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Article Dans Une Revue Human Genetics Année : 2023

Deficiency of the mitochondrial ribosomal subunit, MRPL50, causes autosomal recessive syndromic premature ovarian insufficiency

Shabnam Bakhshalizadeh
Daniella Hock
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Nicole Siddall
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Brianna Kline
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Rajini Sreenivasan
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Katrina Bell
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Franca Casagranda
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Sadishkumar Kamalanathan
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Jayaprakash Sahoo
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Niya Narayanan
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Dukhabandhu Naik
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Varun Suryadevara
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Alison Compton
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Sumudu Amarasekera
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Ridam Kapoor
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Andrea Simpson
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Gorjana Robevska
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Jocelyn van den Bergen
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Svenja Pachernegg
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Katie Ayers
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David Thorburn
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David Stroud
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Gary Hime
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Résumé

Abstract Premature ovarian insufficiency (POI) is a common cause of infertility in women, characterised by amenorrhea and elevated FSH under the age of 40 years. In some cases, POI is syndromic in association with other features such as sensorineural hearing loss in Perrault syndrome. POI is a heterogeneous disease with over 80 causative genes known so far; however, these explain only a minority of cases. Using whole-exome sequencing (WES), we identified a MRPL50 homozygous missense variant (c.335T > A; p.Val112Asp) shared by twin sisters presenting with POI, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction. MRPL50 encodes a component of the large subunit of the mitochondrial ribosome. Using quantitative proteomics and western blot analysis on patient fibroblasts, we demonstrated a loss of MRPL50 protein and an associated destabilisation of the large subunit of the mitochondrial ribosome whilst the small subunit was preserved. The mitochondrial ribosome is responsible for the translation of subunits of the mitochondrial oxidative phosphorylation machinery, and we found patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. These data support a biochemical phenotype associated with MRPL50 variants. We validated the association of MRPL50 with the clinical phenotype by knockdown/knockout of mRpL50 in Drosophila , which resulted abnormal ovarian development. In conclusion, we have shown that a MRPL50 missense variant destabilises the mitochondrial ribosome, leading to oxidative phosphorylation deficiency and syndromic POI, highlighting the importance of mitochondrial support in ovarian development and function.

Dates et versions

hal-04205616 , version 1 (13-09-2023)

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Citer

Shabnam Bakhshalizadeh, Daniella Hock, Nicole Siddall, Brianna Kline, Rajini Sreenivasan, et al.. Deficiency of the mitochondrial ribosomal subunit, MRPL50, causes autosomal recessive syndromic premature ovarian insufficiency. Human Genetics, 2023, 142 (7), pp.879-907. ⟨10.1007/s00439-023-02563-z⟩. ⟨hal-04205616⟩
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