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Étude biochimique d’ABHD5 dans le syndrome de Dorfman-Chanarin et en condition physiologique

Abstract : ABHD5 is a lipase activator whose mutations induce triacylglycerol accumulation called Dorfman–Chanarin syndrome (DCS). DCS is characterized by ichthyosiform erythroderma resulting from acanthosis and orthokeratotic hyperkeratosis. Ultrastructural findings include lipid droplets in basal and granular layers and abnormal lamellar bodies. The ichthyosis pathomechanism is unclear. Because some ichthyoses are associated with defective ceramide syntheses, we examined ceramides in 7 DCS patients. ABHD5 genetic analysis identified 4 different mutations, including 2 original, 1 missense and 1 large deletion. Epidermal ceramides were very low in all DCS patients but expression of ceramide genesis-related enzymes was minimally changed. Because ABHD5 might act indirectly on ceramides, we tried to identify ABHD5 partners. Three interactors were detected : perilipin-1, -2 and -3 (PLIN3) ; the latter is a new partner and involved in endosome transport through Rab9. PLA (protein proximity assay) demonstrated PLIN3’s physical closeness to ABHD5 in epidermis and PLIN3 was weakly expressed in DCS epidermis. These findings suggest that DCS-ichthyosis is linked to a trafficking defect of lamellar granules. Then we identified new ABHD5 alternative transcripts, 1 in mice (absence of exon 2) and 4 in human (absence of exon 6, 5, beginning of 6, 5 and 6). The full length ABHD5 and accessory bands were shown by western blot using human epidermis and fat extracts. The molecular weight of some of these bands was compatible with the predicted molecular weight of the isoforms encoded by these alternative transcripts. However, we were unable to identify these isoforms, nor the full length ABHD5 by mass spectrometry.
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Benjamin Roussel. Étude biochimique d’ABHD5 dans le syndrome de Dorfman-Chanarin et en condition physiologique. Biochimie, Biologie Moléculaire. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCD021⟩. ⟨tel-01793073⟩

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