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Exp Neurol. 2019 Oct;320:112961. doi: 10.1016/j.expneurol.2019.112961. Epub 2019 May 25.

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

Author information

1
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.. Electronic address: Marshall.luckas@cchmc.org.
2
John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.; Signalling ISPG, The Babraham Institute, Babraham, Cambridge CB22 3AT, UK. Electronic address: jg792@cam.ac.uk.
3
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. Electronic address: y.zhu17@med.miami.edu.
4
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131, Ancona, Italy. Electronic address: g.orsomando@univpm.it.
5
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131, Ancona, Italy. Electronic address: c.angeletti@staff.univpm.it.
6
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China. Electronic address: jxl2095@miami.edu.
7
John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.
8
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. Electronic address: jpark@med.miami.edu.
9
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.. Electronic address: rob.hopkin@cchmc.org.
10
John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.; Signalling ISPG, The Babraham Institute, Babraham, Cambridge CB22 3AT, UK. Electronic address: mc469@cam.ac.uk.
11
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong 264005, China. Electronic address: gzhai@med.miami.edu.
12
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.. Electronic address: rolf.stottmann@cchmc.org.

Abstract

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. SIGNIFICANCE: Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) both synthesizes the electron carrier Nicotinamide Adenine Dinucleotide (NAD+) and acts a protein chaperone. NMNAT2 has emerged as a major neuron survival factor. Overexpression of NMNAT2 protects neurons from Wallerian degeneration after injury and declining levels of NMNAT2 have been implicated in neurodegeneration. While the role of NMNAT2 in neurodegeneration has been extensively studied, the role of NMNAT2 in human development remains unclear. In this work, we present the first human variants in NMNAT2 identified in two fetuses with severe skeletal muscle hypoplasia and fetal akinesia. Functional studies in vitro showed that the mutations impair both NMNAT2 NAD+ synthase and chaperone functions. This work identifies the critical role of NMNAT2 in human development.

PMID:
31136762
PMCID:
PMC6708453
[Available on 2020-10-01]
DOI:
10.1016/j.expneurol.2019.112961

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