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Premature ovarian insufficiency in CLPB deficiency: transcriptomic, proteomic and phenotypic insights
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Edité par CCSD ; Endocrine Society -
International audience. 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.
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