Sjögren-Larsson syndrome in Brazil is caused by a common c.1108-1G-->C splice-site mutation in the ALDH3A2 gene.
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Adolescent↗
Biomedical subjects
W B Rizzo
Publications and source records attributed to W B Rizzo.
Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analysis in Sjögren-Larsson syndrome.
Fatty aldehyde dehydrogenase (FALDH) is a microsomal enzyme that catalyzes the oxidation of medium- and long-chain aliphatic aldehydes derived from metabolism of fatty alcohol, phytanic acid, ether glycerolipids and leukotriene B4. The FALDH gene (ALDH3A2) in man and mouse consists of 11 exons and is closely linked to the gene for ALDH3. In both species, alternative splicing results in formation of a second minor protein, FALDHv, that has a unique carboxy-terminal end. The functional significance of this alternate protein is not known. In humans, mutations in the FALDH gene cause Sjögren-Larsson syndrome (SLS), which is characterized by ichthyosis, mental retardation and spasticity. Missense mutations involving 24 amino acid positions in FALDH have been identified. These amino acids are more highly conserved among related class 3 aldehyde dehydrogenase enzymes than expected, suggesting that they are critically important for protein folding, catalysis or stability. Studies of mutations in SLS should prove useful for understanding structure-function correlations in FALDH and other aldehyde dehydrogenase proteins.
Aldehyde Oxidoreductases↗
Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.
BACKGROUND AND AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. METHODS: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU. m(-2). min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-(13)C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum [beta-OH butyrate], release of water-soluble radioactivity from (3)H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). RESULTS: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 micromol. kg(-1). min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU. m(-2). min(-1). NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid beta oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 micromol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. CONCLUSIONS: These data indicate that peripheral insulin resistance, increased fatty acid beta oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.
Adult↗
Microsomal fatty aldehyde dehydrogenase catalyzes the oxidation of aliphatic aldehyde derived from ether glycerolipid catabolism: implications for Sjögren-Larsson syndrome.
The enzyme that catalyzes the oxidation of fatty aldehyde derived from ether glycerolipid catabolism has not been identified. To determine whether microsomal fatty aldehyde dehydrogenase (FALDH) is responsible, we investigated the metabolism of 1-O-[9, 10-(3)H-octadecyl]-glycerol ([(3)H]OG) in FALDH-deficient cultured cells from patients with Sjögren-Larsson syndrome (SLS) and in mutant Chinese hamster ovary (CHO) cells. Intact fibroblasts from SLS patients incubated with [(3)H]OG showed a selective deficiency (38+/-7% of normal) in the incorporation of radioactivity into fatty acid, but no decrease in incorporation of radioactivity into fatty alcohol, total lipids and phosphatidylethanolamine (PE). Consistent with fatty aldehyde accumulation, incorporation of radioactivity into N-alkyl-phosphatidylethanolamine, which is derived from Schiff base formation of free aldehyde with PE, was 4-fold higher in SLS fibroblasts compared to normal controls. Similar results were seen with SLS keratinocytes, whereas FALDH-deficient CHO cells showed a more profound reduction in radioactive fatty acid to 12+/-2% of normal. These results implicate FALDH in the oxidation of ether-derived fatty aldehyde in human and rodent cells. Metabolism of ether glycerolipids is a previously unrecognized source of fatty aldehyde that may contribute to the pathogenesis of SLS.
Aldehyde Oxidoreductases↗
Genomic organization, expression, and alternate splicing of the mouse fatty aldehyde dehydrogenase gene.
Fatty aldehyde dehydrogenase (FALDH) is a microsomal enzyme that catalyzes the oxidation of aliphatic aldehydes to fatty acids. Mutations in the FALDH gene are responsible for the human genetic disorder Sjögren-Larsson syndrome (SLS) which is characterized by ichthyosis, mental retardation, and spasticity. To better understand SLS and the expression of FALDH in mammalian tissues, we investigated the organization and expression of the mouse FALDH gene (recently named ALDH3A2). The mouse gene consists of 11 exons and spans about 25 kb. Primer extension experiments identified the transcription initiation site at nt -121 relative to the translation initiating codon. The major FALDH transcript was 3 kb long and was composed of exons 1-10. A less abundant alternately spliced transcript contained an additional exon (exon 9') inserted between exons 9 and 10 and encodes a protein (FALDHv) with a variant carboxy-terminal domain of unknown function. Northern analysis usingRNA from different tissues showed widespread but variable expression of the gene, which generally correlated with FALDH enzyme activity. Expression of the alternate exon 9' transcript in tissues often differed from that of the major transcript and did not reflect enzyme activity. These results provide a basis for investigating the in vivo expression of FALDH in response to physiologic and pharmacologic manipulation, and are essential for the development of an animal model of SLS.
