Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens Olivier.

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Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens Olivier Patat, Adrien Pagin, Aurore Siegfried, Valérie Mitchell, Nicolas Chassaing, Stanislas Faguer, Laetitia Monteil, Véronique Gaston, Louis Bujan, Monique Courtade-Saïdi, François Marcelli, Guy Lalau, Jean-Marc Rigot, Roger Mieusset, Eric Bieth The American Journal of Human Genetics Volume 99, Issue 2, Pages 437-442 (August 2016) DOI: 10.1016/j.ajhg.2016.06.012 Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 1 Study Flow Chart and Genealogic Tree of the Pedigree with Two Related Individuals with CBAVD (A) Study flow chart showing the procedure for the identification of new male fertility genes from a cohort of azoospermic men with CBAVD. LoF, loss of function. (B) Genealogic tree of the two related CBAVD-affected individuals included in the cohort (II-3 and III-12, arrow). ?, probable infertility. The American Journal of Human Genetics 2016 99, 437-442DOI: (10.1016/j.ajhg.2016.06.012) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 2 Schematic Representation of ADGRG2 Structure with the Position of the Amino Acid Changes Resulting from the Identified Truncating Mutations Like the other members of the adhesion-GPCR family, ADGRG2 is composed of a seven-transmembrane domain and a highly conserved cystein-rich motif, named the GAIN domain, containing GPS, which is the site of autoproteolytic cleavage. The ADGRG2 extracellular domain contains a serine-threonine-proline-rich region (STP). Positions of C-terminal and N-terminal epitopes recognized by the populations of polyclonal antibodies used for immunohistochemistry are indicated by yellow stars. The American Journal of Human Genetics 2016 99, 437-442DOI: (10.1016/j.ajhg.2016.06.012) Copyright © 2016 American Society of Human Genetics Terms and Conditions

Figure 3 Immunohistochemical Staining of ADGRG2 in Sections of Epididymal and Efferent Ducts Obtained from a Control Individual with Non-obstructive Azoospermia and from the CBAVD-Affected Proband Carrying the p.Leu668Argfs∗21 ADGRG2 Truncating Variant With the antibody directed against the N-terminal portion of ADGRG2, subapical staining (arrows) was observed on the control epididymal (A) and efferent (C) ducts. The same staining was observed on sections from the proband, respectively (B and D). In the control subject, staining of stereocilia and apical membrane is observed on the epididymis section (A) (arrowhead), whereas stereocilia are not stained in the proband (B) (arrowhead). With the antibody directed against the C-terminal portion of ADGRG2, positive staining was observed on the control subject at the apical level and stereocilia of cells from the epididymis (E) (arrows) or at the apical level of efferent ducts, especially in crypt-like grooves (G) (arrows). In contrast, in the CBAVD-affected proband whose mutation is predicted to delete the ADGRG2 C-terminal region, such staining was not observed on the epididymal (F) or efferent (H) ducts. Scale bars indicate 50 μm. The American Journal of Human Genetics 2016 99, 437-442DOI: (10.1016/j.ajhg.2016.06.012) Copyright © 2016 American Society of Human Genetics Terms and Conditions