Disease relevance of ALDH3A2

• Mutations in ALDH3A2 cause loss of enzymatic activity and are the molecular basis of Sjögren-Larsson syndrome [1].
• Further oxidation of this substrate by the fatty alcohol:nicotinamide-adenine dinucleotide oxidoreductase (FAO) enzyme complex, in which one component, ALDH3A2, is known to be mutated in Sjögren-Larsson syndrome (characterized by ichthyosis and spastic paraplegia), would lead to 20-carboxy-(R)-trioxilin A3 [2].
• Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurocutaneous disorder caused by mutation in the ALDH3A2 gene that codes for human fatty aldehyde dehydrogenase (FALDH) [3].
• NPH is frequently (16% of cases) associated with Leber amaurosis (termed Senior-Løken syndrome, SLS) [4].
• Toxicity of long-chain aldehydes for FALDH-deficient cells decreased almost to the level of unaffected keratinocytes [3].

Psychiatry related information on ALDH3A2

• Mutations in the fatty aldehyde dehydrogenase (FALDH) gene cause Sjögren-Larsson syndrome (SLS)-a disease characterized by mental retardation, spasticity, and congenital ichthyosis [5].
• Extrarenal manifestations are known, such as retinitis pigmentosa (Senior-Loken syndrome, SLS) and ocular motor apraxia type Cogan [6].

High impact information on ALDH3A2

• Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene [7].
• 2. Sequence analysis of FALDH amplified from fibroblast mRNA and genomic DNA from 3 unrelated SLS patients reveals distinct mutations, including deletions, an insertion and a point mutation [7].
• We have now cloned the human FALDH cDNA and show that it maps to the SLS locus on chromosome 17p11 [7].
• This was confirmed using adjacent microsatellite markers, one of which (AFM220ze3 at the D2S160 locus) gave a lod score of 4.78 at theta = 0.05 in the 18 families with isolated NPH, whereas the same marker excluded linkage with SLS [4].
• These results demonstrate linkage of the purely renal form of NPH to chromosome 2p, and suggest that there may be genetic heterogeneity between NPH and SLS [4].

Chemical compound and disease context of ALDH3A2

• Sj??gren-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 [8].
• The sodium lauryl (dodecyl) sulfate polyacrylamide gel electrophoresis (SLS PAGE) patterns of keratin polypeptides were followed in 29 patients with psoriasis who were treated with middle wavelength ultraviolet (UV) radiation (UV B), oral methoxsalen, and long wavelength UV radiation (PUVA), or systemic antipsoriatic therapy [9].
• Within a preliminary cumulative in vivo study on SLS-irritated skin, proanthocyanidins (ProcyanoPlus) were proven to reduce transepidermal water loss and erythema formation [10].
• In HVs, irritant dermatitis was induced with 10 min daily exposure for 5+4 days (no irritation on weekends) to 3% SLS aq. on the right and 30% nonanoic acid (NON) in n-propanol on the left volar forearm [11].
• Normal fibroblast enzyme activities of fatty aldehyde dehydrogenase and NADPH cytochrome C reductase were not consistent with the diagnosis of Sjögren-Larsson syndrome [12].

Biological context of ALDH3A2

• By analyzing single nucleotide polymorphisms within the ALDH3A2 gene, we detected four different haplotypes among the new mutant alleles [13].
• Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disease caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase (FALDH), an enzyme involved in lipid metabolism [13].
• FALDH is widely expressed as three transcripts of 2, 3.8, and 4.0 kb, which originate from multiple polyadenylation signals in the 3' UTR [5].
• The FALDH gene lies only 50-85 kb from ALDH3, an aldehyde dehydrogenase gene that has homologous sequence and intron/exon structure [5].
• More than 70 mutations in ALDH3A2 have been discovered in SLS patients including amino acid substitutions, deletions, insertions and splicing errors [8].

Anatomical context of ALDH3A2

• We performed mutation analysis in probands or fetuses from 13 unrelated SLS families and identified seven novel ALDH3A2 mutations [13].
• Although this gene is expressed in a variety of human tissues, the expression level of ALDH10 in the liver and skeletal muscle appears to be higher than that in other tissues examined [14].
• To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes [15].
• Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice [15].
• Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation [15].

Associations of ALDH3A2 with chemical compounds

• We also observed silent sequence variants in the FALDH gene and a base pair substitution in exon 5 that alters aspartic acid to asparagine, all of which are considered polymorphisms [16].
• This indicates that FALDH is involved in the breakdown of phytol [17].
• Identification of fatty aldehyde dehydrogenase in the breakdown of phytol to phytanic acid [17].
• FALDH activity in obligate SLS heterozygotes was partially decreased to 49 +/- 7% of mean normal activity using octadecanal as substrate [18].
• Intact SLS fibroblasts oxidized octadecanol to fatty acid at less than 10% of the normal rate, but oxidized free octadecanal normally, suggesting that the FALDH affected in SLS is chiefly involved in the oxidation of fatty alcohol to fatty acid [18].

Other interactions of ALDH3A2

• Juvenile macular dystrophy associated with deficient activity of fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome [19].
• The impaired activity of FALDH leads to the clinical symptom triad of generalized ichthyosis, mental retardation, and spastic diplegia or tetraplegia [20].
• The diagnosis depends on the measurement of fatty aldehyde dehydrogenase in cultured fibroblasts from skin biopsies, and by identifying known mutations by allele-specific polymerase chain reaction assay [21].
• The recent discovery of the role of FALDH in the degradation of leukotriene B4 (LTB4) opened the way to the development of a new therapeutic strategy for SLS, i.e. 5-lipoxygenase inhibition [22].

Analytical, diagnostic and therapeutic context of ALDH3A2

• Our results demonstrate that SLS is caused by a strikingly heterogeneous group of mutations in the FALDH gene and provide a framework for understanding the genetic basis of SLS and the development of DNA-based diagnostic tests [23].
• 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 [24].
• Differential centrifugation studies in fibroblasts indicated that this FALDH enzyme was largely particulate; soluble FALDH activity was normal in SLS cells [18].
• By site-directed mutagenesis we have prepared the T269I and the D267E mutants and the D267E/T269I double mutant of Saccharomyces cerevisiae FALDH with the aim of investigating the role of these residues in the kinetics [25].
• The current lack of treatment is an impetus to develop gene therapy strategies by introducing functional FALDH into defective cells [3].

References