Identification of nonfunctional PABPC1L causing oocyte maturation abnormalities and early embryonic arrest in female...

Area of Science:

• Reproductive Biology
• Human Genetics
• Molecular Biology

Background:

• Oocyte maturation arrest, fertilization failure, and early embryonic arrest are significant contributors to female infertility.
• The genetic underpinnings of these reproductive failures, particularly concerning Poly(A)-binding protein cytoplasmic 1 like (PABPC1L), remain largely unelucidated in humans.
• Previous studies in mice suggested PABPC1L loss-of-function leads to female infertility.

Purpose of the Study:

• To investigate the role of PABPC1L in human female reproduction.
• To identify genetic variants in PABPC1L associated with oocyte maturation abnormalities and early embryonic arrest.
• To elucidate the molecular mechanisms by which PABPC1L mutations impact female fertility.

Main Methods:

• Genetic analysis of two infertile females with recurrent oocyte maturation abnormalities and early embryonic arrest.
• Identification and characterization of mutations in the PABPC1L gene.
• Assessment of PABPC1L protein function, including mRNA binding capacity, chromatin configuration, and transcriptional activity in oocytes.

Main Results:

• Two novel PABPC1L mutations were identified: a homozygous missense mutation (c.536G>A, p.R179Q) and a compound heterozygous mutation (c.793C>T, p.R265W; c.1201C>T, p.Q401*).
• These mutations resulted in nonfunctional PABPC1L protein, leading to impaired chromatin configuration and transcriptional silencing in germinal vesicle (GV) oocytes.
• Mutant PABPC1L exhibited significantly reduced binding to mRNAs crucial for oocyte maturation and early embryonic development.

Conclusions:

• Novel mutations in PABPC1L are identified as a cause of oocyte maturation abnormalities and early embryonic arrest in human females.
• These findings confirm the critical role of PABPC1L in maintaining human female fertility.
• The study highlights PABPC1L as a potential target for understanding and potentially treating infertility related to oocyte and early embryo development.