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Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion

Lookup NU author(s): Dr Charlotte Alston, Dr Ki Pang, Professor Bobby McFarlandORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2018 Wiley Periodicals, Inc. Iron-sulfur (Fe-S) clusters are essential cofactors for proteins that participate in fundamental cellular processes including metabolism, DNA replication and repair, transcriptional regulation, and the mitochondrial electron transport chain (ETC). ISCA2 plays a role in the biogenesis of Fe-S clusters and a recent report described subjects displaying infantile-onset leukodystrophy due to bi-allelic mutation of ISCA2. We present two additional unrelated cases, and provide a more complete clinical description that includes hyperglycinemia, leukodystrophy of the brainstem with longitudinally extensive spinal cord involvement, and mtDNA deficiency. Additionally, we characterize the role of ISCA2 in mitochondrial bioenergetics and Fe-S cluster assembly using subject cells and ISCA2 cellular knockdown models. Loss of ISCA2 diminished mitochondrial membrane potential, the mitochondrial network, basal and maximal respiration, ATP production, and activity of ETC complexes II and IV. We specifically tested the impact of loss of ISCA2 on 2Fe-2S proteins versus 4Fe-4S proteins and observed deficits in the functioning of 4Fe-4S but not 2Fe-2S proteins. Together these data indicate loss of ISCA2 impaired function of 4Fe-4S proteins resulting in a fatal encephalopathy accompanied by a relatively unusual combination of features including mtDNA depletion alongside complex II deficiency and hyperglycinemia that may facilitate diagnosis of ISCA2 deficiency patients.

Publication metadata

Author(s): Alaimo JT, Besse A, Alston CL, Pang K, Appadurai V, Samanta M, Smpokou P, Mcfarland R, Taylor RW, Bonnen PE

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2018

Volume: 39

Issue: 4

Pages: 537-549

Print publication date: 01/04/2018

Online publication date: 03/01/2018

Acceptance date: 27/12/2017

Date deposited: 12/02/2018

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley and Sons Inc.


DOI: 10.1002/humu.23396


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust