A case report of a mild form of multiple acyl-CoA dehydrogenase deficiency due to compound heterozygous mutations in the ETFA gene.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD), previously called glutaric aciduria type II, is a rare congenital metabolic disorder of fatty acids and amino acids oxidation, with recessive autosomal transmission. The prevalence in the general population is estimated to be 9/1,000,000 and the prevalence at birth approximately 1/200,000. The clinical features of this disease are divided into three groups of symptoms linked to a defect in electron transfer flavoprotein (ETF) metabolism. In this case report, we present new pathogenic variations in one of the two ETF protein subunits, called electron transfer flavoprotein alpha (ETFA), in a childhood-stage patient with no antecedent. CASE PRESENTATION: A five-year-old child was admitted to the paediatric emergency unit for seizures without fever. He was unconscious due to hypoglycaemia confirmed by laboratory analyses. At birth, he was a eutrophic full-term new-born with a normal APGAR index (score for appearance, pulse, grimace, activity, and respiration). He had one older brother and no parental consanguinity was reported. A slight speech acquisition delay was observed a few months before his admission, but he had no schooling problems. MADD was suspected based on urinary organic acids and plasma acylcarnitine analyses and later confirmed by genetic analysis, which showed previously unreported ETFA gene variations, both heterozygous (c.354C > A (p.Asn118Lys) and c.652G > A (p.Val218Met) variations). Treatment was based on avoiding fasting and a slow carbohydrate-rich evening meal associated with L-carnitine supplementation (approximately 100 mg/kg/day) for several weeks. This treatment was maintained and associated with riboflavin supplementation (approximately 150 mg/day). During follow up, the patient exhibited normal development and normal scholastic performance, with no decompensation. CONCLUSION: This case report describes new pathogenic variations of the ETFA gene. These compound heterozygous mutations induce the production of altered proteins, leading to a mild form of MADD.

Evidence for a role of Arabidopsis CDT1 proteins in gametophyte development and maintenance of genome integrity.

Meristems retain the ability to divide throughout the life cycle of plants, which can last for over 1000 years in some species. Furthermore, the germline is not laid down early during embryogenesis but originates from the meristematic cells relatively late during development. Thus, accurate cell cycle regulation is of utmost importance to avoid the accumulation of mutations during vegetative growth and reproduction. The Arabidopsis thaliana genome encodes two homologs of the replication licensing factor CDC10 Target1 (CDT1), and overexpression of CDT1a stimulates DNA replication. Here, we have investigated the respective functions of Arabidopsis CDT1a and CDT1b. We show that CDT1 proteins have partially redundant functions during gametophyte development and are required for the maintenance of genome integrity. Furthermore, CDT1-RNAi plants show endogenous DNA stress, are more tolerant than the wild type to DNA-damaging agents, and show constitutive induction of genes involved in DNA repair. This DNA stress response may be a direct consequence of reduced CDT1 accumulation on DNA repair or may relate to the ability of CDT1 proteins to form complexes with DNA polymerase ε, which functions in DNA replication and in DNA stress checkpoint activation. Taken together, our results provide evidence for a crucial role of Arabidopsis CDT1 proteins in genome stability.

Crosstalks between myo-inositol metabolism, programmed cell death and basal immunity in Arabidopsis.

BACKGROUND: Although it is a crucial cellular process required for both normal development and to face stress conditions, the control of programmed cell death in plants is not fully understood. We previously reported the isolation of ATXR5 and ATXR6, two PCNA-binding proteins that could be involved in the regulation of cell cycle or cell death. A yeast two-hybrid screen using ATXR5 as bait captured AtIPS1, an enzyme which catalyses the committed step of myo-inositol (MI) biosynthesis. atips1 mutants form spontaneous lesions on leaves, raising the possibility that MI metabolism may play a role in the control of PCD in plants. In this work, we have characterised atips1 mutants to gain insight regarding the role of MI in PCD regulation. METHODOLOGY/PRINCIPAL FINDINGS: - lesion formation in atips1 mutants depends of light intensity, is due to PCD as evidenced by TUNEL labelling of nuclei, and is regulated by phytohormones such as salicylic acid - MI and galactinol are the only metabolites whose accumulation is significantly reduced in the mutant, and supplementation of the mutant with these compounds is sufficient to prevent PCD - the transcriptome profile of the mutant is extremely similar to that of lesion mimic mutants such as cpr5, or wild-type plants infected with pathogens. CONCLUSION/SIGNIFICANCE: Taken together, our results provide strong evidence for the role of MI or MI derivatives in the regulation of PCD. Interestingly, there are three isoforms of IPS in Arabidopsis, but AtIPS1 is the only one harbouring a nuclear localisation sequence, suggesting that nuclear pools of MI may play a specific role in PCD regulation and opening new research prospects regarding the role of MI in the prevention of tumorigenesis. Nevertheless, the significance of the interaction between AtIPS1 and ATXR5 remains to be established.