Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

Tucker, Elena J.; Bell, Katrina M.; Robevska, Gorjana; Bergen, Jocelyn van den; Ayers, Katie; Listyasari, Nurin Aisyiyah; Faradz, Sultana Mh; Jérôme, D.; Bakhshalizadeh, Shabnam; Sreenivasan, Rajini; Nouyou, Bénédicte; Carré, Wilfrid; Akloul, Linda; Duros, Solène; Domin‐Bernhard, Mathilde; Belaud‐Rotureau, Marc‐Antoine; Touraine, Philippe; Jaillard, Sylvie; Sinclair, Andrew H.

doi:10.1038/s41431-021-00977-9

Cited by 23 publications

(23 citation statements)

References 38 publications

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“…ETAA1 accumulates at DNA damage sites in response to replication stress [38][39][40][41] and HROB is involved in homologous recombination by recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA synthesis 42,43 . Homozygous loss-of-function of HROB is associated with POI 44 and infertility in both sexes in mouse models 42 .…”

Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Stankovic

Shekari

Huang

et al. 2022

Preprint

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Human genetic studies have provided substantial insight into the biological mechanisms governing ovarian ageing, yet previous approaches have been largely restricted to assessing common genetic variation. Here we report analyses of rare (MAF<0.1%) protein-coding variants in the exomes of 106,973 women from the UK Biobank study, implicating novel genes with effect sizes up to ~5 times larger than previously discovered in analyses of common variants. These include protein truncating variants in ZNF518A, which shorten reproductive lifespan by promoting both earlier age at natural menopause (ANM, 5.61 years [4.04-7.18], P=2*10-12) and later puberty timing in girls (age at menarche, 0.56 years [0.15-0.97], P=9.2*10-3). By integrating ChIP-Seq data, we demonstrate that common variants associated with ANM and menarche are enriched in the binding sites of ZNF518A. We also identify further links between ovarian ageing and cancer susceptibility, highlighting damaging germline variants in SAMHD1 that delay ANM and increase all-cause cancer risk in both males (OR=2.1 [1.7-2.6], P=4.7*10-13) and females (OR=1.61 [1.31-1.96], P=4*10-6). Finally, we demonstrate that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights an example of a mechanism for the maternal genome influencing child health.

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Section: Discussionmentioning

confidence: 99%

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Stankovic

Shekari

Huang

et al. 2022

Preprint

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“…Developmental disorders of the reproductive organs, classified as gonadal dysgenesis, are characterised by atypical gonadal development. Homozygous mutations in NUP107 (Table 2) have been identified underlying ovarian dysgenesis (MIM 618078; [108]) and premature ovarian insufficiency [109,110]. Disease modelling in mice and Drosophila as well as specific knock-down of Nup107 in Drosophila gonadal soma led to ovarian dysgenesis-like phenotypes [109,111].…”

Section: Developmental Disorders: Gonadal Dysgenesismentioning

confidence: 99%

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

Jühlen,

Fahrenkrog

2023

FEBS Letters

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The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.

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“…WES data were processed using in-house C-GeVarA pipeline (Constitutional Genetic Variant Analysis). Analysis was performed as previously described (gene-centric and variant-centric approaches) [Tucker et al, 2022].…”

Section: Whole-exome Sequencingmentioning

confidence: 99%

Pseudodicentric Chromosome Originating from an X-Autosome Translocation in a Male Patient with Cryptozoospermia

Toujani

Tucker

Akloul

et al. 2022

Cytogenet Genome Res

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Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies are validated genetic factors leading to spermatogenic quantitative defects, with a frequency depending on the severity of the phenotype. Among the structural chromosomal rearrangements, dicentric chromosomes are generally observed in robertsonian translocations or in cases of Y chromosome isodicentrics. In X-autosome translocations, male carriers are generally infertile, regardless of the position of the breakpoint, due to interrupted spermatogenesis. We report an infertile man bearing an unusual balanced (X;22) translocation, with a centromeric X breakpoint generating a derivative pseudodicentric chromosome psu dic(22;X). Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome. The likely cause of the reproductive phenotype of the patient is discussed based on meiotic chromosomal conformation.

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Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

Cited by 23 publications

References 38 publications

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

Pseudodicentric Chromosome Originating from an X-Autosome Translocation in a Male Patient with Cryptozoospermia

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