NAXE gene and protein information
The NAXE gene is located on chromosome 1q21.2-q22. NAXE encodes a protein called NAD(P)HX epimerase, and is also known as AIBP; PEBEL; YJEFN1; APOA1BP. Expression is fairly ubiquitous across different tissues and cell types. The mouse homologue of NAXE was identified to have two initiating methionines, producing mitochondrial and cytosolic protein isoforms. NAXE was also reported to be secreted.
NAXE 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 further react to form cyclic NAD(P)HX.
• NAD(P)HX epimerase (NAXE) and NAD(P)HX dehydratase (NAXD) are enzymes that repair the ‘damaged’ derivatives.
• NAXE catalyses the epimerisation, or interconversion, between R-NAD(P)HX and S-NAD(P)HX.
• NAXD catalyses the dehydration specifically of the S-form of NAD(P)HX, utilising ATP.
• Secreted NAXE binds the APOA1 high-density lipoprotein (HDL) complex, destabilising lipid rafts and facilitating cholesterol efflux.
NAXE pathogenic variants
• PEBEL1 is autosomal recessive.
• Most variants are inherited from both parents.
• There are rare instances of de novo variants.
• Pathogenic variants across the NAXE 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.
• Repeat expansion: ~200 repeats of GGGCC were identified in NAXE leading to a marked reduction in RNA and protein levels. Genetic analyses determined that homozygosity in the patient was due to maternal chromosome 1 uniparental disomy (UPD).
• Pathogenic variants in NAXE are rare, with a current predicted incidence of 1 in 19,737,293 individuals (GeniE, Broad Institute).
NAXE