NAXD protein isoforms
The NAXD gene (formally known as CARKD) encodes for three proteins. These are generated as a consequence of alternative splicing and from different initiation sites.
• mitoNAXD: Exon 1 contains the mitochondrial propeptide. The mitochondrial transcript is the most highly expressed and has a mitochondrial localisation.
• cytoNAXD: is generated from an alternative start codon in exon 2. This has a cytoplasmic location.
• spNAXD: An alternate exon 1 contains a signal peptide (sp), and this has evidence of endoplasmic reticulum location.
• The presence of NAXD enzyme has been confirmed in the cytoplasm and mitochondria in liver tissue.
NAXD protein function
• NAD(P)H are cofactors prone to damage by hydration, forming ‘damaged’ derivatives collectively termed NAD(P)HX.
• Hydrated derivatives include S- NAD(P)HX and R- NAD(P)HX and are redox inactive. These can react further to form cyclic- NAD(P)HX.
• NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) are enzymes that repair the ‘damaged’ derivatives.
• NAXE acts as an enzyme to catalyse the epimerisation, or interconversion, between R-NAD(P)HX and S-NAD(P)HX.
• NAXD acts as an enzyme to catalyse the dehydration specifically of the S-form of NAD(P)HX, utilising ATP.
NAXD pathogenic variants
• PEBEL2 is autosomal recessive.
• Most variants are inherited from both parents.
• There are rare instances of de novo variants (PMID 30576410).
• Pathogenic variants across the NAXD gene have been reported.
• There do not appear to be any ‘mutation hotspots’.
• Pathogenic variants do not appear to be restricted to a particular type of variant, and variants have included frameshift, splicing, missense, stop gain.
• A full list of variants in the literature is detailed in Van Bergen et al 2022 (PMID: 35866541).
• The location of the variant within the NAXD gene may correlate to the clinical presentation of the patient, outlined above and detailed in Van Bergen et al 2022 (PMID: 35866541).
NAXD