%0 Journal Article %1 lauffer2020activating %A Lauffer, P. %A Miranda-Laferte, E. %A van Duyvenvoorde, H. A. %A van Haeringen, A. %A Werner, F. %A Boudin, E. %A Schmidt, H. %A Mueller, T. D. %A Kuhn, M. %A van der Kaay, D. C. M. %D 2020 %J J Clin Endocrinol Metab %K Adult myOwn uni_network %N 7 %P 2354-66 %R 10.1210/clinem/dgaa190 %T An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature %U https://www.ncbi.nlm.nih.gov/pubmed/32282051https://watermark.silverchair.com/dgaa190.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA1UwggNRBgkqhkiG9w0BBwagggNCMIIDPgIBADCCAzcGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMYbNWbhaARt8AzI-GAgEQgIIDCBWo33Lx4pJ3hgvtEeqU37MKrMS8fjjXELxC_Hp2nkCoDZKFrOyEdLEh-NrHM0liJ3eG9ZZ6_h1rmudvEo0b8UU50lKtFng5LmwarKLQ3cSYpw7N6OgqlnWwb0QV1u6OOY4eYAMAENrJb3q-UEgGPHMRaKrwhH2NhS0ypvlMq4gCpLBZE00wymBYflQ1pawGep-wr50lUlrsnBu-dPE_WXI_wzj_4ZiRdxFVSlICIyJdSS7z89_HD4GUO89EEb6s9RTWXFeNtyPW7yzZ8ndc2IKZq-pHovUehgDFPeMKBgjxr13uy3q94pkCxF6A34m-3CVBwGExSgrroBNfQ11YpbRKmOsiwU3R6-gjF7HJUIU4E1Wny_KgwZk2RGs6AGzsK8yHL2X3U2-oCRlU3ldawGDDJ6ekiU4kBSPqo3BVEqQlToNSYVXD0beIhGG4BvRo7_p_MYfmW9-oj1bY1GpsvLS76uvpDDKtPhQAm0BpKmrC-pQqn3O-M6gvmRnfbpIRMwpUUeTiX2StKhfg0ilwUi2SrejTazNZS4Zn_g_oYqENhU8c828NZakHuXaIpshLRtvNsZTM68x7NmYuSVsT0gm0rzFiDPTnb_tHLmfBNhRACnjVDVd2frB-0GXwmh8oikQO0CEeLmHxddmyNGvW5qDlKV1o5_E6R1i1bqpHCRdcO27OQyEYcGTtd4L-60FCx3Z8MkNNIzUnbGbe1lTkKlzAJI1XZ66VVSiNxdRzTaC95li0IjfhvwamydkjVOmY7lYealAZZTcuQng0LcBk9WtLEaD767Hoyk-RAwltjcY87k2hGxPzOCj0timfPdo1bYyuq5xKyM5SwEoBM5aj1hy3Ha6WWf8RsY4iEFR6vLnCUuEYPiPgr6OSK6_rW0pPqUM-5AXfdoYx8okjaCyd9S7sOAdDLfGRBjeOT74vVSUGpZD3SbXizB85kqskTm_AeIWXkjtimm2pMr5CToldxONwlnipEHRPqiqvnBaEliZOusblHvGPvMFR-mgknj5bKoP6CI-8QmfK %V 105 %X CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B NPR-B, gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). DESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant. RESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B. CONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.

@article{lauffer2020activating, abstract = {CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). DESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant. RESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B. CONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Lauffer, P. and Miranda-Laferte, E. and van Duyvenvoorde, H. A. and van Haeringen, A. and Werner, F. and Boudin, E. and Schmidt, H. and Mueller, T. D. and Kuhn, M. and van der Kaay, D. C. M.}, biburl = {https://www.bibsonomy.org/bibtex/28d6eff44f3fcfc1d02bb9b0f955a4408/jvsi_all}, doi = {10.1210/clinem/dgaa190}, interhash = {65c258167bde3bcb72d3c012749cb72f}, intrahash = {8d6eff44f3fcfc1d02bb9b0f955a4408}, issn = {1945-7197 (Electronic) 0021-972X (Print) 0021-972X (Linking)}, journal = {J Clin Endocrinol Metab}, keywords = {Adult myOwn uni_network}, note = {Lauffer, Peter Miranda-Laferte, Erick van Duyvenvoorde, Hermine A van Haeringen, Arie Werner, Franziska Boudin, Eveline Schmidt, Hannes Mueller, Thomas D Kuhn, Michaela van der Kaay, Danielle C M eng Case Reports Research Support, Non-U.S. Gov't 2020/04/14 J Clin Endocrinol Metab. 2020 Jul 1;105(7):2354-66. doi: 10.1210/clinem/dgaa190.}, number = 7, pages = {2354-66}, timestamp = {2024-02-15T15:11:55.000+0100}, title = {An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/32282051https://watermark.silverchair.com/dgaa190.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAA1UwggNRBgkqhkiG9w0BBwagggNCMIIDPgIBADCCAzcGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMYbNWbhaARt8AzI-GAgEQgIIDCBWo33Lx4pJ3hgvtEeqU37MKrMS8fjjXELxC_Hp2nkCoDZKFrOyEdLEh-NrHM0liJ3eG9ZZ6_h1rmudvEo0b8UU50lKtFng5LmwarKLQ3cSYpw7N6OgqlnWwb0QV1u6OOY4eYAMAENrJb3q-UEgGPHMRaKrwhH2NhS0ypvlMq4gCpLBZE00wymBYflQ1pawGep-wr50lUlrsnBu-dPE_WXI_wzj_4ZiRdxFVSlICIyJdSS7z89_HD4GUO89EEb6s9RTWXFeNtyPW7yzZ8ndc2IKZq-pHovUehgDFPeMKBgjxr13uy3q94pkCxF6A34m-3CVBwGExSgrroBNfQ11YpbRKmOsiwU3R6-gjF7HJUIU4E1Wny_KgwZk2RGs6AGzsK8yHL2X3U2-oCRlU3ldawGDDJ6ekiU4kBSPqo3BVEqQlToNSYVXD0beIhGG4BvRo7_p_MYfmW9-oj1bY1GpsvLS76uvpDDKtPhQAm0BpKmrC-pQqn3O-M6gvmRnfbpIRMwpUUeTiX2StKhfg0ilwUi2SrejTazNZS4Zn_g_oYqENhU8c828NZakHuXaIpshLRtvNsZTM68x7NmYuSVsT0gm0rzFiDPTnb_tHLmfBNhRACnjVDVd2frB-0GXwmh8oikQO0CEeLmHxddmyNGvW5qDlKV1o5_E6R1i1bqpHCRdcO27OQyEYcGTtd4L-60FCx3Z8MkNNIzUnbGbe1lTkKlzAJI1XZ66VVSiNxdRzTaC95li0IjfhvwamydkjVOmY7lYealAZZTcuQng0LcBk9WtLEaD767Hoyk-RAwltjcY87k2hGxPzOCj0timfPdo1bYyuq5xKyM5SwEoBM5aj1hy3Ha6WWf8RsY4iEFR6vLnCUuEYPiPgr6OSK6_rW0pPqUM-5AXfdoYx8okjaCyd9S7sOAdDLfGRBjeOT74vVSUGpZD3SbXizB85kqskTm_AeIWXkjtimm2pMr5CToldxONwlnipEHRPqiqvnBaEliZOusblHvGPvMFR-mgknj5bKoP6CI-8QmfK}, volume = 105, year = 2020 }