Further delineation of defects in MRPS2 causing human OXPHOS deficiency and early developmental abnormalities in zebrafish

Document Type

Article

Publication Title

European Journal of Human Genetics

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.

First Page

1451

Last Page

1461

DOI

10.1038/s41431-025-01858-1

Publication Date

11-1-2025

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