NME_NAXE
- Gene
- NAXE
- Disease
- NME
- Inheritance
- AR
- Classification
- Limited
- Total Score
- 5
- Publications Reviewed
- 1
- Publication Span
- Last Updated
- 08/12/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt, Elbay Aliyev
Description
A biallelic GGGCC repeat expansion of approximately 200 repeat units in the NAXE promoter was identified in one proband with autosomal recessive NAXE-related mitochondrial encephalopathy. The proband's homozygous expansion resulted from maternal chromosome 1 uniparental disomy, with the mother carrying the expansion heterozygously. The expansion was detected by long-read sequencing and supported by RP-PCR/Southern blot family testing, marked reduction of NAXE RNA and protein, reduced nascent promoter transcripts by NET-CAGE, and CpG hypermethylation at and downstream of the repeat. Screening of additional undiagnosed mitochondrial encephalopathy cases did not identify another pathogenic expansion, and available cohort/population data indicate that expanded alleles are very rare. To date, this locus-disease relationship is supported by one publication.
Genetic evidence
Total: 2
| Singular Evidence | Probands | PMID:39455596 | 1.5 | One affected proband (Pt2359, Family A) with NAXE-related mitochondrial encephalopathy carried a biallelic ~200-unit GGGCC repeat expansion in the NAXE promoter. Family testing showed maternal heterozygosity and proband homozygosity due to maternal chromosome 1 UPD; other explanatory variants were not identified. |
| Collective Evidence | Computational | PMID:39455596 | 0.5 | Targeted ExpansionHunter detected the homozygous NAXE promoter GGGCC expansion in Pt2359 and a mild heterozygous expansion signal in the mother; de novo tools ExpansionHunter Denovo and STRling did not detect the expansion. Cohort/TR-gnomAD data support rarity of alleles outside the common short-repeat range. |
Experimental evidence
Total: 3
| Function | Biochemical function | PMID:39455596 | 0.5 | Gene-level: NAXE encodes NAD(P)HX epimerase in the NAD(P)HX repair system, and loss of this enzyme compromises mitochondrial function; this supports disease-relevant biochemical function but is not tandem-repeat/locus-specific. |
| Function | Regulatory impact | PMID:39455596 | 1.5 | TR-specific: the biallelic NAXE promoter GGGCC expansion was associated with markedly reduced NAXE RNA, reduced nascent promoter transcripts by NET-CAGE, and CpG hypermethylation at and downstream of the repeat, supporting transcriptional suppression. |
| Functional Alteration | Patient cells | PMID:39455596 | 1 | Patient-derived fibroblasts from Pt2359 showed disease-relevant functional alteration, including reduced oxygen consumption and reduced oxidative phosphorylation complex II/II+III activity, with reduced NAXE RNA/protein in the same patient-cell context. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.