Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics.

AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS. METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites. CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

miR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.

In clear cell renal cell carcinoma (ccRCC), dysregulated lipid metabolism plays a pivotal role in tumor initiation and progression. This study delves into the unexplored landscape of Dysregulated Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) in ccRCC. Using a combination of "fatty acid metabolism" dataset analysis and differentially expressed genes (DEGs) derived from Gene Expression Omnibus (GEO) database, potential metabolic regulators in ccRCC were identified. Subsequent investigations utilizing public databases, clinical samples, and in vitro experiments revealed that ALDH3A2 was down-regulated in ccRCC, mediated by miR-1182, highlighting its role as an independent prognostic factor for patient survival. Functionally, ALDH3A2 exhibited tumor-suppressive properties, impacting ccRCC cell phenotypes and influencing epithelial-mesenchymal transition. Mechanistically, silencing ALDH3A2 promoted lipid accumulation in ccRCC cells by activating the PI3K-AKT pathway, thereby promoting tumor progression. These findings shed light on the critical role of the miR-1182/ALDH3A2 axis in ccRCC tumorigenesis, emphasizing the potential for targeting lipid metabolism as a promising anti-cancer strategy.

Markers Associated With Tumor Recurrence in Patients With Breast Cancer Achieving a Pathologic Complete Response After Neoadjuvant Chemotherapy.

Background: Patients who achieve a tumor pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have better outcomes than patients with residual tumor. However, tumors still recur in the pCR patients. Therefore, we aim to explore factors associated with tumor recurrence in this patient population. Methods: A total of 1,913 patients diagnosed with breast cancer between 1995 and 2020 and received NAC were included in this analysis. Clinicopathological data of the patients were retrospectively collected. We used Cox regression analysis to assess the associations of clinicopathological factors with patients' outcome. Proteomic study of tumors was applied to identify differentially expressed proteins (DEPs) between tumors from the pCR patients with tumor recurrence and tumors from those without tumor recurrence. PPI network analysis of the corresponding genes of DEPs was used to identify the hub genes. The prognostic value of the corresponding genes of DEPs was evaluated using two online databases, Kaplan-Meier Plotter and bc-GenExMiner. The genes that were significantly associated with patients' survival in both databases, as well as being identified as hub genes, were considered as potential prognostic markers for pCR patients. Publicly available data from Gene Expression Omnibus (GEO) was used to verify the prognostic value of the identified marker. Results: Among the 1,913 included patients, 420 had tumor pCR. The median follow-up for the pCR patients was 32.6 months (IQR, 16.3-55.5). Overall estimated 5-year risk of tumor recurrence for the pCR patients was 11%. Multivariable analysis showed that a higher pre-NAC clinical T stage and N stage were independent predictors for increased risk of tumor recurrence (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.01-6.51, P=0.047 for clinical T stage and HR 3.48, 95%CI 1.37-8.83, P=0.009 for clinical N stage). NAC regimens, the type of breast and axillary surgery, and adjuvant chemotherapy were not associated with tumor recurrence. Finally, aldehyde dehydrogenase (ALDH) 3A2 was identified by the proteomic study and was verified as a potential predictor for tumor recurrence in the pCR patients (with a median follow up of 3.78 years for dataset GSE32603 and 2.74 years for dataset GSE25066 from GEO, tumor recurrence rate: low versus high expression, 20.7% versus 4.5% [data from GSE32603]; 10.9% versus 0% [data from GSE25066]). Conclusions: Clinical T stage, clinical N stage and tumor expression of ALDH3A2 were potential markers for predicting tumor recurrence in the pCR patients after NAC.

End-stage crystalline maculopathy with retinal atrophy in Sjögren-Larsson syndrome: a case report and review of the literature.

Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive neurocutaneous disorder. It is caused by the inheritance of sequence variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). Universal signs of the condition are congenital ichthyosis, spastic paresis of the lower and upper limbs, and reduced intellectual ability. In addition to this clinical triad, patients with SLS experience dry eyes and decreased visual acuity caused by a progressive retinal degeneration. Examination of the retina in patients with SLS often reveals glistening yellow crystal-like deposits surrounding the fovea. This crystalline retinopathy often develops in childhood and is considered pathognomonic for the disease. The metabolic disorder typically shortens lifespan to half that of the unaffected population. However, now that patients with SLS live longer, it becomes increasingly important to understand the natural course of the disease. Our case describes a 58-year-old woman with advanced SLS whose ophthalmic examination illustrates the end-stage of the retinal degeneration. Optical coherence tomography (OCT) and fluorescein angiography confirm the disease is restricted to the neural retina with dramatic thinning of the macula. This case is unique since it is among the most advanced both in terms of chronological age and severity of retinal disease. While the accumulation of fatty aldehydes, alcohols, and other precursor molecules is the probable cause of retinal toxicity, a more complete understanding of the course of retinal degeneration may aid in the development of future treatments. The aim of our presentation of this case is to increase awareness of the disease and to foster interest in therapeutic research which may benefit patients with this rare condition.

Eye issues in Sjogren-Larsson Syndrome Sjögren-Larsson syndrome (SLS) is a rare, inherited condition that affects the skin and nervous system. It is caused by variations in a gene that controls the way fats are broken down in the body. The three key signs of the disease are (1) peeling, dry skin; (2) muscle stiffness and impaired movement of the arms and legs; and (3) reduced intellectual ability. Most signs of the condition appear shortly after birth. Genetic testing and counseling services can help patients and their families to understand what to expect with SLS. Caring for people with SLS requires teamwork by specialists like neurologists and physical therapists. Because eye problems are common, the early consultation of an eye doctor is also important. An eye examination can also confirm the diagnosis of SLS. SLS often causes the eyes to appear red, feel dry, or become irritated. This can make it hard to see in bright light. Decreased vision at night is also common. This is caused by the progressive loss of the central part of the retina which is needed to see fine details. Because SLS shortens lifespan, it is rare for anyone to reach the final stages of the disease. As patients with SLS are living longer, as illustrated by the individual in our case study, it becomes important to understand how the disease progresses. Unfortunately, treatments to restore vision are not yet available. Nevertheless, some protective measures can be taken. Eye examinations in early childhood are important for preventing damage to the eyes. Wearing glasses can improve vision, as well as protect eyes from accidental injury or falls. Eye drops can provide relief from dry eyes, and sunglasses can reduce glare and sensitivity to light. In the future, gene therapy may be used to treat SLS.

Novel ALDH3A2 mutations in structural and functional domains of FALDH causing diverse clinical phenotypes in Sjögren-Larsson syndrome patients.

Mutations in ALDH3A2 cause Sjögren-Larsson syndrome (SLS), a neuro-ichthyotic condition due to the deficiency of fatty aldehyde dehydrogenase (FALDH). We screened for novel mutations causing SLS among Indian ethnicity, characterized the identified mutations in silico and in vitro, and retrospectively evaluated their role in phenotypic heterogeneity. Interestingly, asymmetric distribution of nonclassical traits was observed in our cases. Nerve conduction studies suggested intrinsic-minus-claw hands in two siblings, a novel neurological phenotype to SLS. Genetic testing revealed five novel homozygous ALDH3A2 mutations in six cases: Case-1-NM_000382.2:c.50C>A, NP_000373.1:p.(Ser17Ter); Case-2-NM_000382.2:c.199G>T, NP_000373.1:p.(Glu67Ter); Case-3-NM_000382.2:c.1208G>A, NP_000373.1:p.(Gly403Asp); Case-4-NM_000382.2:c.1325C>T, NP_000373.1:p.(Pro442Leu); Case-5 and -6 NM_000382.2:c.1349G>A, NP_000373.1:p.(Trp450Ter). The mutations identified were predicted to be pathogenic and disrupt the functional domains of the FALDH. p.(Pro442Leu) at the C-terminal α-helix, might impair the substrate gating process. Mammalian expression studies with exon-9 mutants confirmed the profound reduction in the enzyme activity. Diminished aldehyde-oxidizing activity was observed with cases-2 and 3. Cases-2 and 3 showed epidermal hyperplasia with mild intracellular edema, spongiosis, hypergranulosis, and perivascular-interstitial lymphocytic infiltrate and a leaky eosinophilic epidermis. The presence of keratin-containing milia-like lipid vacuoles implies defective lamellar secretion with p.(Gly403Asp). This study improves our understanding of the clinical and mutational diversity in SLS, which might help to fast-track diagnostic and therapeutic interventions of this debilitating disorder.

