Mutations associated with Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS), a rare autosomal disorder characterized by ichthyosis, spastic neurological disorders and oligophrenia, is associated with deficiency of fatty aldehyde dehydrogenase encoded by a gene on chromosome 17q11.2. Mutations of the gene (GDB symbol ALDH10) were recently identified in three SLS patients. Another aldehyde dehydrogenase isozyme. ALDH3, also has a high activity for fatty aldehyde oxidation, and is encoded by a gene in chromosome 17q11.2. Abnormality of the ALDH3 gene could also cause a similar syndrome. The examination of the ALDH3 locus of three additional SLS patients showed that two are heterozygous with C-->G at nt 985 (Pro-->Ala at protein position 329). However, the mutation was found to be common (frequency of the atypical allele is about 0.25) in normal subjects, and not related to SLS. Isoelectric focusing analysis indicated that ALDH3 is hardly expressed in normal as well as patients' fibroblast cells, while ALDH10 expressed in the normal cells is diminished in the three patients' cells. The level of ALDH10 mRNA is also low in the patients' cells. The examination of the ALDH10 locus revealed the existence of a 3 base deletion coupled with a 21 base insertion at intron 6/exon 7 junction in one patient. This abnormality is the same as that found in the patient previously reported by other investigators. One patient is associated with a 2 base deletion at nt 1297 and consequent premature chain termination at protein position 434. Another patient is a compound heterozygote for the same 2 base deletion at nt 1297 and a 5 base insertion at nt 1311 and premature chain termination at protein position 457. Unique characteristics of the SLS mutations are pointed out.