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. 2023 Dec;25(4):644-649.
doi: 10.1007/s12017-023-08754-1. Epub 2023 Sep 8.

Dysregulated COMT Expression in Fragile X Syndrome

Kagistia Hana Utami  1   2 , Nur Amirah Binte Muhammed Yusof  1 , Marta Garcia-Miralles  1   3 , Niels Henning Skotte  4   5 , Srikanth Nama  6 , Prabha Sampath  7   8 , Sarah R Langley  2   9 , Mahmoud A Pouladi  10   11
Affiliations

Dysregulated COMT Expression in Fragile X Syndrome

Kagistia Hana Utami et al. Neuromolecular Med. 2023 Dec.

Abstract

Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

Keywords: COMT; Fragile X syndrome; Isogenic stem cell model; Neurons; Proteomics; RNAseq.

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