MTRFR – Combined Oxidative Phosphorylation Deficiency Type 7

Combined oxidative phosphorylation deficiency type 7 (COXPD7) is an autosomal recessive mitochondrial disorder characterized by early optic atrophy (HP:0000648) and a Leigh syndrome–like brainstem involvement. Clinical onset often includes mild developmental delay and progressive visual loss, with neuroimaging showing bilateral symmetric lesions that in some cases partially reverse (PMID:24284555).

Biallelic loss-of-function variants in MTRFR (HGNC:26784) have been identified in 7 probands from at least 4 unrelated families, including 2 siblings with compound heterozygous frameshift changes and 5 additional individuals reported in a literature review (PMID:24284555). Segregation of the compound heterozygous alleles was confirmed in one sibship, with one sibling serving as an additional affected relative carrying both variants.

The variant spectrum comprises predominantly frameshift mutations: for example, c.96_99dup (p.Pro34fs) and c.210del (p.Gly72fs), both predicted to truncate the C12orf65 protein and abolish its mitochondrial translation rescue function (PMID:24284555). No recurrent or founder alleles have been reported, and carrier frequencies are extremely low.

Functional studies of MTRFR loss-of-function—though performed in the context of hereditary spastic paraplegia—demonstrate that nonsense variants such as c.394C>T (p.Arg132Ter) markedly reduce mitochondrial protein synthesis, destabilize respiratory complexes I and IV on BN-PAGE, and impair enzymatic activities in patient fibroblasts (PMID:23188110). These assays provide mechanistic evidence of mitochondrial translation failure underlying COXPD7 pathology.

Taken together, the available genetic and experimental data support a model of autosomal recessive haploinsufficiency in which MTRFR loss leads to combined oxidative phosphorylation defects and neurological disease. Although additional large cohorts and in vivo models would strengthen this link, current evidence meets a moderate level of clinical validity and functional concordance.

Key Take-home: Biallelic MTRFR loss-of-function variants cause COXPD7, presenting with optic atrophy and Leigh-like lesions, and should be included in diagnostic panels for mitochondrial encephalopathies.

References

• Journal of neuro-ophthalmology • 2014 • Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature. PMID:24284555
• Journal of medical genetics • 2012 • A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). PMID:23188110

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