SJOGREN-LARSSON-SYNDROME IS CAUSED BY A COMMON MUTATION IN NORTHERN EUROPEAN AND SWEDISH PATIENTS

Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder char acterized by congenital ichthyosis, mental retardation, and spastic di plegia or tetraplegia, Patients with SLS have deficient activity of fa tty aldehyde dehydrogenase (FALDH), an enzyme involved in long-chain f atty alcohol oxidation, The cDNA encoding FALDH has recently been clon ed and several different mutations have been found in SLS patients, We have now identified a point mutation (C943 --> T) in 7 of 19 kindreds of European descent, accounting for 24% of the SLS alleles. The C943T mutation was only found in patients of northern European ancestry fro m Sweden, the Netherlands, Germany, and Belgium. Haplotype analysis su ggested that the patients carrying the C943T allele were distantly rel ated, All four Swedish patients were homozygous for C943T, indicating that this mutation is probably the major cause of SLS in the inbred Sw edish families, The mutation leads to the substitution of serine for t he highly conserved proline 315 in the FALDH protein, and expression s tudies confirm that it destroys enzymatic activity, The mutation was r eadily detected with an MulI restriction enzyme digestion test, The fi nding that C943T is a common SLS mutation in northern European and Swe dish patients affords a rapid simple method for diagnosing SLS by scre ening patients for this mutation with DNA-based methods.