Identification of ALDH3A2 as a novel prognostic biomarker in gastric adenocarcinoma using integrated bioinformatics analysis.

BACKGROUND: Extensive research has revealed that genes play a pivotal role in tumor development and growth. However, the underlying involvement of gene expression in gastric carcinoma (GC) remains to be investigated further. METHODS: In this study, we identified overlapping differentially expressed genes (DEGs) by comparing tumor tissue with adjacent normal tissue using the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database. RESULTS: Our analysis identified 79 up-regulated and ten down-regulated genes. Functional enrichment analysis and prognosis analysis were conducted on the identified genes, and the fatty aldehyde dehydrogenase (FALDH) gene, ALDH3A2, was chosen for more detailed analysis. We performed Gene Set Enrichment Analysis (GSEA) and immunocorrelation analysis (infiltration, copy number alterations, and checkpoints) to elucidate the mechanisms of action of ALDH3A2 in depth. The immunohistochemical (IHC) result based on 140 paraffin-embedded human GC samples indicated that ALDH3A2 was over-expressed in low-grade GC cases and the OS of patients with low expression of ALDH3A2 was significantly shorter than those with high ALDH3A2 expression. In vitro results indicated that the expression of ALDH3A2 was negatively correlated with PDCD1, PDCD1LG2, and CTLA-4. CONCLUSION: We conclude that ALDH3A2 might be useful as a potential reference value for the relief and immunotherapy of GC, and also as an independent predictive marker for the prognosis of GC.

Macular crystalline inclusions in Sjögren-Larsson syndrome are dynamic structures that undergo remodeling.

BACKGROUND: Sjögren-Larsson syndrome (SLS) is a rare genetic neurocutaneous disease caused by mutations in ALDH3A2 that results in deficiency of fatty aldehyde dehydrogenase and accumulation of fatty aldehydes and alcohols. The disease is associated with ichthyosis, spasticity, and intellectual disability. Patients exhibit a characteristic retinopathy with macular crystalline inclusions that first appear in early childhood and increase with age. Once formed, the inclusions are thought to be inert and irreversible. We sought to document how the crystalline inclusions change over time. MATERIALS AND METHODS: Serial retinal photographs of 4 SLS subjects (9-23 years old) were taken over a period of 1-3 years. Images were compared by visual inspection and analyzed using ImageJ/Fiji software to observe changes. RESULTS: Visual inspection of retinal photographs of SLS subjects taken over time demonstrated distinctive changes in crystalline inclusions. New inclusions were formed and some established inclusions regressed. These changes were conveniently demonstrated with software-based photographic image analysis. CONCLUSIONS: We conclude that macular inclusions in SLS are not simply inert deposits, but are dynamic structures that form over time and are subject to remodeling. This conclusion provides new insight into the interplay between the metabolic defect and retinal pathology in SLS, and raises the potential for new therapeutic approaches to reverse some aspects of the maculopathy.

Sjögren-Larsson syndrome: The mild end of the phenotypic spectrum.

Sjögren-Larsson syndrome (SLS) is a rare inborn error of lipid metabolism. The syndrome is caused by mutations in the ALDH3A2 gene, resulting in a deficiency of fatty aldehyde dehydrogenase. Most patients have a clearly recognizable severe phenotype, with congenital ichthyosis, intellectual disability, and spastic diplegia. In this study, we describe two patients with a remarkably mild phenotype. In both patients, males with actual ages of 45 and 61 years, the diagnosis was only established at an adult age. Their skin had been moderately affected from childhood onward, and both men remained ambulant with mild spasticity of their legs. Cognitive development, as reflected by school performance and professional career, had been unremarkable. Magnetic resonance spectroscopy of the first patient was lacking the characteristic lipid peak. We performed a literature search to identify additional SLS patients with a mild phenotype. We compared the clinical, radiologic, and molecular features of the mildly affected patients with the classical phenotype. We found 10 cases in the literature with a molecular proven diagnosis and a mild phenotype. Neither a genotype-phenotype correlation nor an alternative explanation for the strikingly mild phenotypes was found. New biochemical techniques to study the underlying metabolic defect in SLS, like lipidomics, may in the future help to unravel the reasons for the exceptionally mild phenotypes. In the meantime, it is important to recognize these mildly affected patients to provide them with appropriate care and genetic counseling, and to increase our insights in the true disease spectrum of SLS.

