Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)

Allison Gregory, Mitesh Lotia, Suh Young Jeong, Rachel Fox, Dolly Zhen, Lynn Sanford, Jeff Hamada, Amir Jahic, Christian Beetz, Alison Freed, Manju A. Kurian, Thomas Cullup, Marlous C.M. van der Weijden, Vy Nguyen, Naly Setthavongsack, Daphne Garcia, Victoria Krajbich, Thao Pham, Randall (Randy) Woltjer, Benjamin P. GeorgeKelly Q. Minks, Alexander R. Paciorkowski, Penelope (Penny) Hogarth, Joseph Jankovic, Susan Hayflick

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere00736
JournalMolecular Genetics and Genomic Medicine
Volume7
Issue number7
DOIs
StatePublished - Jul 1 2019

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Mitochondrial Proteins
Mitochondrial Membranes
Membrane Proteins
Multiplex Polymerase Chain Reaction
Brain
Counseling
Exons
Proteins
Alleles
Pathology
Phenotype
Genes

Keywords

  • C19orf12
  • mitochondrial membrane protein-associated neurodegeneration
  • MPAN
  • NBIA
  • neurodegeneration with brain iron accumulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). / Gregory, Allison; Lotia, Mitesh; Jeong, Suh Young; Fox, Rachel; Zhen, Dolly; Sanford, Lynn; Hamada, Jeff; Jahic, Amir; Beetz, Christian; Freed, Alison; Kurian, Manju A.; Cullup, Thomas; van der Weijden, Marlous C.M.; Nguyen, Vy; Setthavongsack, Naly; Garcia, Daphne; Krajbich, Victoria; Pham, Thao; Woltjer, Randall (Randy); George, Benjamin P.; Minks, Kelly Q.; Paciorkowski, Alexander R.; Hogarth, Penelope (Penny); Jankovic, Joseph; Hayflick, Susan.

In: Molecular Genetics and Genomic Medicine, Vol. 7, No. 7, e00736, 01.07.2019.

Research output: Contribution to journalArticle

Gregory, A, Lotia, M, Jeong, SY, Fox, R, Zhen, D, Sanford, L, Hamada, J, Jahic, A, Beetz, C, Freed, A, Kurian, MA, Cullup, T, van der Weijden, MCM, Nguyen, V, Setthavongsack, N, Garcia, D, Krajbich, V, Pham, T, Woltjer, RR, George, BP, Minks, KQ, Paciorkowski, AR, Hogarth, PP, Jankovic, J & Hayflick, S 2019, 'Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)', Molecular Genetics and Genomic Medicine, vol. 7, no. 7, e00736. https://doi.org/10.1002/mgg3.736
Gregory, Allison ; Lotia, Mitesh ; Jeong, Suh Young ; Fox, Rachel ; Zhen, Dolly ; Sanford, Lynn ; Hamada, Jeff ; Jahic, Amir ; Beetz, Christian ; Freed, Alison ; Kurian, Manju A. ; Cullup, Thomas ; van der Weijden, Marlous C.M. ; Nguyen, Vy ; Setthavongsack, Naly ; Garcia, Daphne ; Krajbich, Victoria ; Pham, Thao ; Woltjer, Randall (Randy) ; George, Benjamin P. ; Minks, Kelly Q. ; Paciorkowski, Alexander R. ; Hogarth, Penelope (Penny) ; Jankovic, Joseph ; Hayflick, Susan. / Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). In: Molecular Genetics and Genomic Medicine. 2019 ; Vol. 7, No. 7.
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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.",
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T1 - Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)

AU - Gregory, Allison

AU - Lotia, Mitesh

AU - Jeong, Suh Young

AU - Fox, Rachel

AU - Zhen, Dolly

AU - Sanford, Lynn

AU - Hamada, Jeff

AU - Jahic, Amir

AU - Beetz, Christian

AU - Freed, Alison

AU - Kurian, Manju A.

AU - Cullup, Thomas

AU - van der Weijden, Marlous C.M.

AU - Nguyen, Vy

AU - Setthavongsack, Naly

AU - Garcia, Daphne

AU - Krajbich, Victoria

AU - Pham, Thao

AU - Woltjer, Randall (Randy)

AU - George, Benjamin P.

AU - Minks, Kelly Q.

AU - Paciorkowski, Alexander R.

AU - Hogarth, Penelope (Penny)

AU - Jankovic, Joseph

AU - Hayflick, Susan

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

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KW - NBIA

KW - neurodegeneration with brain iron accumulation

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