Tucker, Elena J;
Baker, Megan J;
Hock, Daniella H;
Warren, Julia T;
Jaillard, Sylvie;
Bell, Katrina M;
Sreenivasan, Rajini;
... Sinclair, Andrew H; + view all
(2022)
Premature ovarian insufficiency in CLPB deficiency: transcriptomic, proteomic and phenotypic insights.
Journal of Clinical Endocrinology and Metabolism
, 107
(12)
pp. 3328-3340.
10.1210/clinem/dgac528.
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Abstract
CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that most often presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimise co-morbidity and improve health outcomes. OBJECTIVE: To determine the genetic cause of premature ovarian insufficiency (POI), intellectual disability, neutropenia and cataracts. METHODS: We performed whole exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq and quantitative proteomics, as well as clinical update of previously reported patients with variants in the CaseinoLytic Peptidase B (CLPB) gene. RESULTS: We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts and neutropenia that is often fatal in childhood, however, there is likely a reporting bias towards severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common post-pubertal ailment. CONCLUSIONS: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of post-pubertal females with CLPB deficiency. Patients with CLPB deficiency should be referred to paediatric gynaecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimise associated co-morbidities.
| Type: | Article |
|---|---|
| Title: | Premature ovarian insufficiency in CLPB deficiency: transcriptomic, proteomic and phenotypic insights |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1210/clinem/dgac528 |
| Publisher version: | https://doi.org/10.1210/clinem/dgac528 |
| Language: | English |
| Additional information: | © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
| Keywords: | CLPB, genetics, infertility, mitochondria, neutropenia, premature ovarian insufficiency, primary mitochondrial disease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10155638 |
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