Aldehyde Oxidoreductases↗
[Sjögren-Larsson syndrome].
This rare, ubiquitous neurocutaneous disorder is inherited in an autosomal recessive fashion. Its primary clinical manifestations are congenital ichthyosis, spastic diplegia or tetraplegia, and mental retardation. The causative biochemical defect has been identified as a deficiency of the enzyme fatty aldehyde dehydrogenase, a component of fatty alcohol:NAD+ oxidoreductase. We present a case report of an affected 3.5 year old white girl to give an overview of the pre- and postnatal diagnostic procedures as well as of therapeutic options.
Aldehyde Oxidoreductases↗
Effects of fructose and troglitazone on phospholipid fatty acid composition in rat skeletal muscle.
Skeletal muscle phospholipid fatty acid (PLFA) composition is associated with insulin sensitivity in animal models and in man. However, it is not clear whether changes in insulin sensitivity cause a change in PLFA composition or vice versa. The present studies have examined the effects of agents known to increase or decrease insulin sensitivity on PLFA composition of the major phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), in soleus and extensor digitorum longus muscle. Four groups of Sprague-Dawley rats--control, 0.2% troglitazone (Tgz), 60% fructose fed, and fructose + Tgz--were treated for 3 wk. Fructose feeding was associated with a decrease in muscle membrane polyunsaturated fatty acids (PUFA) and n-3 fatty acids in both PC and PE. Administration of Tgz alone resulted in an increase in liver (3.75 +/- 0.93 to 6.93 +/- 1.00 micromol/min/mg tissue, P < 0.05) and soleus muscle (0.34 +/- 0.03 to 0.67 +/- 0.09 micromol/min/mg, P < 0.01) elongase activity, which would be expected to increase membrane PUFA. However, Tgz decreased PLFA associated with greater insulin sensitivity (e.g., PUFA and n-3 fatty acids) and increased PLFA associated with decreased insulin sensitivity (16:0 and n-6 fatty acids) in both PC and PE. Co-administration of fructose and Tgz did not reverse the decrease in PUFA observed with fructose alone. We conclude that the improvement in insulin sensitivity reported with Tgz is associated with an apparently paradoxical effect to decrease PUFA and n-3 PLFA composition in rat skeletal muscle. These studies suggest that Tgz-mediated increases in insulin sensitivity do not result in improved PLFA composition.
Animals↗
Changes in phosphatidylcholine fatty acid composition are associated with altered skeletal muscle insulin responsiveness in normal man.
The fatty acid composition of skeletal muscle cell membrane phospholipids (PLs) is known to influence insulin responsiveness in man. We have recently shown that the fatty acid composition of phosphatidylcholine (PC), and not phosphatidylethanolamine (PE), from skeletal muscle membranes is of particular importance in this relationship. Efforts to alter the PL fatty acid composition in animal models have demonstrated induction of insulin resistance. However, it has been more difficult to determine if changes in insulin sensitivity are associated with changes in the skeletal muscle membrane fatty acid composition of PL in man. Using nicotinic acid (NA), an agent known to induce insulin resistance in man, 9 normal subjects were studied before and after treatment for 1 month. Skeletal muscle membrane fatty acid composition of PC and PE from biopsies of vastus lateralis was correlated with insulin responsiveness using a 3-step hyperinsulinemic-euglycemic clamp. Treatment with NA was associated with a 25% increase in the half-maximal insulin concentration ([ED50] 52.0 +/- 7.5 to 64.6 +/- 9.0 microU/mL, P < .05), consistent with decreased peripheral insulin sensitivity. Significant changes in the fatty acid composition of PC, but not PE, were also observed after NA administration. An increase in the percentage of 16:0 (21% +/- 0.3% to 21.7% +/- 0.4%, P < .05) and decreases in 18:0 (6.2% +/- 0.5% to 5.1% +/- 0.4%, P = .01), long-chain n-3 fatty acids (1.7% +/- 0.2% to 1.4% +/- 0.1%, P < .01), and total polyunsaturated fatty acids ([PUFAs] 8.7% +/- 0.8% to 8.0% +/- 0.8%, P < .05) are consistent with a decrease in fatty acid length and unsaturation in PC following NA administration. The change in ED50 was significantly correlated with the change in PUFAs (r = -.65, P < .05). These studies suggest that the induction of insulin resistance with NA is associated with changes in the fatty acid composition of PC in man.
Adult↗
Sjögren-Larsson syndrome: accumulation of free fatty alcohols in cultured fibroblasts and plasma.
