Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10.
RNA sequencing
aberrant splicing
genomics
mitochondrial disease
proteomics
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
16
07
2020
revised:
06
09
2020
accepted:
28
10
2020
pubmed:
11
11
2020
medline:
1
4
2022
entrez:
10
11
2020
Statut:
ppublish
Résumé
The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet need. Following uninformative exome and genome sequencing of a family quartet including two siblings with suspected mitochondrial disorder, RNA sequencing (RNAseq) was pursued in one sibling. Long-read amplicon sequencing was used to determine and quantify transcript structure. Immunoblotting studies and quantitative proteomics were performed to demonstrate functional impact. Differential expression analysis of RNAseq data identified significantly decreased expression of the mitochondrial OXPHOS Complex I subunit NDUFB10 associated with a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. The cryptic exon contained a rare intronic variant that was homozygous in both affected siblings. Immunoblot and quantitative proteomic analysis of fibroblasts revealed decreased abundance of Complex I subunits, providing evidence of isolated Complex I deficiency. Through multiomic analysis we present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two individuals, providing further support of the gene-disease association. This study highlights the importance of transcriptomic and proteomic analyses as complementary diagnostic tools in patients undergoing genome-wide diagnostic evaluation.
Identifiants
pubmed: 33169436
doi: 10.1002/humu.24135
pmc: PMC7902361
mid: NIHMS1644881
doi:
Substances chimiques
NADH Dehydrogenase
EC 1.6.99.3
Electron Transport Complex I
EC 7.1.1.2
NDUFB10 protein, human
EC 7.1.1.2
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
19-24Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Informations de copyright
© 2020 Wiley Periodicals LLC.
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