MIPEP – MIPEP-related Mitochondrial Disease

MIPEP encodes the mitochondrial intermediate peptidase (MIP), which removes N-terminal targeting signals and an octapeptide from imported OXPHOS subunits. Biallelic MIPEP variants cause an autosomal recessive mitochondrial disease characterized by developmental delay, hypotonia, cardiomyopathy, and infantile lethality. Initial discovery in four unrelated probands highlighted left ventricular non-compaction, developmental delay, seizures, severe hypotonia, cataracts and early death, establishing MIP dysfunction in human disease ([PMID:27799064]).

Subsequent reports expanded the phenotype. A 20-year-old without cardiomyopathy carried compound heterozygous c.791G>A (p.Arg264Gln) and c.1756_1771del (p.Tyr586fs), presenting with global developmental delay, hypotonia, optic neuropathy and ataxia ([PMID:34620555]). A Chinese infant with hypertrophic cardiomyopathy, lactic acidosis and hypotonia harbored c.1081T>A (p.Tyr361Asn) and an exon 1–19 deletion ([PMID:36727025]). In total, six unrelated probands have been reported with biallelic MIPEP variants.

All variants—missense, frameshift, splice-site and multi-exon deletions—segregate in trans or homozygous in consanguineous families, confirming autosomal recessive inheritance and absence of unaffected homozygotes in control cohorts ([PMID:27799064], [PMID:36727025]). Parental carrier status was validated by Sanger or quantitative PCR.

Functional studies in patient fibroblasts and HEK293FT cells reveal deficient MIP activity, impaired post-import processing of OXPHOS complex subunits, and decreased abundance and enzymatic activity of complexes I–V, correlating with mitochondrial dysfunction in vivo ([PMID:34620555]).

Yeast models of human MIPEP missense variants (p.Leu71Gln, p.Leu306Phe, p.Lys343Glu) demonstrate severe loss of Oct1 protease activity, accumulation of non-processed substrates and impaired respiratory growth, confirming a loss-of-function mechanism ([PMID:27799064]).

Together, genetic and experimental data establish MIPEP as a mitochondrial disease gene with Moderate clinical validity (6 probands, segregation, robust functional concordance). Diagnostic sequencing and CNV analysis of MIPEP are recommended in patients with global developmental delay and hypotonia. Key Take-home: MIPEP deficiency should be considered in autosomal recessive mitochondrial disease with neurodevelopmental impairment and OXPHOS deficiency.

References

• Molecular genetics and metabolism • 2021 • Variants in the MIPEP gene presenting with complex neurological phenotype without cardiomyopathy, impair OXPHOS protein maturation and lead to a reduced OXPHOS abundance in patient cells. PMID:34620555
• Genome medicine • 2016 • MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death. PMID:27799064
• Frontiers in cardiovascular medicine • 2022 • Case report: Rare novel MIPEP compound heterozygous variants presenting with hypertrophic cardiomyopathy, severe lactic acidosis and hypotonia in a Chinese infant. PMID:36727025

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