Possible mitochondrial disorder - nuclear genes

Gene: USMG5

Green List (high evidence)

Comment on list classification: There are 2 unrelated families reported in literature where biallelic USMG5 (ATP5MK) variants are shown to cause mitochondrial disease. In addition, functional evidence shows that ATP5MK knockdown leads to loss of ATP synthase in mitochondria. Taken together, there is enough evidence to promote this gene to Green at the next update.

Created: 10 Jun 2026, 9:41 a.m. | Last Modified: 10 Jun 2026, 9:41 a.m.

Panel Version: 5.5

Added new-gene-name tag, new approved HGNC gene symbol for USMG5 is ATP5MK

Created: 10 Jun 2026, 9:41 a.m. | Last Modified: 10 Jun 2026, 9:41 a.m.

Panel Version: 5.5

PMID: 40014158 İpek et al. 2025
4 Turkish brothers affected by mitochondrial disease, aged 13-25 yrs. All 4 had history of neurodegenerative disease, exhibited intellectual disability, muscle weakness, increased deep tendon reflexes in the lower extremities, spasticity, scoliosis, pes cavus deformity, positive Babinski reflex, abnormal gait patterns due to foot deformities, and normal cerebellar tests. Additional findings included geographic tongue (n = 2), strabismus (n = 2), nystagmus (n = 1), ophthalmoplegia (n = 2), hypertrophic upper extremity muscle body build (n = 2), keloid tissue (n = 1), and short stature (n = 3). ES identified a homozygous splice donor variant (c.87+1G > A) in the ATP5MK gene. Unaffected parents were het for the variant. The c.87+1G>A variant has 16 alleles reported in gnomAD, no homozygotes.

PMID 29917077 Barca et al., 2018
Homozygous founder variant (NM_032747.3 c.87+1G>C) reported in three unrelated Ashkenazi Jewish families (allele freq 0.57% in Ashkenazi Jewish populations). Supportive functional studies are also reported: USMG5 mutated fibroblasts have reduced ATP synthesis. Transfection with wild-type USMG5 rescues CV dimerization and ATP production.

PMID: 21345788 Ohsakaya et al., 2011
Knockdown of USMG5 (ATP5MK) in HeLa cells results in loss of ATP synthase in mitochondria.

ATP5MK association with AR Leigh syndrome has been classified as Moderate in ClinGen (Mitochondrial Diseases GCEP, Aug 2020).
Sources: Literature

Created: 10 Jun 2026, 9:37 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6, OMIM:618683; mitochondrial respiratory chain complex deficiency, MONDO:0000066

Publications

• 21345788
• 29903433
• 29917077
• 30240627
• 40014158