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Severe Biallelic Loss-of-function Mutations in Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) in Two Fetuses with Fetal Akinesia Deformation Sequence
The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD+) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. Peripheral
nerve axons in NMNAT2-deficient mice fail to extend and innervate
targets, and skeletal muscle is severely underdeveloped. In addition,
removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal
akinesia deformation sequence (FADS), severely reduced skeletal muscle
mass and hydrops fetalis. Clinical exome sequencing identified compound
heterozygous NMNAT2 variant alleles in both cases. Both protein variants
are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered protein
stability and/or defects in NAD+ synthesis and chaperone functions. Thus,
both patient NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder.Funding for the project comes from the NIH (R.W.S. R01NS085023; R.G.Z. R56NS095893), the UK Medical Research Council grant (J.G. MR/N004582/1), the John and Lucille van Geest Foundation (M.C.) and the Taishan Scholar Project of Shandong Province, China (R.G.Z.)