title: Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia.
abstract: 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.
authors.affiliation: Unité 975, Institut National de la Santé et de la Recherche Médicale, 75013 Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Tesson
authors.forename: Magdalena
authors.initials: M
authors.lastname: Nawara
authors.forename: Mustafa A M
authors.initials: MA
authors.lastname: Salih
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al Balwi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schule
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Emilie
authors.initials: E
authors.lastname: Obre
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bouhouche
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Durand
authors.forename: Andrés Caballero
authors.initials: AC
authors.lastname: Oteyza
authors.forename: Khalid H
authors.initials: KH
authors.lastname: El-Hachimi
authors.forename: Abdulmajeed
authors.initials: A
authors.lastname: Al Drees
authors.forename: Naima
authors.initials: N
authors.lastname: Bouslam
authors.forename: Foudil
authors.initials: F
authors.lastname: Lamari
authors.forename: Salah A
authors.initials: SA
authors.lastname: Elmalik
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Kabiraj
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Seidahmed
authors.forename: Typhaine
authors.initials: T
authors.lastname: Esteves
authors.forename: Marion
authors.initials: M
authors.lastname: Gaussen
authors.forename: Marie-Lorraine
authors.initials: ML
authors.lastname: Monin
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyapay
authors.forename: Doris
authors.initials: D
authors.lastname: Lechner
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.forename: Julie
authors.initials: J
authors.lastname: Lavie
authors.forename: Ludger
authors.initials: L
authors.lastname: Schols
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Mohamed
authors.initials: M
authors.lastname: Yahyaoui
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al Abdulkareem
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Ali
authors.initials: A
authors.lastname: Benomar
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Frederic
authors.initials: F
authors.lastname: Darios
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D010740:Phospholipases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology* / Q000235:genetics*; D055815:Young Adult
chemical_list: D005227:Fatty Acids; D003577:Cytochrome P-450 Enzyme System; C484320:CYP2U1 protein, human; D000072467:Cytochrome P450 Family 2; D010740:Phospholipases