Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights
Year: 2022
Type: article
Abstract: 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.
Authors: Elena J Tucker, Megan J Baker, Daniella H Hock, Julia T Warren, Sylvie Jaillard, Katrina M Bell, Rajini Sreenivasan, Shabnam Bakhshalizadeh, Chloe A Hanna, Nikeisha J Caruana, Saskia B Wortmann, Shamima Rahman, Robert D S Pitceathly, Jean Donadieu, Aurelia Alimi, Vincent Launay, Paul Coppo, Sophie Christin-Maitre, Gorjana Robevska, Jocelyn van den Bergen, Brianna L Kline, Katie L Ayers, Phoebe N Stewart, David A Stroud, Diana Stojanovski, Andrew H Sinclair
Institutions: Royal Children's Hospital, The University of Melbourne, Murdoch Children's Research Institute, Washington University in St. Louis, Inserm, École des Hautes Études en Santé Publique, Institut de Recherche en Santé, Environnement et Travail, Centre Hospitalier Universitaire de Rennes, Université de Rennes, Victoria University, Radboud University Nijmegen, Paracelsus Medical University, Radboud University Medical Center, Amalia Kinderziekenhuis, Great Ormond Street Hospital for Children NHS Foundation Trust, University College London, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, Sorbonne Université, Hôpital Armand-Trousseau, Assistance Publique – Hôpitaux de Paris, Centre Hospitalier de Saint-Brieuc, Laboratoire d'hématologie, Hôpital Saint-Antoine, Royal Hobart Hospital
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,400
Awards: Investigating the role of cardiolipin metabolism in mitochondrial DNA replication and mitochondrial division, Developing a multi-omics platform for the diagnosis of mitochondrial disease, Systems approaches to understanding the assembly of mitochondrial machines, Investigating the genetic cause of genital abnormalities in males, Disorders of Sex Development, Identification and analysis of novel genes and regulatory regions associated with disorders of sex development, Disorders of Sex Development: Genetics, Diagnosis, Informing Clinical Care, G959880536
OpenAlex ID: W4295077809