CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.
Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with 'pure' forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-alpha hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon-intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 +/- 12.1 years (range 4-47 years). After a mean disease duration of 28.3 +/- 13.4 years (10-58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.
INSERM/UPMC UMR_S 975 (ex U679), CRicm, Bat. Pharmacie, Pitié-Salpêtrière Hospital, 47 Boulevard de l'Hôpital, Paris Cedex 13, France.
Cyril
C
Goizet
Amir
A
Boukhris
Alexandra
A
Durr
Christian
C
Beetz
Jeremy
J
Truchetto
Christelle
C
Tesson
Maria
M
Tsaousidou
Sylvie
S
Forlani
Lucie
L
Guyant-Maréchal
Bertrand
B
Fontaine
João
J
Guimarães
Bertrand
B
Isidor
Olivier
O
Chazouillères
Dominique
D
Wendum
Djamel
D
Grid
Françoise
F
Chevy
Patrick F
PF
Chinnery
Paula
P
Coutinho
Jean-Philippe
JP
Azulay
Imed
I
Feki
Fanny
F
Mochel
Claude
C
Wolf
Chokri
C
Mhiri
Andrew
A
Crosby
Alexis
A
Brice
Giovanni
G
Stevanin
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics*; D000072474:Cytochrome P450 Family 7; D005260:Female; D005808:Genes, Recessive; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000235:genetics*; D055815:Young Adult
D018389:Codon, Nonsense; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human