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Biallelic variants in the mitochondrial ribosomal protein MRPL49 cause combined oxidative phosphorylation deficiency

ABSTRACT: Combined oxidative phosphorylation deficiency (COXPD) is a rare, multisystem disorder that exhibits significant clinical and genetic heterogeneity. Through genome sequencing, we identified biallelic variants in MRPL49 in individuals from five unrelated families. These individuals presented a spectrum of symptoms, ranging from Perrault syndrome (characterized by primary ovarian insufficiency and sensorineural hearing loss) to severe childhood-onset conditions such as developmental delay, leukodystrophy, microcephaly, and retinal dystrophy. Multiple assays demonstrated that the disease-associated MRPL49 variants disrupted the stability and function of the mitochondrial ribosome, particularly affecting the large subunit. This disruption led to a reduction in Complex I and Complex IV levels. We describe a new form of MRPL49 variant-associated COXPD, thereby expanding the understanding of how impaired assembly of the mitochondrial ribosomal large subunit results in multisystem phenotypes.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Combined Oxidative Phosphorylation Deficiency

SUBMITTER: Alfredo Cabrera-Orefice

LAB HEAD: Ilka Wittig

PROVIDER: PXD056347 | Pride | 2025-03-04

REPOSITORIES: Pride

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			Action	DRS
	MaxQuant_Results_Output_Files.rar	Other
	P23_003_BN_gel_Scan.jpg	Other
	P23_003_MRPL49_M0040_patient_01.raw	Raw
	P23_003_MRPL49_M0040_patient_02.raw	Raw
	P23_003_MRPL49_M0040_patient_03.raw	Raw

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