CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5.
Brain. 2009-05-12; 132(6): 1589-1600
DOI: 10.1093/brain/awp073
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Goizet C(1), Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M,
Forlani S, Guyant-Maréchal L, Fontaine B, Guimarães J, Isidor B, Chazouillères O,
Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F,
Wolf C, Mhiri C, Crosby A, Brice A, Stevanin G.
Author information:
(1)INSERM/UPMC UMR_S 975 (ex U679), CRicm, Bat. Pharmacie, Pitié-Salpêtrière
Hospital, 47 Boulevard de l’Hôpital, Paris Cedex 13, France.
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.