MT-ND4L – mitochondrial disease

MT-ND4L has a Limited association with mitochondrial disease based on detection of heteroplasmic variants in a broad cohort and a small familial deletion study, without replication of specific pathogenic point mutations. (Limited evidence: heteroplasmic ND4L variants in 179 unrelated patients and a 4977 bp deletion in two siblings) ([PMID:12406974])([PMID:12210349]).

Genetic Evidence

MT-ND4L is inherited via mitochondrial transmission. Screening of 179 unrelated patients by TTGE revealed multiple heteroplasmic variants in ND4L among 68 novel mutations, but none were definitively classified as pathogenic ([PMID:12406974]). A common 4977 bp mtDNA deletion including ND4L was identified in two affected siblings with neuropathy and cirrhosis, but segregation beyond this pedigree is limited ([PMID:12210349]).

Variant Spectrum

No single-nucleotide ND4L variant has been conclusively linked to primary mitochondrial disease. The 4977 bp deletion implicates ND4L loss in multi-system presentations (sensorimotor neuropathy, liver and renal failure), and heteroplasmic missense changes remain of uncertain significance.

Functional Evidence

In E. coli models, ND4L substitutions at subunit interfaces correlate with modest decreases in Complex I deamino-NADH oxidase and proton translocation activities, supporting a potential deleterious effect of ND4L perturbation ([PMID:35306226]). Structural work on an ND6 p.Met64Val mutation indicates disrupted interaction with ND4L, suggesting that ND4L contributes to Complex I assembly and function ([PMID:35567411]).

Conflicting Evidence

There are no reports directly refuting an ND4L role in mitochondrial disease, but the absence of fully characterized pathogenic variants in ND4L and low penetrance in large cohorts indicate uncertain causality.

Integration and Key Take-Home

While heteroplasmic ND4L variants and large-scale deletions co-occur with mitochondrial disease phenotypes, the lack of confirmed pathogenic point mutations and limited segregation data place MT-ND4L at a Limited evidence level for clinical diagnosis. Additional well-defined ND4L variants and functional confirmation are required before routine diagnostic use.

References

• Clinical Chemistry • 2002 • Comprehensive scanning of the entire mitochondrial genome for mutations. PMID:12406974
• American Journal of Medical Genetics • 2002 • Familial childhood onset neuropathy and cirrhosis with the 4977 bp mitochondrial DNA deletion. PMID:12210349
• Proceedings of the National Academy of Sciences of the United States of America • 2007 • Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck. PMID:17456604
• Mitochondrion • 2022 • Human clinical mutations in mitochondrially encoded subunits of Complex I can be successfully modeled in E. coli. PMID:35306226
• Human Molecular Genetics • 2022 • Leber's hereditary optic neuropathy-associated ND6 14484T>C mutation caused pleiotropic effects on the complex I, RNA homeostasis, apoptosis and mitophagy. PMID:35567411

Evidence Based Scoring (AI generated)