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Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)
Allison Gregory1, Mitesh Lotia2, Suh Young Jeong1
1Molecular & Medical Genetics, Pediatrics and Neurology, Oregon Health & Science University, Portland, Oregon.
Background:
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12. Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases.
Methods:
Two large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation-dependent probe amplification were used to characterize the causative sequence variants in C19orf12. Post-mortem brain from affected subjects was examined.
Results:
In two multi-generation non-consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes.
Conclusions:
We present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non-mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling.
Insights
Mitochondrial membrane protein-associated neurodegeneration (MPAN) can be inherited in an autosomal dominant manner, not just recessive. This occurs when a single faulty C19orf12 gene variant disrupts normal protein function.
Area of Science:
- Neurogenetics
- Molecular Neurology
Background:
- Mitochondrial membrane protein-associated neurodegeneration (MPAN) is typically linked to C19orf12 gene variants with autosomal recessive inheritance.
- Previous understanding suggested only recessive inheritance patterns for MPAN.
Purpose of the Study:
- To investigate and present evidence for autosomal dominant inheritance in MPAN.
- To elucidate the underlying molecular mechanism for dominant MPAN cases.
Main Methods:
- Genetic analysis (gene sequencing, MLPA) of C19orf12 in affected families and individuals.
- Examination of post-mortem brain tissue from MPAN subjects.
- Segregation analysis of C19orf12 variants within pedigrees.
Main Results:
- Identified distinct nonsense sequence variations in C19orf12 segregating with MPAN in two multi-generation families.
- Observed brain pathology consistent with autosomal recessive MPAN.
- Found a significant number of MPAN cases with single heterozygous pathogenic C19orf12 variants, including de novo mutations.
Conclusions:
- Presented three lines of clinical evidence supporting autosomal dominant MPAN.
- Proposed a dominant-negative mechanism where truncated C19orf12 proteins impair normal protein function.
- Highlighted the impact of these findings on MPAN diagnosis and genetic counseling.
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