Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).

Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).

Publication date: May 13, 2019

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.

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.

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.

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.

Gregory, A., Lotia, M., Jeong, S.Y., Fox, R., Zhen, D., Sanford, L., Hamada, J., Jahic, A., Beetz, C., Freed, A., Kurian, M.A., Cullup, T., van der Weijden, M.C.M., , Nguyen, Setthavongsack, N., Garcia, D., , Krajbich, Pham, T., Woltjer, R., George, B.P., Minks, K.Q., Paciorkowski, A.R., Hogarth, P., Jankovic, J., and Hayflick, S.J. Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). 20768. 2019 Mol Genet Genomic Med.

Concepts Keywords
Allele Behr syndrome
Autosomal Dominant Dominance
Autosomal Recessive Mitochondrion
Brain Neurodegeneration
Causative Senescence
Cohort Neurological disorders
Consanguineous Organ systems
Counseling Nervous system
Exon Branches of biology
Heterozygous Counseling
Ligation
Loss Function
Membrane Protein
Mitochondrial Membrane
Multiplex
Neurodegeneration
Pathogenic
Phenotype
Protein
Recessive
Sequencing
Singleton

Semantics

Type Source Name
disease DOID NBIA
gene UNIPROT IMPACT
disease MESH multi
gene UNIPROT SLC35G1
gene UNIPROT LARGE1
gene UNIPROT C19orf12
disease DOID MPAN

Original Article

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