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

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.