Novel <i>NUDT2</i> variant causes intellectual disability and polyneuropathy

Diaz, Frank; Khosa, Shaweta; Niyazov, Dmitriy; Lee, Hane; Person, Richard; Morrow, Michelle M.; Signer, Rebecca; Dorrani, Naghmeh; Zheng, Allison; Herzog, Matthew; Freundlich, Robert E.; Birath, J. Brandon; Cervantes-Manzo, Yurivia; Martínez‐Agosto, Julian A.; Palmer, Christina G.S.; Nelson, Stanley F.; Fogel, Brent L.; Mishra, Shrikant

doi:10.1002/acn3.51209

Cited by 6 publications

(3 citation statements)

References 11 publications

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“…The attributed action of the proteins encoded by these genes was concordant with their function in the central nervous system (CNS), but their expression in adipose tissue in association with cognition is unprecedented. Variants in the NUDT2 gene have been recently associated with intellectual disability ( 16 , 17 ). AMPH encodes for a protein highly concentrated in presynaptic terminals ( 18 ) and is one of the six proteins altered in the cerebrospinal fluid of patients with mild cognitive impairment and Alzheimer’s disease ( 19 ).…”

Section: Resultsmentioning

confidence: 99%

Adipose tissue coregulates cognitive function

Oliveras-Cañellas,

Castells-Nobau,

de la Vega-Correa

et al. 2023

Sci. Adv.

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Obesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)–brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle–associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.

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Section: Resultsmentioning

confidence: 99%

Adipose tissue coregulates cognitive function

Oliveras-Cañellas,

Castells-Nobau,

de la Vega-Correa

et al. 2023

Sci. Adv.

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“…There is limited research on the role of NUDT2 and EST2 in dementia. NUDT2 is a protein that belongs to the nudix hydrolase family and is involved in the regulation of nucleotide metabolism, mutation in the NUDT2 gene was reported to be associated with neurodevelopmental delay and intellectual disability, and polyneuropathies with demyelinating and/or axonal features (59,60). ETS2 is a transcription factor shown to play a role in cell proliferation, differentiation, and apoptosis (61).…”

Section: Discussionmentioning

confidence: 99%

Profiling the autoantibody repertoire reveals autoantibodies associated with mild cognitive impairment and dementia

Ehtewish,

Mesleh,

Ponirakis

et al. 2023

Front. Neurol.

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BackgroundDementia is a debilitating neurological disease affecting millions of people worldwide. The exact mechanisms underlying the initiation and progression of the disease remain to be fully defined. There is an increasing body of evidence for the role of immune dysregulation in the pathogenesis of dementia, where blood-borne autoimmune antibodies have been studied as potential markers associated with pathological mechanisms of dementia.MethodsThis study included plasma from 50 cognitively normal individuals, 55 subjects with MCI (mild cognitive impairment), and 22 subjects with dementia. Autoantibody profiling for more than 1,600 antigens was performed using a high throughput microarray platform to identify differentially expressed autoantibodies in MCI and dementia.ResultsThe differential expression analysis identified 33 significantly altered autoantibodies in the plasma of patients with dementia compared to cognitively normal subjects, and 38 significantly altered autoantibodies in the plasma of patients with dementia compared to subjects with MCI. And 20 proteins had significantly altered autoantibody responses in MCI compared to cognitively normal individuals. Five autoantibodies were commonly dysregulated in both dementia and MCI, including anti-CAMK2A, CKS1B, ETS2, MAP4, and NUDT2. Plasma levels of anti-ODF3, E6, S100P, and ARHGDIG correlated negatively with the cognitive performance scores (MoCA) (r2 –0.56 to −0.42, value of p < 0.001). Additionally, several proteins targeted by autoantibodies dysregulated in dementia were significantly enriched in the neurotrophin signaling pathway, axon guidance, cholinergic synapse, long-term potentiation, apoptosis, glycolysis and gluconeogenesis.ConclusionWe have shown multiple dysregulated autoantibodies in the plasma of subjects with MCI and dementia. The corresponding proteins for these autoantibodies are involved in neurodegenerative pathways, suggesting a potential impact of autoimmunity on the etiology of dementia and the possible benefit for future therapeutic approaches. Further investigations are warranted to validate our findings.

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“…Interestingly, Nudt2 is also implicated in cognition where biallelic disruption of the NUDT2 gene leads to intellectual disabilities in affected individuals ( 86 , 87 , 88 ). The mechanism by which Nudt2 contributes to cognitive function will be an exciting future area of inquiry.…”

Section: Future Perspectivesmentioning

confidence: 99%