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An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia

From the Laboratory of Neurogenetics (Dr. Higgins, J.M. Loveless, and A. De Biase) and the Laboratory of Neuromuscular Genetics (Dr. Rosen, S. Goswami, and C. Cozzo), Wadsworth Center, New York State Department of Health, Albany; and the Clinical Neurogenetics Unit (Dr. Higgins) and the Family Studies Unit (L.E. Nee), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Address correspondence and reprint requests to Dr. Joseph J. Higgins, Director, Center for Human Genetic Studies, Mid-Hudson Family Health Institute/Westchester Medical Center, 279 Main Street, Suite 202, New Paltz, NY 12561; e-mail: jhiggins{at}fpinstitute.org

Objective: To identify the genetic mutation responsible for autosomal dominant spastic paraplegia (HSP) in a large family with a "pure" form of the disorder. Background: The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21-p22. Some of these families have mutations in the splice-site or coding regions of the spastin gene (SPAST). Methods: Linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by single-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods were used to investigate incongruous mobility shifts. Results:The genomic sequence of SPAST showed a heterozygous four–base pair deletion (delTAAT) near the 3' splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes). Conclusions: This study identifies an atypical intronic microdeletion in SPAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.

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