• PMID: 31167797
• Gene Name: RXFP2
• Condition: Bilateral cryptorchidism
• Association: Associated
• Mutation: c.1496G>A .p.Gly499Glu
• Population size: 4
• Population details: 4 bilateral cryptorchidism
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Familial bilateral cryptorchidism is caused by recessive variants in RXFP2

Ayers K, Kumar R, Robevska G, Bruell S, Bell K, Malik MA, Bathgate RA, Sinclair A.

BACKGROUND: Cryptorchidism or failure of testicular descent is the most common genitourinary birth defect in males. While both the insulin-like peptide 3 (INSL3) and its receptor, relaxin family peptide receptor 2 (RXFP2), have been demonstrated to control testicular descent in mice, their link to human cryptorchidism is weak, with no clear cause-effect demonstrated. OBJECTIVE: To identify the genetic cause of a case of familial cryptorchidism. METHODS: We recruited a family in which four boys had isolated bilateral cryptorchidism. A fourth-degree consanguineous union in the family was reported. Whole exome sequencing was carried out for the four affected boys and their parents, and variants that segregated with the disorder and had a link to testis development/descent were analysed. Functional analysis of a RXFP2 variant in cell culture included receptor localisation, ligand binding and cyclic AMP (cAMP) pathway activation. RESULTS: Genomic analysis revealed a homozygous missense variant in the RXFP2 gene (c.1496G>A .p.Gly499Glu) in all four affected boys and heterozygous in both parents. No other variant with a link to testis biology was found. The RXFP2 variant is rare in genomic databases and predicted to be damaging. It has not been previously reported. Functional analysis demonstrated that the variant protein had poor cell surface expression and failed to bind INSL3 or respond to the ligand with cAMP signalling. CONCLUSION: This is the first reported genomic analysis of a family with multiple individuals affected with cryptorchidism. It demonstrates that recessive variants in the RXFP2 gene underlie familial cryptorchidism and solidifies the link between this gene and testicular descent in humans. CI - © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Ayers, Katie AU - Ayers K AUID- ORCID: 0000-0002-6840-3186 AD - Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia katie.ayers@mcri.edu.au drrakesh.pgi@gmail.com. AD - Murdoch Children's Research Institute, Parkville, Melbourne, Victoria, Australia. FAU - Kumar, Rakesh AU - Kumar R AD - Paediatric Endocrinology and Diabetes Unit, Department of Paediatric Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India katie.ayers@mcri.edu.au drrakesh.pgi@gmail.com. FAU - Robevska, Gorjana AU - Robevska G AD - Murdoch Children's Research Institute, Parkville, Melbourne, Victoria, Australia. FAU - Bruell, Shoni AU - Bruell S AD - Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Victoria, Australia. AD - Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia. FAU - Bell, Katrina AU - Bell K AD - Murdoch Children's Research Institute, Parkville, Melbourne, Victoria, Australia. FAU - Malik, Muneer A AU - Malik MA AD - Department of Paediatric Surgery, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. FAU - Bathgate, Ross A AU - Bathgate RA AD - Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne, Victoria, Australia. AD - Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia.