1. Department of Dermatology, Niigata University School of Medicine, Niigata, Japan
2. ^*Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan

Correspondence: Dr Noriaki Aoki, Department of Dermatology, Niigata University School of Medicine, Asahimachi-dori, Niigata 951–8510, Japan.

Received 31 January 2000; Accepted 16 February 2000.

To the Editor:

Sjögren–Larsson syndrome (SLS; MIM# 270200) is an autosomal recessive disorder characterized by mental retardation, di- or tetraplegia and congenital ichthyosis (^{Rizzo 1993}). The ichthyosis in SLS is usually present at birth, but there have been reports of a much later onset of ichthyosis, at an age of <1 y of age. Mental retardation is variable, but is severe (IQ < 50) in about 70% of cases. Additional clinical features include glistening white dots on the retina, seizures, short stature, and speech defects. Patients with SLS have deficient activity of fatty aldehyde dehydrogenase (FALDH), an enzyme that is necessary for the oxidation of fatty alcohol to fatty acid through its involvements as a component of the fatty alcohol:NAD⁺ oxidoreductase enzyme complex (^{Rizzo & Craft 1991}).

The FALDH gene has been mapped to the SLS locus on 17p11.2 (^{Rogers et al. 1995}). It is approximately 31 kb and consists of 10 exons, resulting in a cDNA of 1455 bp, which is translated into a protein with 485 amino acids (^{Rogers et al. 1997}). Here we report a novel point mutation in the FALDH gene (AG transversion at nucleotide 1157) resulting in the change of asparagine to serine at amino acid 386, i.e., N386S, and show the successful DNA diagnosis in a family.

A 1 y old girl visited our university clinic on July 17 1999. She presented with congenital ichthyosis, and showed spastic tetraplegia and mental retardation. Histologic examination revealed orthohyperkeratosis, acanthosis, and papillomatosis, and the granular cell layer of the epidermis was slightly thickened. Alcohol dehydrogenase staining was performed on the skin of this patient and a normal control after freezing the samples in an OCT compound according to the method of^{Judge et al. (1990)}, and revealed a reduction in alcohol dehydrogenase activity only in the patient's skin. Her parents were not relatives and both of them were healthy.

After informed consent, blood samples were collected and genomic DNA were extracted from the buffy coats (QIAGEN, Hilden, Germany). Genomic DNA from normal healthy Japanese people were used as controls. A 213-bp polymerase chain reaction fragment containing exon 8 of FALDH gene was amplified using specific primers (SLS-E8F, 5'-ACTTCACTGACCTGGACACC-T-3' and SLS-E8R, 5'-GCAGCCCATACAATCCACTCA-3'). Amplification conditions were 95°C for 3 min, followed by 35 cycles of 95°C for 45 s, 65°C for 30 s, and 72°C for 1 min, and then final extension at 72°C for 7 min. The patient's amplified fragment as well as that from the father and the mother was directly sequenced by using the ABI-PRISM dye terminator and the 373 sequencer (Applied Biosystems, Foster City, CA). The sequence from the patient revealed a homozygous point mutation (1157 AG) in exon 8 of the FALDH gene, which changes codon 386 from asparagine to serine. The heterozygosity was demonstrated in both of her parents (Figure 1). This mutation was excluded to be present in 50 normal unrelated individuals.

Figure 1.

. Sequence analysis of the FALDH gene. DNA sequence of exon 8 of the FALDH gene is shown from a healthy individual, an heterozygous parent, and an affected child. The arrow denotes nucleotide position 1157 in the FALDH cDNA.

Full figure and legend (34K)

Since the first report about the mutations in FALDH gene of the SLS patients, 20 different pathogenic mutations to date have been identified, seven with small deletions, one with gross deletion, three with insertions, one with deletion/insertion, and eight with missense mutations (^{De Laurenzi et al. 1996;Sillen et al. 1997}). Interestingly, nonsense mutation was not detected in this gene. Missense mutations have been reported in 38 patients, of which 30 have CT transversion at nucleotide 943 resulting in the change of proline to serine at amino acid 315, and it is indicated that this mutation is the major cause of SLS in the inbred Swedish families (^{De Laurenzi et al. 1997}). So far, nothing is described about the mutation (N386S) found in this case. A BLAST database search shows that the asparagine residue at position 386 is highly conserved in a variety of species and different types of aldehyde dehydrogenases, e.g., succinate semialdehyde dehydrogenase in man, the rat, and Bacillus subtilis, and aldehyde dehydrogenase in Cladosporium herbarum. In addition, the analysis of the secondary structure of the rat class 3 aldehyde dehydrogenase revealed that Asn 388, which corresponds to Asn 386 in human FALDH, appears to stabilize adjacent elements of secondary structure (^{Liu et al. 1997}). These findings therefore suggest that the substitution of this strictly conserved amino acid residue could account for the enzyme deficiency of FALDH in SLS patients.