Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency

Abstract

Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.

Intimate Relations—Mitochondria and Ageing

“…All of the RNA components of the mitochondrial translation machinery are encoded in mtDNA, the protein components of the ribosome and accessory proteins such as aminoacyl tRNA synthetases being nuclearly encoded. Mutations in nuclear genes encoding protein components of the ribosome affect the accuracy of translation and are associated with a diverse range of pathologies including ovarian insufficiency [ 260 ], encephalopathy [ 261 ], Leigh syndrome [ 262 ] and stress related behavioral alterations in mice [ 263 ]. A similar diversity of presentation is seen in mutations affecting mitochondrial aminoacyl tRNA synthetases and the reasons for this diversity from an apparently similar mechanism are discussed by González-Serrano [ 264 ].…”

High Expression Level of miR-1260 Family in the Peripheral Blood of Patients with Ovarian Carcinoma

“…The String analysis showed that miR-1260a was mostly associated with the ribosomal protein family effective in translation. There are some studies in the literature investigating the effects of this protein family of the development of ovarian cancer [37,38]. The results of this studies showed that the ribosomal proteins had signi cant and critical functions in the development of ovarian cancer, and therefore was emphasized to provide information on the pathophysiology, and treatment of ovarian dysfunctions.…”

“…Some studies in the literature investigated the effects of this protein family on the development of ovarian cancer [37,38]. These studies showed that ribosomal proteins had signi cant, and critical functions in the development of ovary, and therefore may provide data about the pathophysiology, and treatment of ovarian dysfunctions.…”

Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

“…Whole exome sequencing (WES) of two patients from Family I was performed using DNA (1µg) extracted from whole blood and fragmented and enriched using the Truseq DNA PCR Free kit (Illumina). Samples were sequenced on a HiSeq2500 (Illumina) with 2x100bp read length and analyzed as described (Chen et al, 2018). Raw fastq files were mapped to the reference human genome GRCh37 using BWA (Li and Durbin, 2009) (v.0.7.12).…”