Novel and recurrent ALDH3A2 mutations in Italian patients with Sjögren-Larsson syndrome

Abstract

Sjögren-Larsson syndrome (SLS; MIM#270200) is an autosomal recessive neurocutaneous disease caused by mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that catalyzes the oxidation of medium- and long- chain aliphatic aldehydes fatty acids. We studied two unrelated Italian SLS patients with ichthyosis, developmental delay, spastic diplegia and brain white matter disease. One patient was homozygous for a novel ALDH3A2 insertion mutation (c.767insA) in exon 5. The other SLS patient was a compound heterozygote for two previously reported mutations: a slice site mutation (c.1094C > T; S365L) in exon 7. Analysis of fibroblast RNA by RT-PCR indicated that the spice-site mutation caused skipping of exons 2 and 3. The c.1094C > T mutation, previously associated with two ALDH3A2 haplotypes, was found on a third distinct haplotype in our patient, which indicates that arose independently in this kindred. These results add to understanding of the genetic basis of SLS and will be useful for DNA diagnosis of this disease.

Fig. 1

Electron micrographs from involved skin. a Membrane-bound electron-lucent vacuoles (asterisks) in the granular layer: remnants of lamellar structures (arrowhead) are visible at the periphery of a vacuole. The intercellular space at the interface between the granular layer and the stratum corneum appear focally and irregularly enlarged, in particular at places of keratinosome fusion with the apical cell surface (arrows, bar = 500 nm). b The intercellular spaces of the lower stratum corneum appear also focally widened and partly filled with a laminated or amorphous material (asterisk). Unusual plasma membrane invaginations containing parallel stacks of lamellae are also visible (arrowhead). Numerous vacuoles, which appear empty or filled with lamellar structures reminiscent of keratinosomes (arrow) and/or an amorphous material, are present within the cytoplasm of horny cells (bar = 200 nm). Sequence analysis of the ALDH3A2 gene, exon 5 of patient 1 and exon 7 of patient 2. c Wild-type sequence of exon 5. d Heterozygous mutation (present in both parents), showing the insertion of an adenine, the mutation is visible as a scrambling of the chromatogram (beginning from black arrow). e Homozygous insertion of an adenine into a stretch of three adenines (red arrow). This mutation leads to a frame-shift with a premature stop codon, TAA, underlined in red. f Wild-type sequence of exon 7. g Heterozygous mutation that results in C to T transversion (black arrow), determining the aminoacid substitution S365L in patient 2

Fig. 2

Sequence analysis of the ALDH3A2 gene, exons 1–4, of patient 2. The entire CDS was amplified, and the two products obtained directly sequenced. a The chromatograms analysis of the smaller product shows the deletion generating the skipping of exons 2 and 3, resulting in the loss of 106 amino acids. b The chromatogram of the genomic sequence shows the heterozygous c.471 + 2T→G transversion (black arrow). c The electrophoresis analysis showing the full length and a smaller transcript lacking 318 bp due to the skipping of exons 2–3. In this case, the PCR was performed with primers amplifying exon 1 to exon 4 of the patient’s cDNA (see Materials and methods)