Sjögren-Larsson syndrome (SLS) is an inherited disorder associated with deficient oxidation of long-chain aliphatic alcohols. Previous studies have reported modest elevations in total (free + esterified) fatty alcohols in SLS, but free fatty alcohols have not been selectively measured, in part because of their low concentrations in most tissues and the presence of trace fatty alcohol contaminants in some solvents used for their analysis. We adapted methods to measure free fatty alcohols in cultured cells and plasma that minimize exogenous alcohol contamination. Fatty alcohols were analyzed as acetate derivatives, using capillary column gas chromatography. By this method, cultured skin fibroblasts from SLS patients were found to have 7- and 8-fold elevations in the mean content of hexadecanol (16:0-OH) and octadecanol (18:0-OH), respectively. The mean plasma 16:0-OH and 18:0-OH concentrations in SLS patients (n = 11) were 9- and 22-fold higher than in normal controls, respectively. In SLS fibroblasts, most of the fatty alcohol (59%) that accumulated was free rather than esterified alcohol, whereas free alcohol accounted for 23% of the total alcohol in normal cells. These results indicate that elevations in free fatty alcohols provide a sensitive marker for the enzymatic defect in SLS. The ability to measure free fatty alcohols in cultured cells and plasma should prove useful for investigations of normal fatty alcohol metabolism and the deranged metabolism in SLS.
Adolescent↗
Sjögren-Larsson syndrome: explaining the skin-brain connection.
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Brain↗
The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene.
Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH). To define the molecular defects causing SLS, we performed mutation analysis of the FALDH gene in probands from 63 kindreds with SLS. Among these patients, 49 different mutations-including 10 deletions, 2 insertions, 22 amino acid substitutions, 3 nonsense mutations, 9 splice-site defects, and 3 complex mutations-were found. All of the patients with SLS were found to carry mutations. Nineteen of the missense mutations resulted in a severe reduction of FALDH enzyme catalytic activity when expressed in mammalian cells, but one mutation (798G-->C [K266N]) seemed to have a greater effect on mRNA stability. The splice-site mutations led to exon skipping or utilization of cryptic acceptor-splice sites. Thirty-seven mutations were private, and 12 mutations were seen in two or more probands of European or Middle Eastern descent. Four single-nucleotide polymorphisms (SNPs) were found in the FALDH gene. At least four of the common mutations (551C-->T, 682C-->T, 733G-->A, and 798+1delG) were associated with multiple SNP haplotypes, suggesting that these mutations originated independently on more than one occasion or were ancient SLS genes that had undergone intragenic recombination. 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.
Aldehyde Oxidoreductases↗
Proton MR spectroscopy of Sjögren-Larsson's syndrome.
We performed single-voxel proton MR spectroscopy (1H-MRS) in two children with Sjögren-Larsson's syndrome (SLS). Both patients showed two abnormal spectral peaks at 1.3 ppm and 0.9 ppm that were obtained with short echo times. These two abnormal spectral peaks were seen in high-intensity areas on T2-weighted images and also in basal ganglia of normal intensities. 1H-MRS may be useful for establishing the diagnosis and investigating the natural history of SLS, and for evaluating the efficacy of therapeutic approaches to SLS.
Aldehyde Oxidoreductases↗
Involvement of microsomal fatty aldehyde dehydrogenase in the alpha-oxidation of phytanic acid.
We investigated the role of microsomal fatty aldehyde dehydrogenase (FALDH) in the conversion of pristanal into pristanic acid. Cultured skin fibroblasts from controls and patients with Sjögren-Larsson syndrome (SLS) who are genetically deficient in FALDH activity were incubated with [2,3-(3)H]phytanic acid. The release of aqueous-soluble radioactivity by the SLS cells was decreased to 25% of normal, consistent with an intact formation of pristanal but a deficiency of further oxidation. SLS cells also accumulated four-fold more radioactivity in N-alkyl-phosphatidyl ethanolamine, which arises from incorporation of free aldehyde into phosphatidyl ethanolamine. Recombinant human FALDH expressed in Chinese hamster ovary cells readily oxidized pristanal and cultured fibroblasts from SLS patients showed a severe deficiency in FALDH activity (13% of normal) when pristanal was used as substrate. Nevertheless, SLS patients did not accumulate phytanic acid in their plasma. We conclude that FALDH is involved in the oxidation of pristanal to pristanic acid and that this reaction is deficient in patients with SLS.
Aldehyde Oxidoreductases↗
Isolation of a Chinese hamster fibroblast variant defective in dihydroxyacetonephosphate acyltransferase activity and plasmalogen biosynthesis: use of a novel two-step selection protocol.
