Universität zu Köln

Huppke, Peter, Wegener, Eike, Gilley, Jonathan, Angeletti, Carlo, Kurth, Ingo, Drenth, Joost P. H., Stadelmann, Christine ORCID: 0000-0003-1766-5458, Barrantes-Freer, Alonso, Brueck, Wolfgang, Thiele, Holger, Nuernberg, Peter, Gaertner, Jutta, Orsomando, Giuseppe ORCID: 0000-0001-6640-097X and Coleman, Michael P. (2019). Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia. Exp. Neurol., 320. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1090-2430

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Huppke, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Wegener, Eike UNSPECIFIED UNSPECIFIED UNSPECIFIED Gilley, Jonathan UNSPECIFIED UNSPECIFIED UNSPECIFIED Angeletti, Carlo UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurth, Ingo UNSPECIFIED UNSPECIFIED UNSPECIFIED Drenth, Joost P. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stadelmann, Christine UNSPECIFIED orcid.org/0000-0003-1766-5458 UNSPECIFIED Barrantes-Freer, Alonso UNSPECIFIED UNSPECIFIED UNSPECIFIED Brueck, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaertner, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Orsomando, Giuseppe UNSPECIFIED orcid.org/0000-0001-6640-097X UNSPECIFIED Coleman, Michael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-133383
DOI:	10.1016/j.expneurol.2019.112958
Journal or Publication Title:	Exp. Neurol.
Volume:	320
Date:	2019
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1090-2430
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NICOTINAMIDE MONONUCLEOTIDE ADENYLYLTRANSFERASE; MOUSE MODEL; DEGENERATION; SPECIFICITY; SUBSTRATE; RESCUE; INJURY Multiple languages Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13338