Department of Pediatrics and Pediatric Neurology, University Medical Center Göttingen, Georg August University Göttingen, Germany.
John van Geest Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK; Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK.
Exp Neurol. 2019 Oct;320:112958. doi: 10.1016/j.expneurol.2019.112958. Epub 2019 May 24.
We identified a homozygous missense mutation in the gene encoding NAD synthesizing enzyme NMNAT2 in two siblings with childhood onset polyneuropathy with erythromelalgia. No additional homozygotes for this rare allele, which leads to amino acid substitution T94M, were present among the unaffected relatives tested or in the 60,000 exomes of the ExAC database. For axons to survive, axonal NMNAT2 activity has to be maintained above a threshold level but the T94M mutation confers a partial loss of function both in the ability of NMNAT2 to support axon survival and in its enzymatic properties. Electrophysiological tests and histological analysis of sural nerve biopsies in the patients were consistent with loss of distal sensory and motor axons. Thus, it is likely that NMNAT2 mutation causes this pain and axon loss phenotype making this the first disorder associated with mutation of a key regulator of Wallerian-like axon degeneration in humans. This supports indications from numerous animal studies that the Wallerian degeneration pathway is important in human disease and raises important questions about which other human phenotypes could be linked to this gene.
我们在两名患有儿童起病多发性神经病伴红斑性肢痛症的兄弟姐妹中发现了编码 NAD 合成酶 NMNAT2 的基因中的纯合错义突变。在未受影响的亲属或在 ExAC 数据库的 60,000 个外显子中，没有这种罕见等位基因的其他纯合子，该等位基因导致氨基酸替换 T94M。为了使轴突存活，轴突 NMNAT2 活性必须维持在阈值以上，但 T94M 突变既降低了 NMNAT2 支持轴突存活的能力，也降低了其酶活性。对患者腓肠神经活检的电生理测试和组织学分析与远端感觉和运动轴突丧失一致。因此，NMNAT2 突变很可能导致这种疼痛和轴突丧失表型，这是第一个与人类 Wallerian 样轴突退化关键调节剂突变相关的疾病。这支持了许多动物研究的结果，即 Wallerian 退化途径在人类疾病中很重要，并提出了关于哪些其他人类表型可能与该基因相关的重要问题。
