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Familial Bilateral Cryptorchidism Is Developmental defects J Med Genet: first published as 10.1136/jmedgenet-2019-106203 on 5 June 2019. Downloaded from ORIGINAL RESEARCH Familial bilateral cryptorchidism is caused by recessive variants in RXFP2 Katie Ayers ,1,2 Rakesh Kumar,3 Gorjana Robevska,2 Shoni Bruell,4,5 Katrina Bell,2 Muneer A Malik,6 Ross A Bathgate,4,5 Andrew Sinclair1,2 3 ► Additional material is ABSTRact structure derived from the primitive mesenchyme. published online only. To view Background Cryptorchidism or failure of testicular During the transabdominal phase, the hypertrophy please visit the journal online (http:// dx. doi. org/ 10. 1136/ descent is the most common genitourinary birth defect in and growth of the gubernaculum steers the testis jmedgenet- 2019- 106203). males. While both the insulin-like peptide 3 (INSL3) and to the caudal part of abdomen. The descent of its receptor, relaxin family peptide receptor 2 (RXFP2), the testis requires hormonal factors produced by For numbered affiliations see have been demonstrated to control testicular descent in the fetal testis itself, such as INSL3 and androgens end of article. mice, their link to human cryptorchidism is weak, with no (see Mäkelä et al4 for a review). Several genes and clear cause–effect demonstrated. pathways have been implicated in testicular descent Correspondence to Dr Katie Ayers, Murdoch Objective To identify the genetic cause of a case of and cryptorchidism, mainly from work in mouse 4 Children’s Research Institute, familial cryptorchidism. models. This includes the insulin-like peptide 3 Parkville, VIC 3052, Australia; Methods We recruited a family in which four boys (INSL3) hormone and its receptor, relaxin family katie. ayers@ mcri. edu. au had isolated bilateral cryptorchidism. A fourth-degree peptide receptor 2 (RXFP2), which are essential and Professor Rakesh Kumar, consanguineous union in the family was reported. Whole Department of Paediatric for transabdominal migration of the testis in the 5–10 Surgery, Post Graduate exome sequencing was carried out for the four affected mouse. These genes are expressed in Leydig Institute of Medical Education boys and their parents, and variants that segregated cells,11 from where it is thought that the INSL3 and Research (PGIMER), with the disorder and had a link to testis development/ hormone dilates the gubernaculum and allows the Chandigarh, India; descent were analysed. Functional analysis of a RXFP2 drrakesh. pgi@ gmail. com opening of the inguinal canal during the transab- variant in cell culture included receptor localisation, dominal descent phase.3 KA and RK contributed equally. ligand binding and cyclic AMP (cAMP) pathway While mutations in these genes cause cryptor- activation. chidism in rodent models, the evidence for them Received 10 April 2019 Results Genomic analysis revealed a homozygous directly causing cryptorchidism in humans is weak, Revised 9 May 2019 missense variant in the RXFP2 gene (c.1496G>A Accepted 10 May 2019 and few studies have convincingly shown cause– Published Online First 5 June .p.Gly499Glu) in all four affected boys and heterozygous effect, with most studies only suggesting associa- 2019 in both parents. No other variant with a link to testis tion. The INSL3 receptor RXFP2, also known as biology was found. The RXFP2 variant is rare in genomic leucine‐rich repeat‐containing G protein‐coupled http://jmg.bmj.com/ databases and predicted to be damaging. It has not been receptor 8 (LGR8) or G-protein-coupled receptor previously reported. Functional analysis demonstrated affecting testis descent (GREAT), is located at that the variant protein had poor cell surface expression chromosome 13 and encodes a protein with an and failed to bind INSL3 or respond to the ligand with extracellular ligand‐binding domain, seven trans- cAMP signalling. 12 membrane domains and one intracellular domain. Conclusion This is the first reported genomic analysis When mutated in mice, this gene causes intra-ab- of a family with multiple individuals affected with 8 10 dominal bilateral cryptorchidism. Evidence for on September 26, 2021 by guest. Protected copyright. cryptorchidism. It demonstrates that recessive variants its involvement in humans is scant, and just one in the RXFP2 gene underlie familial cryptorchidism variant, p.Thr222Pro, has been described in patients and solidifies the link between this gene and testicular with consistent functional evidence. In 2002, Golov descent in humans. and colleagues published a single patient carrying this heterozygous variant,8 and further research suggested that this variant was over-represented BACKGROUND in Italian patients with cryptorchidism and not in 13 Cryptorchidism (OMIM 219050) or failure of controls. Functional analysis suggested