ASTL is mutated in female infertility.

Area of Science:

• Genetics
• Reproductive Biology
• Human Molecular Genetics

Background:

• Female infertility is a common concern with numerous genetic underpinnings.
• While single gene causes are identified, they represent a minority of infertility cases.
• Ovastacin, encoded by ASTL, plays a key role in fertilization via zona pellucida hardening.

Purpose of the Study:

• To investigate the genetic basis of infertility in a consanguineous family.
• To identify novel gene variants associated with female infertility.
• To explore the role of ASTL in human female fertility.

Main Methods:

• Genetic analysis of a consanguineous family with unexplained infertility.
• Whole-exome sequencing to identify homozygous variants.
• Phenotypic correlation with known functions of ASTL and zona pellucida hardening.

Main Results:

• Identified homozygous truncating variants in ASTL in affected females.
• Observed a phenotype of markedly reduced fertility, mirroring Astl-/- mouse models.
• Established ASTL as a causative gene for human female infertility.

Conclusions:

• This study reports ASTL as a novel gene linked to human female infertility.
• Defects in ASTL impair ovastacin function, leading to failed zona pellucida hardening and reduced fertility.
• Recommends including ASTL in genetic testing panels for female infertility.