Cambi F, Tang X M, Cordray P, Fain P R, Keppen L D, Barker D F
Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
Neurology. 1996 Apr;46(4):1112-7. doi: 10.1212/wnl.46.4.1112.
X-linked hereditary spastic paraplegias (HSP) present with two distinct phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (nystagmus, dysarthria, mental retardation) present in the complicated form. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked complicated HSP (SPG2) and PMD. To answer this question, we carried out linkage analysis in a new pedigree with pure HSP (K101) and refined linkage in pedigree K313. The PLP gene was also screened for mutation by direct sequencing and reverse-transcriptase polymerase chain reaction (RT-PCR). In both families, the disease locus mapped to Xq22 with Lod scores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was identified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This finding demonstrates that a form of X-linked pure spastic paraplegia, X-linked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-producing mutation may be in the noncoding portions of PLP or in a nearby gene.
X连锁遗传性痉挛性截瘫（HSP）表现为两种不同的表型，即单纯型和复杂型。单纯型的特征是痉挛和步态困难，但缺乏复杂型中出现的其他特征（眼球震颤、构音障碍、智力迟钝）。复杂型具有异质性，由位于Xq28的L1CAM基因（SPG1）或位于Xq22的PLP基因（SPG2）突变引起，该基因与佩利措伊斯-梅茨巴赫病（PMD）等位。由于在一个家系（K313）中，单纯型HSP也被定位到Xq22，这就引发了一个问题，即是否存在一种与X连锁复杂型HSP（SPG2）和PMD等位的单纯型HSP。为了回答这个问题，我们对一个患有单纯型HSP的新家系（K101）进行了连锁分析，并对家系K313进行了精细连锁分析。还通过直接测序和逆转录聚合酶链反应（RT-PCR）对PLP基因进行了突变筛查。在两个家系中，疾病位点都定位到Xq22，在K313中，COL4A5 2B6在零重组时的Lod分数为5.3，在K101中，DXS101的Lod分数为2.4。从K313的患病个体中鉴定出PLP基因外显子5中的一个T到C的转换。这种转换导致PLP/DM20主要细胞外环中的丝氨酸突变为脯氨酸。这一发现表明，一种X连锁单纯性痉挛性截瘫、X连锁复杂型HSP（SPG2）和PMD是等位基因疾病。在K101家系的PLP编码序列或内含子/外显子连接处均未发现突变证据，这表明致病突变可能存在于PLP的非编码部分或附近基因中。
