Sjögren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency - PubMed (original) (raw)
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Sjögren-Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency
William B Rizzo. Mol Genet Metab. 2007 Jan.
Abstract
Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. Affected patients display ichthyosis, mental retardation and spastic diplegia. More than 70 mutations in ALDH3A2 have been discovered in SLS patients including amino acid substitutions, deletions, insertions and splicing errors. Most mutations are private, but several common mutations reflect founder effects, consanguinity or recurrent mutational events. FALDH oxidizes fatty aldehyde substrates arising from metabolism of fatty alcohols, leukotriene B4, ether glycerolipids and other potential sources such as sphingolipids. The pathogenesis of the cutaneous and neurologic symptoms is thought to result from abnormal lipid accumulation in the membranes of skin and brain; the formation of aldehyde Schiff base adducts with amine-containing lipids or proteins; or defective eicosanoid metabolism. Therapeutic approaches are being developed to target specific metabolic defects associated with FALDH deficiency or to correct the genetic defect by gene transfer.
Figures
Figure 1
Clinical features of SLS illustrating the hyperkeratosis and thickened skin folds on the neck (A), axilla (B) and flexure of the arm (C). Retinal glistening white dots are present around the fovea (D). Retinal photo courtesy of Dr. Jack A. Cohen, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL.
Figure 2
Diagram of the ALDH3A2 gene locus on chromosome 17p11.2. The ALDH3A2 gene is located about 60 kb from the ALDH3A1 gene, which is thought to have arisen from a duplication of ALDH3A2. In the expanded diagram of ALDH3A2, numbered exons are not drawn to scale. Note that the coding regions of exons 1 and 10 are filled in black, whereas the non-coding sequence is unfilled. The boxed diagram illustrates the two alternatively spliced transcripts and the differing carboxy-termini of their FALDH protein products.
Figure 3
Role of FALDH in lipid metabolism and the biochemical defects in SLS. The shaded bar indicates FALDH-catalyzed reactions. Dotted arrows and question marks are putative FALDH- or FAO-dependent reactions that have not yet been confirmed. Lipids in bold typeface are putative substrates for FALDH/FAO. Abbreviations used: HpETE, hydro(pero)xyeicosatetraenoic acid; LTB4, leukotriene B4; 5-LOX, 5-lipoxygenase; eLOX3, epidermal lipoxygenase-type 3; 12R-LOX, 12_R_-lipoxygenase; (R)-HXA3, (R)-hepoxolin A3; (R)-TXA3, (R)-trioxilin A3; 20-OH-, 20-CHO- and 20-COOH-refer to lipids with hydroxyl-, keto- and carboxyl-groups, respectively, at the 20-carbon (ω) positions of LTB4 and (R)-TXA3.
References
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