PUBLICATION
Further delineation of defects in MRPS2 causing human OXPHOS deficiency and early developmental abnormalities in zebrafish
- Authors
- Kandettu, A., Yeole, M., Sekar, H., Garapati, K., Kaur, N., Anand, A., Hegde, P., Nair, K., Medishetti, R., Bhat, V., Radhakrishnan, P., Mundkur, S.C., Shrikiran, H.A., Pandey, A., Sevilimedu, A., Chakrabarty, S., Shukla, A.
- ID
- ZDB-PUB-250515-9
- Date
- 2025
- Source
- European journal of human genetics : EJHG : (Journal)
- Registered Authors
- Medishetti, Raghavender, Sekar, Hamsini, Sevilimedu, Aarti
- Keywords
- none
- MeSH Terms
-
- Mitochondria/genetics
- Mitochondria/metabolism
- Humans
- Mitochondrial Diseases*/genetics
- Mitochondrial Diseases*/pathology
- Zebrafish/genetics
- Zebrafish/growth & development
- Ribosomal Proteins*/genetics
- Ribosomal Proteins*/metabolism
- Mitochondrial Proteins*/genetics
- Mitochondrial Proteins*/metabolism
- Female
- Pedigree
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Animals
- Oxidative Phosphorylation*
- Male
- PubMed
- 40360742 Full text @ Eur. J. Hum. Genet.
Citation
Kandettu, A., Yeole, M., Sekar, H., Garapati, K., Kaur, N., Anand, A., Hegde, P., Nair, K., Medishetti, R., Bhat, V., Radhakrishnan, P., Mundkur, S.C., Shrikiran, H.A., Pandey, A., Sevilimedu, A., Chakrabarty, S., Shukla, A. (2025) Further delineation of defects in MRPS2 causing human OXPHOS deficiency and early developmental abnormalities in zebrafish. European journal of human genetics : EJHG. :.
Abstract
Mitochondrial ribosomal protein-small 2 (MRPS2) encodes a vital structural protein essential for assembling mitoribosomal small subunit and thus mitochondrial translation. Any defect in mitochondrial translation impacts OXPHOS activity and cellular respiration. Defects in MRPS2 have been implicated recently in four families with combined oxidative phosphorylation deficiency-36 (MIM# 617950). We herein describe two individuals from two unrelated families with variable phenotypes of acute onset severe metabolic decompensation and symptomatic hypoglycemia. Exome sequencing identified bi-allelic variants in MRPS2 (NM_016034.5) in the affected individuals: P1: c.490 G > A p.(Glu164Lys); and P2: c.413 G > A p.(Arg138His). Further evaluation of the variant c.490 G > A p.(Glu164Lys) in patient-derived skin fibroblasts revealed decreased expression of MRPS2 transcript and protein levels of MRPS2 along with expression of complex I and IV proteins. Proteomics analysis revealed decreased expression of small subunit proteins and increased expression of large subunit proteins. Also, reduced complex I and IV enzyme activities, mitochondrial respiration (OCR), and altered mitochondrial morphology on confocal imaging were observed. Additionally, mrps2 knockout zebrafish larvae demonstrated an abnormal developmental phenotype and reduced Complex IV activity. With these findings, we identify additional families with variants in MRPS2, illustrating the variable clinical spectrum and validate the pathogenicity of defects in MRPS2 through in-vitro and in-vivo assays.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping