CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5
CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5
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DOI：
10.1093/brain/awp073
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发表时间：
2009-06-01
期刊：
影响因子：
14.5
通讯作者：
Stevanin, Giovanni
中科院分区：
文献类型：
--
作者：
Goizet, Cyril;Boukhris, Amir;Stevanin, Giovanni
已经定位了34个不同的遗传性痉挛截瘫基因座，并确定了16个相关基因。常染色体隐性遗传型痉挛性截瘫通常具有复杂的临床表型，但SPG5、SPG24和SPG28基因座被认为与单纯形式的疾病有关。最近，在SPG5家族中发现了5个突变的CYP7B1基因，编码细胞色素P450氧合甾醇7-羟基酶，在脑和肝脏中表达。用直接测序法分析了82例常染色体隐性遗传性痉挛性截瘫患者和90例散发性单纯遗传性痉挛性截瘫患者的CYP7B1基因编码区和外显子边界。我们在9个家系中发现了8个CYP7B1基因突变，其中包括6个新的突变。其中3个为无义突变(p.R63X、p.R112X、p.Y275X)，5个为错义突变(p.T297A、p.R417H、p.R417C、p.F470I、p.R486C)，最后4个集中在蛋白质C末端的外显子6。残基R417为突变热点。16例患者平均发病年龄为16.4~12.1岁(447岁)。平均病程28.3~13.4年(1058)，所有病例的痉挛和功能障碍均为中到重度。有趣的是，遗传性痉挛截瘫在7个SPG5家系中是单纯的，但在2个家系中是复杂的。此外，在七个纯家族中的两个中的三个患者的脑磁共振成像上观察到了脑白质高信号。最后，一个家庭的指示病例患有慢性自身免疫性肝炎，而他的大哥死于肝硬变和肝功能衰竭。然而，这种联系是否是偶然的仍未得到解决。在我们的常染色体隐性遗传性痉挛截瘫家系中，CYP7B1突变的频率为7.3(n 6/82)，在我们的散发性纯痉挛截瘫家系中为3.3(n 3/90)。最近发现的细胞色素P7B1是导致SPG5的基因，突显了一种新的涉及遗传性痉挛截瘫决定论的分子机制。
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- hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exonintron 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 447 years). After a mean disease duration of 28.3 13.4 years (1058), 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.