Functional study of a novel missense single‐nucleotide variant of NUP 107 in two daughters of M exican origin with premature ovarian insufficiency

BackgroundHypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus w...

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Veröffentlicht in:Molecular genetics & genomic medicine 2018-03, Vol.6 (2), p.276-281
Hauptverfasser: Ren, Yu, Diao, Feiyang, Katari, Sunita, Yatsenko, Svetlana, Jiang, Huaiyang, Wood‐Trageser, Michelle A., Rajkovic, Aleksandar
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container_end_page 281
container_issue 2
container_start_page 276
container_title Molecular genetics & genomic medicine
container_volume 6
creator Ren, Yu
Diao, Feiyang
Katari, Sunita
Yatsenko, Svetlana
Jiang, Huaiyang
Wood‐Trageser, Michelle A.
Rajkovic, Aleksandar
description BackgroundHypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C>T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility.ConclusionsOur findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.
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Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C&gt;T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility.ConclusionsOur findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.</description><identifier>ISSN: 2324-9269</identifier><identifier>EISSN: 2324-9269</identifier><identifier>DOI: 10.1002/mgg3.345</identifier><language>eng</language><publisher>Bognor Regis: John Wiley &amp; Sons, Inc</publisher><subject>Amenorrhea ; Base pairs ; CRISPR ; Cytoplasm ; DNA microarrays ; Estrogens ; Fertility ; Gene deletion ; Gene sequencing ; Genetic diversity ; Genetic variance ; Genomes ; Homology ; Human performance ; Hypogonadism ; Infertility ; Meiosis ; Mitosis ; Ovaries ; Parents ; Protein transport</subject><ispartof>Molecular genetics &amp; genomic medicine, 2018-03, Vol.6 (2), p.276-281</ispartof><rights>2018. 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Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C&gt;T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. 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genomic medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ren, Yu</au><au>Diao, Feiyang</au><au>Katari, Sunita</au><au>Yatsenko, Svetlana</au><au>Jiang, Huaiyang</au><au>Wood‐Trageser, Michelle A.</au><au>Rajkovic, Aleksandar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functional study of a novel missense single‐nucleotide variant of NUP 107 in two daughters of M exican origin with premature ovarian insufficiency</atitle><jtitle>Molecular genetics &amp; genomic medicine</jtitle><date>2018-03</date><risdate>2018</risdate><volume>6</volume><issue>2</issue><spage>276</spage><epage>281</epage><pages>276-281</pages><issn>2324-9269</issn><eissn>2324-9269</eissn><abstract>BackgroundHypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C&gt;T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility.ConclusionsOur findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.</abstract><cop>Bognor Regis</cop><pub>John Wiley &amp; Sons, Inc</pub><doi>10.1002/mgg3.345</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-4809-8601</orcidid><orcidid>https://orcid.org/0000-0002-1710-4389</orcidid><oa>free_for_read</oa></addata></record>
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subjects Amenorrhea
Base pairs
CRISPR
Cytoplasm
DNA microarrays
Estrogens
Fertility
Gene deletion
Gene sequencing
Genetic diversity
Genetic variance
Genomes
Homology
Human performance
Hypogonadism
Infertility
Meiosis
Mitosis
Ovaries
Parents
Protein transport
title Functional study of a novel missense single‐nucleotide variant of NUP 107 in two daughters of M exican origin with premature ovarian insufficiency
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