ENPP1 homozygous stop-loss variant causing generalized arterial calcifications of infancy: About a severe neonatal clinical case.

Generalized Arterial Calcifications of Infancy (GACI) is an extremely rare autosomal recessive genetic condition, mostly due to pathogenic variations in the ENPP1 gene (GACI1, MIM #208000, ENPP1, MIM #173335). To date 46 likely pathogenic or pathogenic distinct variations in ENPP1 have been described, including nonsense, frameshift, missense, splicing variations, and large deletions. Here we report a case of GACI in a male newborn with a homozygous stop-loss variant in ENPP1 treated in Nancy Regional University Maternity Hospital. Based on proband main clinical signs, clinical exome sequencing was performed and showed a deletion of one nucleotide leading to frameshift and stop-loss (NM_006208.3 (ENPP1):c.2746del,p.(Thr916Hisfs*23)). Clinical presentation is characterized by primary neonatal arterial hypertension resulting in hypertrophic cardiomyopathy decompensated by three cardiogenic shocks and a neonatal deep right sylvian stroke. The child died at 24 days of life. This is the first report of a pathogenic stop-loss variant in ENPP1. It is an opportunity to remind clinicians of GACI disease, a rare and severe etiology in neonates with severe hypertension, and possibility of bisphosphonates therapy.

Side effects of the sterol biosynthesis inhibitor fungicide, propiconazole, on a beneficial arbuscular mycorrhizal fungus.

The Sterol Biosynthesis Inhibitor (SBI) fungicide, propiconazole, is extensively used in modern agriculture to control fungal diseases. Unfortunately, little is known about its potential side effects on non-target plant-beneficial soil organisms such as arbuscular mycorrhizal fungi (AMF). The direct impact of increasing propiconazole concentrations (0.02; 0.2 and 2 mg x L(-1)) on the lipid metabolism of the AMF Glomus irregulare in relation with its development, was studied by using axenic cultures. The propiconazole impact on G. irregulare was investigated, firstly, through sterol (the target-metabolism of SBI fungicides), phospholipids (PL) and their associated fatty acids (PLFA) analysis (the main membrane components) and secondly by measuring malondialdehyde (MDA) (a biomarker of lipid peroxidation) formation. Finally, the storage lipid quantity, triacylglycerol (TAG), was quantified. Our results demonstrated that the drastic reduction of G. irregulare development (germination, germ tube elongation, colonization, extraradical hyphae growth and sporulation) could be explained not only by the decreases of the total sterol end-products (24-methylcholesterol and 24-ethylcholesterol) and by 24-methylene dihydrolanosterol (a sterol precursor) accumulation, suggesting an inhibition of a key enzyme in sterol biosynthesis pathway (14alpha-demethylase), but also by the increases in phosphatidylcholine (PC) and PLFA (C16:0; C18:0 and C18:3) quantities as well as by MDA accumulation. Moreover, TAG quantity was found to be reduced in the presence of propiconazole, suggesting their use by G. irregulare in a response to propiconazole toxicity. In conclusion, taken together, the findings of the current study highlighted a relationship between the SBI fungicide toxicity against the beneficial AMF G. irregulare and (1) the disturbance in the sterol metabolism, (2) the membrane alteration (PC decrease, lipid peroxidation) as well as (3) the reduction in storage lipids, TAG. More generally, this work could contribute to investigate the toxicity of agricultural chemicals on AMF and underlined the emergency of using sustainable alternative method to control plant diseases. Furthermore, these data can provide a useful approach in soil ecotoxicology studies and risk assessment.

Cyclopropyl sterol and phospholipid composition of membrane fractions from maize roots treated with fenpropimorph.

Maize (Zea mays L.) caryopses were grown in the presence of fenpropimorph, a systemic fungicide, for 7 days in the dark. Membrane fractions enriched, respectively, in endoplasmic reticulum, plasma membrane, and mitochondria were isolated from control and treated maize roots and analyzed for their free sterol, phospholipid, and fatty acid composition. In treated plants, the intracellular distribution of free sterols was dramatically modified both qualitatively and quantitatively. The normally occurring Delta(5)-sterols disappeared almost completely and were replaced by 9beta, 19-cyclopropyl sterols, mainly cycloeucalenol and 24-methyl pollinastanol. These new compounds were found to accumulate in all the membrane fractions in such a way that the endoplasmic reticulum-rich fraction became the richest one in free sterols instead of the plasma membrane. In contrast, the fenpropimorph treatment of maize roots was shown not to affect either the relative proportions or the amounts of the individual phospholipids, but an increase in the unsaturation index of phospholipid-fatty acyl chains of the endoplasmic reticulum-rich fraction was observed. The present data suggest that, in higher plant membranes, cyclopropyl sterols could play a structural role similar to that of the bulk of Delta(5)-sterols.