Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence

Abstract

Please cite this article as: M. Lukacs, J. Gilley, Y. Zhu, et al., Severe biallelic lossof-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence, Experimental Neurology,

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

“…These data further implicate programmed axon death to human disease. It appears that this degeneration pathway can be aberrantly activated in humans not only by genetic mutation of NMNAT2 3,4 , but also by SARM1 activation in severe neurotoxicity within hours of vacor ingestion 17 . Although vacor use is banned, this study raises important questions of whether other pesticides or environmental chemicals in use today also activate programmed axon death.…”

Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes

“…Functional studies established that these variants impair NMNAT2 function and supported this gene’s association with fetal akinesia deformation sequence. 29

Fig. 1 Fetal magnetic resonance images (MRIs) demonstrating phenotypes of select prenatal exome sequencing (pES) cases.

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Uncovering the Invisible: Mono-ADP-ribosylation Moved into the Spotlight

“…Hence, although NAD + is thought to freely shuttle between the nucleus and the cytoplasm in vivo, neither enzyme seems to be able to functionally compensate for the loss of the respective other one. Comparably, mutations in either the NMNAT1- or the NMNAT2-encoding gene in humans were shown to result in the early development of severe disorders [ 49 , 50 ], again suggesting that the regulation of these proteins is compartmentalized and non-redundant in vivo. Recent studies have now challenged the well-established role of NMNAT-catalyzed NAD + production and might provide explanations for the above-described discrepancies between in vitro and in vivo studies.…”