We have developed a two-step selection protocol to generate a population of Chinese hamster ovary (CHO) cell variants that are plasmalogen-deficient, but contain intact, functional peroxisomes (plasmalogen-/peroxisome+). This involved sequential exposures of a mutagenized cell population to photodynamic damage by using two different pyrene-labelled sensors, 9-(1'-pyrene)nonanol and 12-(1'-pyrene)dodecanoic acid. By this procedure we generated several isolates, all except one of which displayed a severe decrease in plasmalogen biosynthesis. Further characterization of one of the plasmalogen-deficient isolates, NRel-4, showed that it contained intact, functional peroxisomes. Whole-cell homogenates from NRel-4 displayed severely decreased dihydroxyacetone phosphate acyltransferase, which catalyses the first step in plasmalogen biosynthesis. NRel-4 and another, recently described, plasmalogen-deficient cell line, NZel-1 [Nagan, Hajra, Das, Moser, Moser, Lazarow, Purdue and Zoeller (1997) Proc. Natl. Acad. Sci. U.S. A. 94, 4475-4480] were hypersensitive to singlet oxygen, supporting the notion of plasmalogens as radical oxygen scavengers. Wild-type-like resistance could be conferred on NRel-4 upon restoration of plasmalogen content by supplementation with a bypass compound, sn-1-hexadecylglycerol. NRel-4 and other plasmalogen-/peroxisome+ strains will allow us to examine further the role of ether lipids in cellular functions without complications associated with peroxisome deficiency, and might serve as an animal cell model for certain forms of the human genetic disorder rhizomelic chondrodysplasia punctata.
Acyltransferases↗
Inherited disorders of fatty alcohol metabolism.
The importance of long-chain aliphatic alcohols to human biology has recently been emphasized by the discovery of several inborn errors of fatty alcohol metabolism. These inherited diseases include isolated defects in the oxidation of fatty alcohol to fatty acid (Sjögren-Larsson syndrome) and deficient incorporation of fatty alcohol into ether lipids (isolated alkyl dihydroxyacetone phosphate synthase deficiency). In addition, disorders of peroxisomal biogenesis (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease) and peroxisomal protein import (rhizomelic chondrodysplasia punctata) have impaired ether lipid synthesis along with other associated defects in peroxisomal metabolism. All of the inherited disorders of fatty alcohol metabolism are associated with severe neurologic disease, but the contribution of tissue fatty alcohol accumulation to the pathogenesis is not clear. Molecular genetic studies have recently identified many of the disease-causing mutations in these disorders, which should lead to more accurate diagnosis and genetic counseling. Although prenatal diagnosis offers a method for preventing these genetic diseases, no effective therapy exists to alleviate the symptoms.
Aldehyde Oxidoreductases↗
Pre- and postnatal growth retardation, scaling skin, moderate mental retardation and quadrispasticity, hypospadias grade 2 and hydro-uretero nephrosis, postaxial polydactyly. A distinct MCA/MR syndrome?
We report a moderately mentally retarded 7-year-old male with a unique combination of clinical symptoms and signs: severe pre- and postnatal growth retardation, scaling skin and quadrispasticity, hypospadias grade 2 and hydro-uretero nephrosis, postaxial polydactyly type B on the right hand. Normal fibroblast enzyme activities of fatty aldehyde dehydrogenase and NADPH cytochrome C reductase were not consistent with the diagnosis of Sjögren-Larsson syndrome. The nosology of 'bird-headed' dwarfism is briefly discussed.
Abnormalities, Multiple↗
Skeletal muscle phosphatidylcholine fatty acids and insulin sensitivity in normal humans.
The fatty acid composition of skeletal muscle membrane phospholipids (PL) is known to influence insulin responsiveness in humans. However, the contribution of the major PL of the outer (phosphatidylcholine, PC) and inner (phosphatidylethanolamine, PE) layers of the sarcolemma to insulin sensitivity is not known. Fatty acid composition of PC and PE from biopsies of vastus lateralis from 27 normal men and women were correlated with insulin sensitivity determined by the hyperinsulinemic euglycemic clamp technique at insulin infusion rates of 0.4, 1.0, and 10.0 mU . kg-1 . min-1. Significant variation in the half-maximal insulin concentration (ED50) was observed in the normal volunteers (range 24.0-146.0 microU/ml), which correlated directly with fasting plasma insulin (r = 0.75, P < 0.0001). ED50 was inversely correlated with the degree of membrane unsaturation (C20-C22 polyunsaturated fatty acids; r = 0. 58, P < 0.01) and directly correlated with fatty acid elongation (ratio of 16:0 to 18:0, r = 0.45, P < 0.05) in PC. However, no relationship between fatty acid composition and insulin sensitivity was observed in PE (NS). These studies suggest that the fatty acid composition of PC may be of particular importance in the relationship between fatty acids and insulin sensitivity in normal humans.
Adult↗