Sjogren-Larsson Syndrome: Mechanisms and Management.

Sjogren Larsson syndrome (SLS) is a rare autosomal recessive inborn error of lipid metabolism due to mutations in the ALDH3A2 that result in a deficiency of fatty aldehyde dehydrogenase (FALDH). The syndrome has a high prevalence in Sweden where it was first described, but now known to occur worldwide. The classical triad of ichthyosis, mental retardation and spasticity characterizes clinical features. Preterm birth is common. "Glistening white dots" in the retina is a pathognomic clinical feature. Magnetic resonance imaging of the brain demonstrates leukoencephalopathy predominant in the periventricular region. Cerebral MR spectroscopy reveals a characteristic abnormal lipid peak at 1.3ppm and a small peak at 0.9ppm. The primary role of FALDH is oxidation of medium and long-chain aliphatic aldehydes derived from fatty alcohol, phytanic acid, ether glycerolipids and sphingolipids. The diagnosis is based on the typical phenotype, demonstration of the enzyme deficiency and presence of biallelic mutations in the ALDH3A2. The management of SLS largely remains symptomatic currently. However, several potential therapeutic options are being developed, keeping in view of the fundamental metabolic defects or correcting the genetic defect. This review aims to summarize the clinical, genetic and biochemical findings, pathogenetic mechanisms and the current therapeutic options, in SLS.

Compound heterozygous mutations in the ALDH3A2 gene cause Sjögren-Larsson syndrome: a case report.

Purpose: Sjögren-Larsson syndrome is a rare, autosomal, recessive neurocutaneous disorder caused by mutations in the ALDH3A2 gene, which encodes the fatty aldehyde dehydrogenase enzyme. Deficiency in fatty aldehyde dehydrogenase results in an abnormal accumulation of toxic fatty aldehydes in the brain and skin, which cause spasticity, intellectual disability, ichthyosis, and other clinical manifestations. We present the clinical features and mutation analyses of a case of SLS.Materials and Methods: The family history and clinical data of the patient were collected. Genomic DNA was extracted from peripheral blood samples of the patient and her parents, and next-generation sequencing was performed. The candidate mutation sites that required further validation were then sequenced by Sanger sequencing. Bioinformatics software PSIPRED and RaptorX were used to predict the secondary and tertiary structures of proteins.Results: The patient, a five-year-old girl with complaints of cough for three days and intermittent convulsions for seven hours, was admitted to the hospital. Other clinical manifestations included spastic paraplegia, mental retardation, tooth defects, and ichthyosis. Brain magnetic resonance imaging showed periventricular leukomalacia. Genetic screening revealed compound heterozygous mutations in the ALDH3A2 gene: a frameshift mutation c.779delA (p.K260Rfs*6) and a missense mutation c.1157A > G (p.N386S). Neither of the ALDH3A2 alleles in the compound heterozygote patient were able to generate normal fatty aldehyde dehydrogenase, which were likely responsible for her phenotype of Sjögren-Larsson syndrome.Conclusion: The compound heterozygous mutations found in the ALDH3A2 gene support the diagnosis of Sjögren-Larsson syndrome in the patient and expand the genotype spectrum of the gene.

Genetic assessment of ten Egyptian patients with Sjögren-Larsson syndrome: expanding the clinical spectrum and reporting a novel ALDH3A2 mutation.

Assessment of ten Egyptian patients with Sjögren-Larsson syndrome (SLS) detected; unusual clinical manifestations, a first report of brain atrophy in SLS, some patients exhibited neither retinal dots nor white matter changes previously reported as essential manifestations. We identified five mutations in ALDH3A2 gene including a novel one and suggest a founder effect. Sjögren-Larsson syndrome is a rare autosomal recessive inborn error of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase and result in a triad of ichthyosis, spasticity, and mental retardation. Clinical, radiological, biochemical, and neurophysiological evaluation in ten SLS patients descending from seven unrelated Egyptian pedigrees was followed by Sanger sequencing of ALDH3A2 performed by ABI 3500. All patients presented with SLS triad; ichthyosis, spasticity of four limbs and hyperreflexia with an intelligent quotient (IQ) ranging from (39 to 69). Other manifestations were dysmorphic features, seizures, and skeletal and ophthalmological affection. Mutational analysis of ALDH3A2 gene revealed three missense, one splice site, and one novel stop codon mutation; c.991G>T (p.E331X). Biochemical studies showed decrease of fatty aldehyde dehydrogenase activity. Our results reinforce the distinct clinical, radiological, and biochemical features of ALDH3A2-related SLS which are the clue for targeted molecular testing. Moreover, we present additional unreported clinical findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

