Cargando…
Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights
CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693831/ https://www.ncbi.nlm.nih.gov/pubmed/36074910 http://dx.doi.org/10.1210/clinem/dgac528 |
_version_ | 1784837643273502720 |
---|---|
author | Tucker, Elena J Baker, Megan J Hock, Daniella H Warren, Julia T Jaillard, Sylvie Bell, Katrina M Sreenivasan, Rajini Bakhshalizadeh, Shabnam Hanna, Chloe A Caruana, Nikeisha J Wortmann, Saskia B Rahman, Shamima Pitceathly, Robert D S Donadieu, Jean Alimi, Aurelia Launay, Vincent Coppo, Paul Christin-Maitre, Sophie Robevska, Gorjana van den Bergen, Jocelyn Kline, Brianna L Ayers, Katie L Stewart, Phoebe N Stroud, David A Stojanovski, Diana Sinclair, Andrew H |
author_facet | Tucker, Elena J Baker, Megan J Hock, Daniella H Warren, Julia T Jaillard, Sylvie Bell, Katrina M Sreenivasan, Rajini Bakhshalizadeh, Shabnam Hanna, Chloe A Caruana, Nikeisha J Wortmann, Saskia B Rahman, Shamima Pitceathly, Robert D S Donadieu, Jean Alimi, Aurelia Launay, Vincent Coppo, Paul Christin-Maitre, Sophie Robevska, Gorjana van den Bergen, Jocelyn Kline, Brianna L Ayers, Katie L Stewart, Phoebe N Stroud, David A Stojanovski, Diana Sinclair, Andrew H |
author_sort | Tucker, Elena J |
collection | PubMed |
description | CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determine the genetic cause of syndromic 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 toward 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 postpubertal ailment. CONCLUSION: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities. |
format | Online Article Text |
id | pubmed-9693831 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-96938312022-11-28 Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights Tucker, Elena J Baker, Megan J Hock, Daniella H Warren, Julia T Jaillard, Sylvie Bell, Katrina M Sreenivasan, Rajini Bakhshalizadeh, Shabnam Hanna, Chloe A Caruana, Nikeisha J Wortmann, Saskia B Rahman, Shamima Pitceathly, Robert D S Donadieu, Jean Alimi, Aurelia Launay, Vincent Coppo, Paul Christin-Maitre, Sophie Robevska, Gorjana van den Bergen, Jocelyn Kline, Brianna L Ayers, Katie L Stewart, Phoebe N Stroud, David A Stojanovski, Diana Sinclair, Andrew H J Clin Endocrinol Metab Clinical Research Article CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determine the genetic cause of syndromic 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 toward 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 postpubertal ailment. CONCLUSION: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities. Oxford University Press 2022-09-09 /pmc/articles/PMC9693831/ /pubmed/36074910 http://dx.doi.org/10.1210/clinem/dgac528 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/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 |
spellingShingle | Clinical Research Article Tucker, Elena J Baker, Megan J Hock, Daniella H Warren, Julia T Jaillard, Sylvie Bell, Katrina M Sreenivasan, Rajini Bakhshalizadeh, Shabnam Hanna, Chloe A Caruana, Nikeisha J Wortmann, Saskia B Rahman, Shamima Pitceathly, Robert D S Donadieu, Jean Alimi, Aurelia Launay, Vincent Coppo, Paul Christin-Maitre, Sophie Robevska, Gorjana van den Bergen, Jocelyn Kline, Brianna L Ayers, Katie L Stewart, Phoebe N Stroud, David A Stojanovski, Diana Sinclair, Andrew H Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights |
title | Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights |
title_full | Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights |
title_fullStr | Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights |
title_full_unstemmed | Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights |
title_short | Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights |
title_sort | premature ovarian insufficiency in clpb deficiency: transcriptomic, proteomic and phenotypic insights |
topic | Clinical Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693831/ https://www.ncbi.nlm.nih.gov/pubmed/36074910 http://dx.doi.org/10.1210/clinem/dgac528 |
work_keys_str_mv | AT tuckerelenaj prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT bakermeganj prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT hockdaniellah prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT warrenjuliat prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT jaillardsylvie prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT bellkatrinam prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT sreenivasanrajini prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT bakhshalizadehshabnam prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT hannachloea prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT caruananikeishaj prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT wortmannsaskiab prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT rahmanshamima prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT pitceathlyrobertds prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT donadieujean prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT alimiaurelia prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT launayvincent prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT coppopaul prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT christinmaitresophie prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT robevskagorjana prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT vandenbergenjocelyn prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT klinebriannal prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT ayerskatiel prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT stewartphoeben prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT strouddavida prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT stojanovskidiana prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights AT sinclairandrewh prematureovarianinsufficiencyinclpbdeficiencytranscriptomicproteomicandphenotypicinsights |