Mutant prolactin receptor and familial hyperprolactinemia

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Hyperprolactinemia, elevated prolactin levels, is typically linked to pituitary tumors or rare genetic syndromes.
• Understanding the molecular basis of hyperprolactinemia is crucial for diagnosing and managing related reproductive disorders.

Observation:

• Three sisters presented with hyperprolactinemia, oligomenorrhea, and infertility.
• Clinical evaluation excluded pituitary tumors and multiple endocrine neoplasia syndromes as the cause.

Findings:

• A heterozygous mutation in the prolactin receptor gene (PRLR) was identified in the affected sisters.
• This mutation (His188Arg) disrupts the prolactin receptor's ligand-binding site, impairing downstream signaling via JAK2/STAT5.
• The mutation results in a germline, loss-of-function, causing familial hyperprolactinemia due to prolactin insensitivity.

Implications:

• Identifies a novel genetic cause of familial hyperprolactinemia and prolactin insensitivity.
• Highlights the importance of genetic testing for unexplained hyperprolactinemia and related reproductive dysfunction.
• Provides insights into the critical role of the prolactin receptor in reproductive health.