Truncated DAZL mutation reduces NANOS3 expression in primordial germ cells and leads to premature ovarian insufficiency

Primary ovarian insufficiency (POI) is a complex disorder that affects many genes and the underlying molecular mechanisms remain to be fully elucidated. In this study, a homozygous point mutation, c.808C>T, in the DAZL gene of a POI patient was identified. This homozygous variant causes a C-terminal truncation of DAZL and down-regulation of germ-line gene NANOS3 expression, among other dysregulated genes, in human primordial germ cells (hPGCs) in vitro. Mechanistically, we discovered that the truncated DAZL had defects in regulating mRNA translation for NANOS3, VASA, and SYCP3 - all essential for gametogenesis. Additionally, the truncated DAZL showed impaired interaction with Poly(A)-binding proteins (PABPs), a crucial component of the translation initiation complex. At the cellular level, the truncated mutation resulted in increased apoptosis of in vitro hPGCs. Our findings reveal that the c.808C>T mutation in DAZL causes dysregulated expressions of many genes, increases germ cell apoptosis and ultimately leads to POI. To examine the potential effect of the mutant DAZL on PGC gene expressions, WT DAZL or the truncated DAZL was overexpressed in hPGCLCs during in vitro differentiation. We then performed gene expression profiling analysis using data obtained from RNA-seq at two time points. Comparative gene expression profiling analysis of RNA-seq data for WT DAZL hPGCLCs and c.808C>T DAZL hPGCLCs.