Gregory, A;
Lotia, M;
Jeong, SY;
Fox, R;
Zhen, D;
Sanford, L;
Hamada, J;
... Hayflick, SJ; + view all
(2019)
Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).
Molecular Genetics & Genomic Medicine
, Article e736. 10.1002/mgg3.736.
(In press).
Preview |
Text
Kurian_Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)_AOP.pdf - Published Version Download (925kB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN) |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/mgg3.736 |
| Publisher version: | https://doi.org/10.1002/mgg3.736 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | C19orf12, MPAN, NBIA, mitochondrial membrane protein-associated neurodegeneration, neurodegeneration with brain iron accumulation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10075069 |
Archive Staff Only
 |
View Item |
