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A novel variant of NPPC causes abnormal post-translational cleavage: A candidate gene for premature ovarian insufficiency

  • Jong-Yoon Park
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si 13488, South Korea
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  • Minyeon Go
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si 13488, South Korea
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  • Sang Woo Lyu
    Affiliations
    Department of Obstetrics and Gynecology, CHA Fertility Center, Gangnam, CHA University, Seoul 06125, South Korea
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  • Tae Ki Yoon
    Affiliations
    Department of Obstetrics and Gynecology, CHA Fertility Center, Seoul station, Seoul 04637, South Korea
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  • Kyung Min Kang
    Affiliations
    Genetics Laboratory, CHA Fertility Center, Gangnam, CHA University, Seoul 06125, South Korea
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Ji Won Kim
    Correspondence
    Corresponding author: Department of Obstetrics and Gynecology, CHA Fertility Center, Gangnam, CHA University, Seoul 06125, Wouth Korea
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Obstetrics and Gynecology, CHA Fertility Center, Gangnam, CHA University, Seoul 06125, South Korea
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.
    Sung Han Shim
    Correspondence
    Corresponding author at: Genetics Laboratory, CHA Fertility Center, Gangnam, CHA University, Seoul 06135, Korea. Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si 13488, South Korea.
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Biomedical Science, College of Life Science, CHA University, Seongnam-si 13488, South Korea

    Genetics Laboratory, CHA Fertility Center, Gangnam, CHA University, Seoul 06125, South Korea
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • This study suggested the involvement of a novel genetic variant in the pathogenesis of premature ovarian insufficiency (POI).
      • The 14 candidate variants in 13 genes were detected in nonconsanguineous family members with POI using whole exome sequencing.
      • Genomic sequencing revealed novel variants in the NPPC gene.
      • The cGMP activity of NPR2-expressing cells was decreased by interaction with the mutant NPPC peptide secreted by the cells expressing NPPC131A>G.
      • A mutation of the NPPC gene might influence preantral follicle development and/or sustain meiotic arrest in oocytes.

      Abstract

      Objective

      Premature ovarian insufficiency (POI) is a clinical disease that is diagnosed by the loss of ovarian function before the age of 40. Despite recent progress in molecular diagnosis, the genetic etiology of POI is not well established. The aim of this study is to reveal pathogenic genetic variants involved in POI.

      Study design and main outcome measures

      To reveal pathogenic genetic variants involved in POI, whole exome sequencing was performed in nonconsanguineous family members with POI. Constitutional variants were filtered against population databases and a missense mutation of natriuretic peptide C (NPPC) (c.131A>G, p.Q44R) was selected as a convincing candidate mutation among 14 heterozygous mutant alleles in 13 genes.

      Results

      The wild-type NPPC and mutant NPPC (NPPC131A>G) were expressed in HeLa cells, and cells expressing NPPC131A>G secreted unique peptides. The ProP 1.0 Server, a neural network prediction tool, predicted the presence of a cleavage site at the substituted arginine residue (p.Q44R) of NPPC. The molecular weight of predicted cleaved peptides processed from mutant NPPC precursor corresponded to that of the actual mutant peptide. The cGMP synthetic activity of NPR2-expressing cells was significantly decreased by interaction with the mutant NPPC peptide compared with wild-type NPPC.

      Conclusions

      The peptide generated by a rare mutation of NPPC might influence paracrine C-type natriuretic peptide (CNP)-mediated preantral follicle development and/or sustain meiotic arrest in oocytes. We therefore suggest that a mutation of the NPPC gene is involved in the pathogenesis of POI.

      Keywords

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