Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia.

Christelle Tesson, Magdalena Nawara, Mustafa A.M. Salih, Rodrigue Rossignol, Maha S. Zaki, Mohammed Al Balwi, Rebecca Schule, Cyril Mignot, Emilie Obre, Ahmed Bouhouche, Filippo M. Santorelli, Christelle M. Durand, Andrés Caballero Oteyza, Khalid H. El-Hachimi, Abdulmajeed Al Drees, Naima Bouslam, Foudil Lamari, Salah A. Elmalik, Mohammad M. Kabiraj, Mohammed Z. Seidahmed, Typhaine Esteves, Marion Gaussen, Marie-Lorraine Monin, Gabor Gyapay, Doris Lechner, Michael Gonzalez, Christel Depienne, Fanny Mochel, Julie Lavie, Ludger Schols, Didier Lacombe, Mohamed Yahyaoui, Ibrahim Al Abdulkareem, Stephan Zuchner, Atsushi Yamashita, Ali Benomar, Cyril Goizet, Alexandra Durr, Joseph G. Gleeson, Frederic Darios, Alexis Brice, Giovanni Stevanin
The American Journal of Human Genetics. 2012-12-01; 91(6): 1051-1064
DOI: 10.1016/j.ajhg.2012.11.001


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Tesson C(1), Nawara M, Salih MA, Rossignol R, Zaki MS, Al Balwi M, Schule R,
Mignot C, Obre E, Bouhouche A, Santorelli FM, Durand CM, Oteyza AC, El-Hachimi
KH, Al Drees A, Bouslam N, Lamari F, Elmalik SA, Kabiraj MM, Seidahmed MZ,
Esteves T, Gaussen M, Monin ML, Gyapay G, Lechner D, Gonzalez M, Depienne C,
Mochel F, Lavie J, Schols L, Lacombe D, Yahyaoui M, Al Abdulkareem I, Zuchner S,
Yamashita A, Benomar A, Goizet C, Durr A, Gleeson JG, Darios F, Brice A, Stevanin
G.

Author information:
(1)Unité 975, Institut National de la Santé et de la Recherche Médicale, 75013
Paris, France.

Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous
groups of neurological disorders, both clinically and genetically. The disease
comprises pure and complex forms that clinically include slowly progressive
lower-limb spasticity resulting from degeneration of the corticospinal tract. At
least 48 loci accounting for these diseases have been mapped to date, and
mutations have been identified in 22 genes, most of which play a role in
intracellular trafficking. Here, we identified mutations in two functionally
related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of
HSP by using either the classical positional cloning or a combination of
whole-genome linkage mapping and next-generation sequencing. Interestingly, three
subjects with CYP2U1 mutations presented with a thin corpus callosum,
white-matter abnormalities, and/or calcification of the basal ganglia. These
genes code for two enzymes involved in fatty-acid metabolism, and we have
demonstrated in human cells that the HSP pathophysiology includes alteration of
mitochondrial architecture and bioenergetics with increased oxidative stress. Our
combined results focus attention on lipid metabolism as a critical HSP pathway
with a deleterious impact on mitochondrial bioenergetic function.

Copyright © 2012 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.

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