Curation NME NAXE

Gene NAXE

Disease NME

Inheritance AR

Score

2 + 3 = 5 / 18

Genetic + experimental = total

Classification

Limited

Refuted

Moderate

Definitive

Last Updated 08/12/2025

Pubs Reviewed 1

Publication Span –

Publication Interval –

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.

All criTRia Curations Locus Page

Genetic evidence

Total: 2

Per page

Category	Type	Citation	Score	Details
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

Per page

Category	Type	Citation	Score	Details
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.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.