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

Objective: To identify the genetic mutation responsible for autosomal domin ant spastic paraplegia (HSP) in a large family with a "pure" form of the di sorder. Background: The disease locus in most families with HSP is genetica lly 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 (S PAST). Methods: Linkage and mutational analyses were used to identify the l ocation and the nature of the genetic defect causing the disorder in a larg e family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by si ngle-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods w ere used to investigate incongruous mobility shifts. Results: The genomic s equence of SPAST showed a heterozygous four-base pair deletion (deITAAT) ne ar 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 S PAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.