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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...

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Autores principales: 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
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
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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.
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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
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