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Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia

From the Department of Neurology (Drs. Cambi and Tang), Thomas Jefferson University, Philadelphia, PA; the Departments of Physiology (Dr. Barker and P. Cordray) and Medical Informatics (Dr. Fain), University of Utah School of Medicine, Salt Lake City; and the Department of Pediatrics (Dr. Keppen), University of South Dakota School of Medicine, Sioux Falls, SD.
Work carried out in the laboratory of D.F.B. was supported by MDA. Work carried out in the laboratory of F.C. was supported in part by grant NS01726-02.
Received May 26, 1995. Accepted in final form July 14, 1995.
Address correspondence and reprint requests to Dr. Franca Cambi, 1020 Locust St. #391, Philadelphia, PA 19107.

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.

NEUROLOGY 1996;46: 1112-1117

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