Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

• Published in: American journal of human genetics Vol. 91; no. 6; pp. 1051 - 1064
• Main Authors: Tesson, Christelle, Nawara, Magdalena, Salih, Mustafa A.M., Rossignol, Rodrigue, Zaki, Maha S., Al Balwi, Mohammed, Schule, Rebecca, Mignot, Cyril, Obre, Emilie, Bouhouche, Ahmed, Santorelli, Filippo M., Durand, Christelle M., Oteyza, Andrés Caballero, El-Hachimi, Khalid H., Al Drees, Abdulmajeed, Bouslam, Naima, Lamari, Foudil, Elmalik, Salah A., Kabiraj, Mohammad M., Seidahmed, Mohammed Z., Esteves, Typhaine, Gaussen, Marion, Monin, Marie-Lorraine, Gyapay, Gabor, Lechner, Doris, Gonzalez, Michael, Depienne, Christel, Mochel, Fanny, Lavie, Julie, Schols, Ludger, Lacombe, Didier, Yahyaoui, Mohamed, Al Abdulkareem, Ibrahim, Zuchner, Stephan, Yamashita, Atsushi, Benomar, Ali, Goizet, Cyril, Durr, Alexandra, Gleeson, Joseph G., Darios, Frederic, Brice, Alexis, Stevanin, Giovanni
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 07-12-2012; Cell Press; Elsevier
• Subjects: Adolescent; Adult; Attention; Basal ganglia; Bioenergetics; Biological and medical sciences; Calcification (ectopic); Child; Child, Preschool; Chromosome Mapping; Corpus callosum; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 Family 2; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzymes; Fatty Acids - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene mapping; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Heat shock proteins; Hereditary spastic parplegia; Humans; Infant; Infant, Newborn; Lipid metabolism; Male; Medical genetics; Medical sciences; Mitochondria; Mitochondria - enzymology; Mitochondria - genetics; Molecular and cellular biology; Mutation; Neurodegeneration; Neurological diseases; Neurology; Oxidative stress; Paralysis; Phenotype; Phospholipases - genetics; Phospholipases - metabolism; Protein Transport; Pyramidal tracts; Spastic Paraplegia, Hereditary - enzymology; Spastic Paraplegia, Hereditary - genetics; spasticity; Young Adult; Hereditary spastic paraplegia; Nervous system diseases; Mitochondria; Enzyme; Central nervous system disease; Alteration; Genetics; Degenerative disease; Spinal cord disease; Fatty acids; Genetic disease; Cerebral disorder
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.11.001

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.