A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism

Rebecca M. Harris, Courtney Finlayson, Jeffrey Weiss, Lisa Fisher, Lisa Hurley, Tim Barrett, Donna Emge, Ross A.D. Bathgate, Alexander I. Agoulnik, J. Larry Jameson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Using genome-wide mutagenesis with N-ethyl-N-nitrosourea (ENU), a mouse mutant with cryptorchidism was identified. Genome mapping and exon sequencing identified a novel missense mutation (D294G) in Relaxin/insulin-like family peptide receptor 2 (Rxfp2). The mutation impaired testicular descent and resulted in decreased testis weight in Rxfp2 DG/DG mice compared to Rxfp2 +/DG and Rxfp2 +/+ mice. Testicular histology of the Rxfp2 DG/DG mice revealed spermatogenic defects ranging from germ cell loss to tubules with Sertoli-cell-only features. Genetic complementation analysis using a loss-of-function allele (Rxfp2 -) confirmed causality of the D294G mutation. Specifically, mice with one of each mutant allele (Rxfp2 DG/-) exhibited decreased testis weight and failure of the testes to descend compared to their Rxfp2 +/- littermates. Total and cell-surface expression of mouse RXFP2 protein and intracellular cAMP accumulation were measured. Total expression of the D294G protein was minimally reduced compared to wild-type, but cell-surface expression was markedly decreased. When analyzed for cAMP accumulation, the EC50 was similar for cells transfected with wild-type and mutant RXFP2 receptor. However, the maximum cAMP response that the mutant receptor reached was greatly reduced compared to the wild-type receptor. In silico modeling of leucine rich repeats (LRRs) 7-9 indicated that aspartic acid 294 is located within the β-pleated sheet of LRR8. We thus postulate that mutation of D294 results in protein misfolding and aberrant trafficking. The ENU-induced D294G mutation underscores the role of the INSL3/RXFP2-mediated pathway in testicular descent and expands the repertoire of mutations known to affect receptor trafficking and function.

Original languageEnglish (US)
Pages (from-to)442-449
Number of pages8
JournalMammalian Genome
Issue number9-10
StatePublished - Oct 2010

ASJC Scopus subject areas

  • Genetics


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