Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. / Amarasekera, Sumudu S.C.; Hock, Daniella H.; Lake, Nicole J.; Calvo, Sarah E.; Grønborg, Sabine W.; Krzesinski, Emma I.; Amor, David J.; Fahey, Michael C.; Simons, Cas; Wibrand, Flemming; Mootha, Vamsi K.; Lek, Monkol; Lunke, Sebastian; Stark, Zornitza; Østergaard, Elsebet; Christodoulou, John; Thorburn, David R.; Stroud, David A.; Compton, Alison G.

In: Human Molecular Genetics, Vol. 32, No. 15, 2023, p. 2441-2454.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Amarasekera, SSC, Hock, DH, Lake, NJ, Calvo, SE, Grønborg, SW, Krzesinski, EI, Amor, DJ, Fahey, MC, Simons, C, Wibrand, F, Mootha, VK, Lek, M, Lunke, S, Stark, Z, Østergaard, E, Christodoulou, J, Thorburn, DR, Stroud, DA & Compton, AG 2023, 'Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease', Human Molecular Genetics, vol. 32, no. 15, pp. 2441-2454. https://doi.org/10.1093/hmg/ddad069

APA

Amarasekera, S. S. C., Hock, D. H., Lake, N. J., Calvo, S. E., Grønborg, S. W., Krzesinski, E. I., Amor, D. J., Fahey, M. C., Simons, C., Wibrand, F., Mootha, V. K., Lek, M., Lunke, S., Stark, Z., Østergaard, E., Christodoulou, J., Thorburn, D. R., Stroud, D. A., & Compton, A. G. (2023). Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. Human Molecular Genetics, 32(15), 2441-2454. https://doi.org/10.1093/hmg/ddad069

Vancouver

Amarasekera SSC, Hock DH, Lake NJ, Calvo SE, Grønborg SW, Krzesinski EI et al. Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. Human Molecular Genetics. 2023;32(15):2441-2454. https://doi.org/10.1093/hmg/ddad069

Author

Amarasekera, Sumudu S.C. ; Hock, Daniella H. ; Lake, Nicole J. ; Calvo, Sarah E. ; Grønborg, Sabine W. ; Krzesinski, Emma I. ; Amor, David J. ; Fahey, Michael C. ; Simons, Cas ; Wibrand, Flemming ; Mootha, Vamsi K. ; Lek, Monkol ; Lunke, Sebastian ; Stark, Zornitza ; Østergaard, Elsebet ; Christodoulou, John ; Thorburn, David R. ; Stroud, David A. ; Compton, Alison G. / Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. In: Human Molecular Genetics. 2023 ; Vol. 32, No. 15. pp. 2441-2454.

Bibtex

@article{66741803e8254be385db7eadb142c223,

title = "Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease",

abstract = "MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted. ",

author = "Amarasekera, {Sumudu S.C.} and Hock, {Daniella H.} and Lake, {Nicole J.} and Calvo, {Sarah E.} and Gr{\o}nborg, {Sabine W.} and Krzesinski, {Emma I.} and Amor, {David J.} and Fahey, {Michael C.} and Cas Simons and Flemming Wibrand and Mootha, {Vamsi K.} and Monkol Lek and Sebastian Lunke and Zornitza Stark and Elsebet {\O}stergaard and John Christodoulou and Thorburn, {David R.} and Stroud, {David A.} and Compton, {Alison G.}",

year = "2023",

doi = "10.1093/hmg/ddad069",

language = "English",

volume = "32",

pages = "2441--2454",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "15",

}

RIS

TY - JOUR

T1 - Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease

AU - Amarasekera, Sumudu S.C.

AU - Hock, Daniella H.

AU - Lake, Nicole J.

AU - Calvo, Sarah E.

AU - Grønborg, Sabine W.

AU - Krzesinski, Emma I.

AU - Amor, David J.

AU - Fahey, Michael C.

AU - Simons, Cas

AU - Wibrand, Flemming

AU - Mootha, Vamsi K.

AU - Lek, Monkol

AU - Lunke, Sebastian

AU - Stark, Zornitza

AU - Østergaard, Elsebet

AU - Christodoulou, John

AU - Thorburn, David R.

AU - Stroud, David A.

AU - Compton, Alison G.

PY - 2023

Y1 - 2023

N2 - MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted.

AB - MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted.

U2 - 10.1093/hmg/ddad069

DO - 10.1093/hmg/ddad069

M3 - Journal article

C2 - 37133451

AN - SCOPUS:85165163787

VL - 32

SP - 2441

EP - 2454

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 15

ER -

ID: 387270330