NUDT2 loss-of-function variants are associated with a recessive neurodevelopmental disease with mental retardation, movement disorder and peripheral neuropathy
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. Overall design: RNA-Seq was used to identify results of Nudt2 mutations found in patient fibroblasts