Potential role of ALDH3A2 on the lipid and glucose metabolism regulated by (-)-hydroxycitric acid in chicken embryos.

This study aimed to investigate the effect of (-)-hydroxycitric acid ((-)-HCA) on lipid and glucose metabolism, and further analyzed these actions whether associated with modulation of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) expression in chicken embryos. Results showed that (-)-HCA decreased triglyceride content and lipid droplet counts, while these effects induced by (-)-HCA were reversed in chicken embryos pre-transfected with sh4-ALDH3A2. (-)-HCA decreased malic enzyme, acetyl-CoA carboxylase, fatty acid synthase, and sterol regulatory element binding protein-1c mRNA level, while increased carnitine palmitoyl transferase 1A (CPT1A) and peroxisome proliferators-activated receptor α (PPARα) mRNA level; and the action of (-)-HCA on lipid metabolism factors had completely eliminated in embryos pre-transfected with sh4-ALDH3A2. Chicken embryos pre-transfected with sh4-ALDH3A2 had eliminated the increasing of serum glucose and hepatic glycogen content induced by (-)-HCA. (-)-HCA decreased phosphofructokinase-1 and increased G6P, fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase mRNA level in chicken embryos. Similarly, the effect of (-)-HCA on these key enzyme mRNA level was reversed in embryos pre-transfected with sh4-ALDH3A2. Furthermore, (-)-HCA increased PPAR-γ-coactivator-1α (PGC-1α), PPARα, hepatic nuclear factor-4A, PEPCK, and CPT1A protein level, and these actions of (-)-HCA disappeared in embryos pre-transfected with sh4-ALDH3A2. These results indicated that (-)-HCA reduced fat accumulation and accelerated gluconeogenesis via activation of PGC-1α signaling pathway, and these effects of (-)-HCA might associate with the increasing of ALDH3A2 expression level in chicken embryos.

Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.

Insulation by myelin lipids is essential to fast action potential conductivity: changes in their quality or amount can cause several neurologic disorders. Sjögren-Larsson syndrome (SLS) is one such disorder, which is caused by mutations in the fatty aldehyde dehydrogenase ALDH3A2. To date, the molecular mechanism underlying SLS pathology has remained unknown. In this study, we found that Aldh3a2 is expressed in oligodendrocytes and neurons in the mouse brain, and neurons of Aldh3a2 knockout (KO) mice exhibited impaired metabolism of the long-chain base, a component of sphingolipids. Aldh3a2 KO mice showed several abnormalities corresponding to SLS symptoms in behavioral tests, including increased paw slips on a balance beam and light-induced anxiety. In their brain tissue, 2-hydroxygalactosylceramide, an important lipid for myelin function and maintenance, was reduced by the inactivation of fatty acid 2-hydroxylase. Our findings provide important new insights into the molecular mechanisms responsible for neural pathogenesis caused by lipid metabolism abnormalities.-Kanetake, T., Sassa, T., Nojiri, K., Sawai, M., Hattori, S., Miyakawa, T., Kitamura, T., Kihara, A. Neural symptoms in a gene knockout mouse model of Sjögren-Larsson syndrome are associated with a decrease in 2-hydroxygalactosylceramide.

Genotype and phenotype variability in Sjögren-Larsson syndrome.

The Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient-to-patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments. Thus, with this study, patient-centered literature data was merged into a concise genotype-based, open-access database (www.LOVD.nl/ALDH3A2). One hundred and seventy eight individuals with 90 unique SLS-causing variants were included with phenotypic data being available for more than 90%. While the three lead symptoms did occur in almost all cases, more heterogeneity was observed for other frequent clinical manifestations of SLS. However, a stringent genotype-phenotype correlation analysis was hampered by the considerable variability in reporting phenotypic features. Consequently, we compiled a set of recommendations of how to generate comprehensive SLS patient descriptions in the future. This will be of benefit on multiple levels, for example, in clinical diagnosis, basic research, and the development of novel treatment options for SLS.

