An ancient founder mutation in PROKR2 impairs human reproduction

Area of Science:

• Genetics
• Reproductive Endocrinology
• Human Evolution

Background:

• Congenital gonadotropin-releasing hormone (GnRH) deficiency causes impaired sexual maturation and infertility.
• While typically caused by rare, private mutations, PROKR2 L173R is a notable exception, found frequently across diverse populations.

Purpose of the Study:

• To investigate the genetic ancestry and origin of the PROKR2 L173R mutation.
• To understand the inheritance patterns and evolutionary implications of this prevalent GnRH deficiency mutation.

Main Methods:

• Haplotype mapping in 22 unrelated GnRH-deficient patients and 30 relatives carrying the PROKR2 L173R mutation.
• Age estimation of the mutation using a haplotype-decay model.

Main Results:

• The PROKR2 L173R mutation was consistently found on a shared ~123 kb haplotype in informative subjects.
• This shared haplotype, with a population frequency ≤10%, indicates PROKR2 L173R is a founder mutation.
• The mutation's estimated age is approximately 9000 years.
• Inheritance of GnRH deficiency associated with PROKR2 L173R exhibited variable penetrance, influenced by recessive inheritance or digenicity.

Conclusions:

• PROKR2 L173R is an ancient founder mutation responsible for a significant proportion of GnRH deficiency cases.
• The complex inheritance and ancient origin suggest potential evolutionary advantages for mutation carriers.
• Further research is needed to explore the evolutionary selection mechanisms and reproductive implications.