Autosomal dominant mitochondrial membrane protein‐associated neurodegeneration (MPAN)

Abstract

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.

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

“…Second, a previous report suggested that the C19orf12 variant has dominant effect, similar to our observations. But this report is not yet listed in OMIM 28 . Next, to test if the genetic properties of recessive variants are different from those of dominant variants, several parameters were compared.…”

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…Nowadays, about 50 C19ORF12 variants have been found to relate to the MPAN phenotype, including missense/nonsense, indels and splicing mutations (HGMD ® Professional 2020.1; accessed 7 October 2020). Although MPAN is considered an AR condition, a single C19ORF12 mutation can lead to the same clinical phenotype as biallelic variants [ 129 ]. The mutations with AR inheritance are degraded by the NMD (nonsense-mediated decay) system, generating haploinsufficiency.…”

“…In contrast, the mutations with autosomal dominant (AD) inheritance may be located in the final part of C19ORF12 mRNA and may escape from NMD. Therefore, the resulting protein would have a dominant negative effect on the WT that may explain the duality in MPAN inheritance [ 129 ]. Interestingly, alternative clinical phenotypes to MPAN have been reported for distinct C19ORF12 variants: the c.187G>C (p.A63P) mutation causes an AR form of spastic paraplegia with amyotrophy (SPG43) [ 130 , 131 ], the c.197-199del3 variant leads to MPAN phenotype aggravated with traits of juvenile amyotrophic lateral sclerosis (ALS) [ 132 ], and a clinical picture of Karak pallido-pyramidal syndrome has been described for the c.157G>A (p.G53R) mutation [ 133 ].…”

Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability

“…Although the study on the first family with MPAN reports it as an autosomal recessive condition, 3 dominant inheritance of the disease was confirmed recently. 4 Independent of the inheritance pattern, most MPAN cases are phenotypically similar at both clinical and neuropathologic levels. 4 …”

“… 4 Independent of the inheritance pattern, most MPAN cases are phenotypically similar at both clinical and neuropathologic levels. 4 …”