학술논문
Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights
Clinical Research Article
Clinical Research Article
Document Type
Academic Journal
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; Bergen, Jocelyn van den; Kline, Brianna L.; Ayers, Katie L.; Stewart, Phoebe N.; Stroud, David A.; Stojanovski, Diana; Sinclair, Andrew H.
Source
Journal of Clinical Endocrinology & Metabolism. December 2022, Vol. 107 Issue 12, p3328, 13 p.
Subject
Language
English
ISSN
0021-972X
Abstract
Mitochondria are the main source of eukaryotic cellular energy. Mitochondrial dysfunction is associated with many human pathologies, including mitochondrial diseases, a group of genetic disorders associated with defects in energy [...]
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. Key Words: CLPB, premature ovarian insufficiency, genetics, neutropenia, primary mitochondrial disease, mitochondria, infertility Abbreviations: 3-MGA-uria, 3-methylglutaconic aciduria; ACN, acetonitrile; CLPB, caseinolytic peptidase B; dDIA, direct data-independent acquisition; FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; MAF, minor allele frequency; OXPHOS, oxidative phosphorylation; POI, premature/primary ovarian insufficiency; PTC, premature termination codon; SDS-PAGE, sodium dodecyl sulfate--polyacrylamide gel electrophoresis; [UPR.sup.MT], mitochondrial unfolded protein response; WES, whole-exome sequencing.
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. Key Words: CLPB, premature ovarian insufficiency, genetics, neutropenia, primary mitochondrial disease, mitochondria, infertility Abbreviations: 3-MGA-uria, 3-methylglutaconic aciduria; ACN, acetonitrile; CLPB, caseinolytic peptidase B; dDIA, direct data-independent acquisition; FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; MAF, minor allele frequency; OXPHOS, oxidative phosphorylation; POI, premature/primary ovarian insufficiency; PTC, premature termination codon; SDS-PAGE, sodium dodecyl sulfate--polyacrylamide gel electrophoresis; [UPR.sup.MT], mitochondrial unfolded protein response; WES, whole-exome sequencing.