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.
| Original language | English |
|---|---|
| Pages (from-to) | 1051-1064 |
| Number of pages | 14 |
| Journal | American Journal of Human Genetics |
| Volume | 91 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 7 2012 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. / 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 L; Yamashita, Atsushi; Benomar, Ali; Goizet, Cyril; Durr, Alexandra; Gleeson, Joseph G.; Darios, Frederic; Brice, Alexis; Stevanin, Giovanni.
In: American Journal of Human Genetics, Vol. 91, No. 6, 07.12.2012, p. 1051-1064.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia
AU - Tesson, Christelle
AU - Nawara, Magdalena
AU - Salih, Mustafa A M
AU - Rossignol, Rodrigue
AU - Zaki, Maha S.
AU - Al Balwi, Mohammed
AU - Schule, Rebecca
AU - Mignot, Cyril
AU - Obre, Emilie
AU - Bouhouche, Ahmed
AU - Santorelli, Filippo M.
AU - Durand, Christelle M.
AU - Oteyza, Andrés Caballero
AU - El-Hachimi, Khalid H.
AU - Al Drees, Abdulmajeed
AU - Bouslam, Naima
AU - Lamari, Foudil
AU - Elmalik, Salah A.
AU - Kabiraj, Mohammad M.
AU - Seidahmed, Mohammed Z.
AU - Esteves, Typhaine
AU - Gaussen, Marion
AU - Monin, Marie Lorraine
AU - Gyapay, Gabor
AU - Lechner, Doris
AU - Gonzalez, Michael
AU - Depienne, Christel
AU - Mochel, Fanny
AU - Lavie, Julie
AU - Schols, Ludger
AU - Lacombe, Didier
AU - Yahyaoui, Mohamed
AU - Al Abdulkareem, Ibrahim
AU - Zuchner, Stephan L
AU - Yamashita, Atsushi
AU - Benomar, Ali
AU - Goizet, Cyril
AU - Durr, Alexandra
AU - Gleeson, Joseph G.
AU - Darios, Frederic
AU - Brice, Alexis
AU - Stevanin, Giovanni
PY - 2012/12/7
Y1 - 2012/12/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870900912&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870900912&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2012.11.001
DO - 10.1016/j.ajhg.2012.11.001
M3 - Article
C2 - 23176821
AN - SCOPUS:84870900912
VL - 91
SP - 1051
EP - 1064
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 6
ER -