Medicine, Department of Medical Genetics, Hacettepe University, Ankara, Türkiye. ekimtaskiran@gmail.com.
  • Utine GE; Faculty of Medicine, Department of Pediatric Genetics, Hacettepe University, Ankara, Türkiye. geutine@hacettepe.edu.tr.
Mol Biol Rep ; 51(1): 979, 2024 Sep 13.
Article en En | MEDLINE | ID: mdl-39269588
ABSTRACT

BACKGROUND:

Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females and is characterized by a period of normal development followed by severe cognitive, motor, and communication impairment. The syndrome is predominantly caused by mutations in the MECP2. This study aimed to use comprehensive multi-omic analysis to identify the molecular and metabolic alterations associated with Rett syndrome. METHODS AND

RESULTS:

Transcriptomic and metabolomic profiling was performed using neuron-like cells derived from the fibroblasts of 3 Rett syndrome patients with different MECP2 mutations (R168X, P152R, and R133C) and 1 healthy control. Differential gene expression, alternative splicing events, and metabolite changes were analyzed to identify the key pathways and processes affected in patients with Rett syndrome. Transcriptomic analysis showed there was significant down-regulation of genes associated with the extracellular matrix (ECM) and cytoskeletal components, which was particularly notable in patient P3 (R133C mutation), who had non-random X chromosome inactivation. Additionally, significant changes in microtubule-related gene expression and alternative splicing events were observed, especially in patient P2 (P152R mutation). Metabolomic profiling showed that there were alterations in metabolic pathways, particularly up-regulation of ketone body synthesis and degradation pathways, in addition to an increase in free fatty acid levels. Integrated analysis highlighted the interplay between structural gene down-regulation and metabolic shifts, underscoring the adaptive responses to cellular stress in Rett neurons.

CONCLUSION:

The present findings provide valuable insights into the molecular and metabolic landscape of Rett syndrome, emphasizing the importance of combining omic data to enlighten the molecular pathophysiology of this syndrome.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Rett / Proteína 2 de Unión a Metil-CpG / Transcriptoma / Mutación / Neuronas Límite: Female / Humans Idioma: En Revista: Mol Biol Rep Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Síndrome de Rett / Proteína 2 de Unión a Metil-CpG / Transcriptoma / Mutación / Neuronas Límite: Female / Humans Idioma: En Revista: Mol Biol Rep Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos