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NUDT2 loss-of-function variants are associated with a recessive neurodevelopmental disease with mental retardation, movement disorder and peripheral neuropathy

ABSTRACT: We present cases of a neurological disorder in children characterized by developmental delays in mental and motor skills, gait disturbances, and peripheral neuropathy. The disorder is associated with rare variants in the NUDT2 gene, which encodes a Nudix family mRNA decapping enzyme. The spectrum of variants includes two previously reported truncating variants and two novel variants, namely the missense c.174G>T and the in-frame deletion c.410_412del. We report that these new variants result in a marked reduction in enzymatic hydrolase activity of the encoded protein, strongly suggesting loss of function of NUDT2 as the cause of the disorder. Morover, we document that loss of function may be due to reduced enzymatic activity or impaired protein stability of NUDT2 variants. Consistent with its function in mRNA decapping, NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, likely due at least in part to changes in mRNA stability. Our results confirm that a reduction or loss of NUDT2-dependent mRNA decapping activity is associated with recessive neurological disease in pediatric patients. Taken together, these findings underscore the importance of a physiologically balanced mRNA processing for neuronal development and homeostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230789 | GEO | 2023/12/11

REPOSITORIES: GEO

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Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.

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NUDT2 loss-of-function variants are associated with a recessive neurodevelopmental disease with mental retardation, movement disorder and peripheral neuropathy

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