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Article: A dominant negative mutation at the ATP binding domain of AMHR2 is associated with a defective anti-Müllerian hormone signaling pathway

TitleA dominant negative mutation at the ATP binding domain of AMHR2 is associated with a defective anti-Müllerian hormone signaling pathway
Authors
Issue Date2016
PublisherOxford University Press. The Journal's web site is located at http://molehr.oxfordjournals.org/
Citation
Molecular Human Reproduction, 2016, v. 22 n. 9, p. 669-678 How to Cite?
AbstractSTUDY QUESTION Does a heterozygous mutation in AMHR2, identified in whole-exome sequencings (WES) of patients with primary ovarian insufficiency (POI), cause a defect in anti-Müllerian hormone (AMH) signaling? SUMMARY ANSWER The I209N mutation at the adenosine triphosphate binding domain of AMHR2 exerts dominant negative defects in the AMH signaling pathway. WHAT IS KNOWN ALREADY Previous studies have demonstrated the associations of several sequence variants in AMH or AMHR2 with POI, but no functional assay has been performed to verify whether there was any defect on AMH signaling. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Ninety-six unrelated female Chinese Han patients were diagnosed with idiopathic POI and subjected to WES. In silico analysis was done for the sequence variants followed by molecular assays to examine the functional effects of the sequence variants in human granulosa cells. In silico analysis, immunostaining, Western analysis, genome-wide expression analysis, quantitatively polymerase chain reaction were applied to the characterization of the sequence variants. MAIN RESULTS AND THE ROLE OF CHANCE We identified one novel heterozygous missense variant, p.Ala17Glu (A17E), in AMHR2. Subsequently, A17E and two independently reported missense variants, p.Ile209Asn (I209N) and p.Leu354Phe (L354F), were evaluated for effects on the AMH signaling pathway. In silico analysis predicted that all three variants may be deleterious. However, only one variant, I209N, showed severe defects in transducing the AMH signal as well as impaired SMAD1/5/8 phosphorylation. Furthermore, using genome-wide gene expression analysis, we identified genes whose expression was affected by the mutation, these included genes previously reported to participate in AMH signaling as well as newly identified genes. They are EMILIN2, FAM155A, GATA2, HES5, ID1, ID2, RLTPR, SMAD7, CBL, MALAT1 and SMARCA2. LARGE SCALE DATA None. LIMITATIONS, REASONS FOR CAUTION Although the in vitro assays demonstrated the causative effect of I209N on AMH signaling, further studies need to validate its long-term effects on folliculogenesis and POI. WIDER IMPLICATIONS OF THE FINDINGS These results will aid both researchers and clinicians in understanding the molecular pathology of AMH signaling and POI to develop diagnostic assays or therapeutics approaches. STUDY FUNDING AND COMPETING INTEREST(S) Research funding is provided by the Ministry of Science and Technology of China [2012CB944704; 2012CB966702], and the National Natural Science Foundation of China [Grant number: 31171429]. The authors declare no conflict of interest.
Persistent Identifierhttp://hdl.handle.net/10722/231245
ISSN
2015 Impact Factor: 3.943
2015 SCImago Journal Rankings: 1.611

 

DC FieldValueLanguage
dc.contributor.authorLi, L-
dc.contributor.authorZhou, X-
dc.contributor.authorWang, X-
dc.contributor.authorWang, J-
dc.contributor.authorZhang, W-
dc.contributor.authorWang, B-
dc.contributor.authorCao, Y-
dc.contributor.authorKee, K-
dc.date.accessioned2016-09-20T05:21:45Z-
dc.date.available2016-09-20T05:21:45Z-
dc.date.issued2016-
dc.identifier.citationMolecular Human Reproduction, 2016, v. 22 n. 9, p. 669-678-
dc.identifier.issn1360-9947-
dc.identifier.urihttp://hdl.handle.net/10722/231245-
dc.description.abstractSTUDY QUESTION Does a heterozygous mutation in AMHR2, identified in whole-exome sequencings (WES) of patients with primary ovarian insufficiency (POI), cause a defect in anti-Müllerian hormone (AMH) signaling? SUMMARY ANSWER The I209N mutation at the adenosine triphosphate binding domain of AMHR2 exerts dominant negative defects in the AMH signaling pathway. WHAT IS KNOWN ALREADY Previous studies have demonstrated the associations of several sequence variants in AMH or AMHR2 with POI, but no functional assay has been performed to verify whether there was any defect on AMH signaling. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Ninety-six unrelated female Chinese Han patients were diagnosed with idiopathic POI and subjected to WES. In silico analysis was done for the sequence variants followed by molecular assays to examine the functional effects of the sequence variants in human granulosa cells. In silico analysis, immunostaining, Western analysis, genome-wide expression analysis, quantitatively polymerase chain reaction were applied to the characterization of the sequence variants. MAIN RESULTS AND THE ROLE OF CHANCE We identified one novel heterozygous missense variant, p.Ala17Glu (A17E), in AMHR2. Subsequently, A17E and two independently reported missense variants, p.Ile209Asn (I209N) and p.Leu354Phe (L354F), were evaluated for effects on the AMH signaling pathway. In silico analysis predicted that all three variants may be deleterious. However, only one variant, I209N, showed severe defects in transducing the AMH signal as well as impaired SMAD1/5/8 phosphorylation. Furthermore, using genome-wide gene expression analysis, we identified genes whose expression was affected by the mutation, these included genes previously reported to participate in AMH signaling as well as newly identified genes. They are EMILIN2, FAM155A, GATA2, HES5, ID1, ID2, RLTPR, SMAD7, CBL, MALAT1 and SMARCA2. LARGE SCALE DATA None. LIMITATIONS, REASONS FOR CAUTION Although the in vitro assays demonstrated the causative effect of I209N on AMH signaling, further studies need to validate its long-term effects on folliculogenesis and POI. WIDER IMPLICATIONS OF THE FINDINGS These results will aid both researchers and clinicians in understanding the molecular pathology of AMH signaling and POI to develop diagnostic assays or therapeutics approaches. STUDY FUNDING AND COMPETING INTEREST(S) Research funding is provided by the Ministry of Science and Technology of China [2012CB944704; 2012CB966702], and the National Natural Science Foundation of China [Grant number: 31171429]. The authors declare no conflict of interest.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://molehr.oxfordjournals.org/-
dc.relation.ispartofMolecular Human Reproduction-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here]. -
dc.titleA dominant negative mutation at the ATP binding domain of AMHR2 is associated with a defective anti-Müllerian hormone signaling pathway-
dc.typeArticle-
dc.identifier.emailZhou, X: zhouxy@hku.hk-
dc.identifier.doi10.1093/molehr/gaw040-
dc.identifier.hkuros266404-
dc.identifier.volume22-
dc.identifier.issue9-
dc.identifier.spage669-
dc.identifier.epage678-
dc.publisher.placeUnited Kingdom-

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