that this 13 testicular descent is the most common genitouri- variant has compromised activity. Since then, with nary birth defect in males, found in between 1.6% the increased availability of genomic sequencing and 9.0% of boys.1 It can affect one (unilateral) or and large genetic variation databases, the associa- © Author(s) (or their both (bilateral) testes and can be isolated or asso- tion of this variant with cryptorchidism has been employer(s)) 2019. Re-use called into question. Of note, this is the only variant permitted under CC BY-NC. No ciated with additional anomalies. Cryptorchidism, commercial re-use. See rights if left untreated, can cause serious complications in RXFP2 present in ClinVar and it is now classi- and permissions. Published such as testicular cancer or infertility.2 Testicular fied as a variant of uncertain significance. Indeed, by BMJ. descent from an intra-abdominal position into the this variant was reclassified based on a study in To cite: Ayers K, Kumar R, scrotum is often described as having two main 2010 in which the authors screened for the RXFP2 Robevska G, et al. phases: the transabdominal phase and the inguino- p.Thr222Pro variant in 577 Spanish men (187 with J Med Genet scrotal phase. This descent is guided by the guber- cryptorchidism and 390 controls) and in 550 Italian 2019;56:727–733. naculum (the rudder of the testis), a ligament-like men (199 with cryptorchidism and 351 controls) Ayers K, et al. J Med Genet 2019;56:727–733. doi:10.1136/jmedgenet-2019-106203 727 Developmental defects J Med Genet: first published as 10.1136/jmedgenet-2019-106203 on 5 June 2019. Downloaded from and found that in the Spanish study population, the variant was plates and transfected the following day with receptor DNA present at similar frequency in both cases (3 of 187; 1.6%) and using LipofectAMINE 2000 (Invitrogen). controls (7 of 390; 1.8%) while in the Italian study population, the variant was more frequent in cases (9 of 199; 4.5%) than 14 Mutagenesis in controls (5 of 351; 1.4%), with an OR of 3.17 (p=0.031). The mutation of glycine-499 to glutamic acid in human RXFP2 It was concluded that p.Thr222Pro is a frequent variant in the was achieved by QuikChange mutagenesis with PrimeStar poly- Spanish population with no pathogenic effect, although the merase (Takara Clontech) on N-terminally FLAG-tagged human variant seemed to confer a mild risk for cryptorchidism in the 14 RXFP2 in pcDNA3.1 according to manufacturer’s instructions Italian population. Several other studies in different popula- and similarly to previously described.22 Notably, FLAG tagging tions have shown no enrichment of this variant in patients with 23 15 of the receptor does not affect ligand binding or activation. cryptorchidism compared with controls. Indeed, the genome The sequence of pcDNA3.1-FLAG-RXFP2 Gly499Glu was aggregation database (gnomAD) lists this variant as having a confirmed by DNA sequencing on both strands (Centre of Trans- minor allele frequency of 0.004403, and homozygous variants lational Pathology, University of Melbourne) to ensure that there are described. Taken together these data exclude a clear-cut were no additional mutations. cause–effect relationship between the p.Thr222Pro variant and cryptorchidism. One roadblock to finding definitive genetic causes of crypt- FLAG receptor expression assays orchidism is the lack of convincing familial cases in which Cell surface and total cellular expression of FLAG-tagged RXFP2 receptors expressed in HEK293T cells was measured using a genetics have been applied. Only a handful of publications have 24 described comprehensive familial cases of cryptorchidism,16–20 method described previously. Twenty-four hours after trans- with none conclusively identifying a genetic cause. In summary, fection in 24 well plates, cells were washed once in assay buffer (Tris buffered saline pH 7.4, 2 mM CaCl ) and fixed for 15 min since its initial description, the exact role of RXFP2 in human 2 cryptorchidism has remained elusive, with no clear cause–effect by addition of assay buffer containing 3.7% formaldehyde (for yet demonstrated. cell surface) or 3.7% formaldehyde/0.25% Triton-X (for total Here we carried out exome sequencing analysis in a family cell expression). Cells were then washed twice with assay buffer, in which four boys had familial bilateral cryptorchidism and blocked for 45 min in assay buffer containing 1% bovine serum found a rare recessive missense variant in RXFP2. This provides albumin, incubated at room temperature with mouse anti-FLAG the first rigorous human genetic evidence that RXFP2 variants M1 monoclonal antibody (Sigma Aldrich), washed once in assay directly cause cryptorchidism. It also implies that RXFP2 has an buffer, incubated at room temperature in goat
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