Activin/Smad2 and Wnt/ß-catenin up-regulate HAS2 and ALDH3A2 to facilitate mesendoderm differentiation of human embryonic stem cells.

Activin and Wnt signaling are necessary and sufficient for mesendoderm (ME) differentiation of human embryonic stem cells (ESCs). In this study, we report that during ME differentiation induced by Activin and Wnt, Activin/Smad2 induces a decrease of the repressive histone modification of H3K27me3 by promoting the proteasome-dependent degradation of enhancer of zeste 2 polycomb (EZH2)-repressive complex 2 subunit. As a result, recruitment of the forkhead protein FOXH1 on open chromatin regions integrates the signals of Activin/Smad2 and Wnt/ß-catenin to activate the expression of the ME genes including HAS2 and ALDH3A2 Consistently, H3K27me3 decrease is enriched on open chromatin around regulatory regions. Furthermore, knockdown of HAS2 or ALDH3A2 greatly attenuates ME differentiation. These findings unveil a pathway from extracellular signals to epigenetic modification-mediated gene activation during ME commitment.

Identification of a novel deletion within ALDH3A2 gene in an Iranian Family with Sjögren-Larsson Syndrome.

Sjögren-Larsson syndrome (SLS) is a rare type of congenital ichthyosis with neurological problems and intellectual disability. Homozygous mutations in ALDH3A2 gene are known to be responsible for this syndrome. Here, we report an Iranian family with congenital SLS bearing a novel two-base-pair deletion within ALDH3A2 genomic sequence. Our finding expands the mutation spectrum of ALDH3A2 that is applicable for further molecular studies and management of SLS.

Novel mutations and a severe neurological phenotype in Sjögren-Larsson syndrome patients from Iran.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spasticity and intellectual disability. The disease is caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase. We describe 7 Iranian SLS patients from 5 unrelated consanguineous families. Sequencing of ALDH3A2 identified 4 novel mutations, including a 26-bp deletion (c.25_50del), small in-frame deletion (c.370_372del; p.G124del), a termination (p.Q35Ter) and a missense mutation (p.Lys211Glu). Bacterial expression of the p.Lys211Glu and p.G124del mutations showed little or no detectable enzyme activity. Three of the patients exhibited an unusual neuro-regressive clinical course associated with seizures, which may reflect the presence of unidentified genetic or environmental modifiers in this consanguineous population. This cohort represents the largest group of Iranian patients with molecularly confirmed SLS and expands the mutational and clinical spectrum of this disease.

Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.

Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression ofALDH3A2in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels ofALDH3A2were determined by quantitative reverse transcription-polymerase chain reaction. To investigate the effect of age onALDH3A2expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis onALDH3A2expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis (EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF,ALDH3A2expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed,ALDH3A2expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cellALDH3A2expression levels correlate with age, cause of infertility, and ovarian response to stimulation.

Case of Sjögren-Larsson syndrome with a large deletion in the ALDH3A2 gene confirmed by single nucleotide polymorphism array analysis.

Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder inherited in an autosomal recessive fashion. SLS patients are characterized by lipid metabolism error, primarily leading to cardinal signs of ichthyosis, spasticity and mental retardation. Additional signs include short stature, epilepsy, retinal abnormalities and photophobia. More than 90 mutations of the ALDH3A2 gene have been reported for SLS, and such variants can be successfully detected at a rate of 94% by direct DNA sequencing. We performed direct sequencing of ALDH3A2 gene from the index patient, however, no mutation could be detected. HumanCytoSNPs12 array analysis and subsequent targeted single nucleotide polymorphism analysis revealed a novel deletion mutation at chromosome 17p11.2. This 67-Kb region includes the first five coding exons of ALDH3A2, and is flanked by rs2245639 and rs962801. To the best of our knowledge, this mutation is novel and our findings broaden the mutation spectrum of ALDH3A2 causing SLS phenotype.