{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T06:49:27Z","timestamp":1773384567844,"version":"3.50.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,4,2]],"date-time":"2023-04-02T00:00:00Z","timestamp":1680393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recently, rare heterozygous AMH protein-altering variants were identified in women with polycystic ovary syndrome (PCOS), causing reduced anti-M\u00fcllerian hormone (AMH) signaling. However, the exact functional mechanism remains unknown. Here, we analyzed the processing, secretion, and signaling of these AMH variants. Functional analysis of six PCOS-specific AMH variants (V12G, P151S, P270S, P352S, P362S, H506Q) and one control-specific variant (A519V) was performed in the mouse granulosa cell-line KK-1. Human (h) AMH-151S and hAMH-506Q have \u223c90% decreased AMH signaling compared to wild-type (wt) AMH signaling. Coexpression of hAMH-151S or hAMH-506Q with wt-hAMH dose-dependently inhibited wt-hAMH signaling. Western blotting revealed that hAMH-151S and hAMH-506Q proteins were detected in the cell lysate but not in the supernatant. Confocal microscopy showed that HEK293 cells expressing hAMH-151S and hAMH-506Q had higher cellular AMH protein levels with endoplasmic reticulum (ER) retention compared to cells expressing wt-hAMH. Using two AMH ELISA kits, hAMH-151S was detected in the cell lysate, while only very low levels were detected in the supernatant. Both hAMH-362S and hAMH-519V were detectable using the automated AMH ELISA but showed severely reduced immunoactivity in the manual ELISA. Surprisingly, hAMH-506Q was undetectable in both the cell lysate and supernatant using either ELISA. However, in PCOS cases, heterozygous carriers of the P151S and H506Q variants still had detectable AMH in both assays. Thus, P151S and H506Q disrupt normal processing and secretion of AMH, causing ER retention. Additionally, AMH variants can impair the AMH immunoactivity. An AMH variant may be considered when serum AMH levels are relatively low in PCOS cases.<\/jats:p>","DOI":"10.1093\/molehr\/gaad011","type":"journal-article","created":{"date-parts":[[2023,4,2]],"date-time":"2023-04-02T13:21:12Z","timestamp":1680441672000},"source":"Crossref","is-referenced-by-count":14,"title":["Functional analysis of rare anti-M\u00fcllerian hormone protein-altering variants identified in women with PCOS"],"prefix":"10.1093","volume":"29","author":[{"given":"L","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"McLuskey","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Dunaif","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7182-3571","authenticated-orcid":false,"given":"J A","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam , Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,4,2]]},"reference":[{"key":"2023042919454695300_gaad011-B1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1002\/cyto.a.20896","article-title":"Quantifying colocalization by correlation: the Pearson correlation coefficient is superior to the Mander's overlap 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polycystic ovary syndrome produces more antim\u00fcllerian hormone than its counterpart in a normal ovary: an observational cross-sectional study","volume":"103","author":"Bhide","year":"2015","journal-title":"Fertil Steril"},{"key":"2023042919454695300_gaad011-B5","doi-asserted-by":"crossref","first-page":"4533","DOI":"10.1210\/en.2012-1158","article-title":"The role of anti-M\u00fcllerian hormone (AMH) during follicle development in a monovulatory species (sheep)","volume":"153","author":"Campbell","year":"2012","journal-title":"Endocrinology"},{"key":"2023042919454695300_gaad011-B6","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.fertnstert.2013.04.019","article-title":"Antim\u00fcllerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells","volume":"100","author":"Chang","year":"2013","journal-title":"Fertil 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