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Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans

Fan, S ; Sharif University of Technology | 2021

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  1. Type of Document: Article
  2. DOI: 10.1016/j.ajhg.2021.01.010
  3. Publisher: Cell Press , 2021
  4. Abstract:
  5. Human infertility is a multifactorial disease that affects 8%–12% of reproductive-aged couples worldwide. However, the genetic causes of human infertility are still poorly understood. Synaptonemal complex (SC) is a conserved tripartite structure that holds homologous chromosomes together and plays an indispensable role in the meiotic progression. Here, we identified three homozygous mutations in the SC coding gene C14orf39/SIX6OS1 in infertile individuals from different ethnic populations by whole-exome sequencing (WES). These mutations include a frameshift mutation (c.204_205del [p.His68Glnfs∗2]) from a consanguineous Pakistani family with two males suffering from non-obstructive azoospermia (NOA) and one female diagnosed with premature ovarian insufficiency (POI) as well as a nonsense mutation (c.958G>T [p.Glu320∗]) and a splicing mutation (c.1180−3C>G) in two unrelated Chinese men (individual P3907 and individual P6032, respectively) with meiotic arrest. Mutations in C14orf39 resulted in truncated proteins that retained SYCE1 binding but exhibited impaired polycomplex formation between C14ORF39 and SYCE1. Further cytological analyses of meiosis in germ cells revealed that the affected familial males with the C14orf39 frameshift mutation displayed complete asynapsis between homologous chromosomes, while the affected Chinese men carrying the nonsense or splicing mutation showed incomplete synapsis. The phenotypes of NOA and POI in affected individuals were well recapitulated by Six6os1 mutant mice carrying an analogous mutation. Collectively, our findings in humans and mice highlight the conserved role of C14ORF39/SIX6OS1 in SC assembly and indicate that the homozygous mutations in C14orf39/SIX6OS1 described here are responsible for infertility of these affected individuals, thus expanding our understanding of the genetic basis of human infertility. © 2021 The Author(s)
  6. Keywords:
  7. Glutamic acid ; Glutamine ; Histidine ; DNA binding protein ; Nuclear protein ; SYCE1 protein, mouse ; SYCP1 protein, human ; Animal experiment ; Animal model ; Animal tissue ; Azoospermia ; Chinese ; Complex formation ; Controlled study ; Frameshift mutation ; Gene ; Gene expression ; Gene mutation ; Germ cell ; Homozygosity ; Human ; Human tissue ; Major clinical study ; Mouse ; Mutant ; Nonhuman ; Nonsense mutation ; Pakistani ; Premature ovarian failure ; Priority journal ; RNA splicing ; SIX6OS1 gene ; Spermatocyte ; Whole exome sequencing ; Young adult ; Genetics ; Metabolism ; Pathophysiology ; Physiology ; Stop codon ; Adult ; Azoospermia ; Chromosome Pairing ; Codon, Nonsense ; DNA-Binding Proteins ; Female ; Homozygote ; Humans ; Male ; Meiosis ; Middle Aged ; Mutation ; Nuclear Proteins ; Pedigree ; Primary Ovarian Insufficiency ; Spermatocytes ; Synaptonemal Complex ; Whole Genome Sequencing
  8. Source: American Journal of Human Genetics ; Volume 108, Issue 2 , 2021 , Pages 324-336 ; 00029297 (ISSN)
  9. URL: https://www.cell.com/ajhg/fulltext/S0002-9297(21)00010-0