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A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia
Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum co...
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| Published in: | Molecular endocrinology (Baltimore, Md.) Md.), 2002-11, Vol.16 (11), p.2538-2546 |
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| container_title | Molecular endocrinology (Baltimore, Md.) |
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| creator | Malloy, Peter J Xu, Rong Peng, Lihong Clark, Pamela A Feldman, David |
| description | Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)2D3]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [3H]1,25-(OH)2D3 in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)2D3 or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)2D3-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR. |
| doi_str_mv | 10.1210/me.2002-0152 |
| format | article |
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The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)2D3]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [3H]1,25-(OH)2D3 in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)2D3 or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)2D3-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/me.2002-0152</identifier><identifier>PMID: 12403843</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Alopecia - genetics ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Base Sequence ; Binding Sites ; Calcitriol - metabolism ; Calcitriol - pharmacology ; Cesarean Section ; COS Cells ; Cytochrome P-450 Enzyme System - genetics ; European Continental Ancestry Group ; Genotype ; Humans ; Hypophosphatemia, Familial - genetics ; Infant, Newborn ; Male ; Mutation ; Polymorphism, Restriction Fragment Length ; Receptors, Calcitriol - chemistry ; Receptors, Calcitriol - genetics ; Receptors, Calcitriol - metabolism ; RNA, Messenger - genetics ; Steroid Hydroxylases - genetics ; steroid receptor coactivator 1 ; Transcriptional Activation ; United States ; vitamin D 24-hydroxylase ; vitamin D receptor-interacting protein ; Vitamin D3 24-Hydroxylase</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2002-11, Vol.16 (11), p.2538-2546</ispartof><rights>Copyright © 2002 by The Endocrine Society 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-b9bde1883d934e3d2d4870fd719c9726287bcb6178942cfc8ab094a170d44b6d3</citedby><cites>FETCH-LOGICAL-c498t-b9bde1883d934e3d2d4870fd719c9726287bcb6178942cfc8ab094a170d44b6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,783,787,27936,27937</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12403843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malloy, Peter J</creatorcontrib><creatorcontrib>Xu, Rong</creatorcontrib><creatorcontrib>Peng, Lihong</creatorcontrib><creatorcontrib>Clark, Pamela A</creatorcontrib><creatorcontrib>Feldman, David</creatorcontrib><title>A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)2D3]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [3H]1,25-(OH)2D3 in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)2D3 or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)2D3-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.</description><subject>Alopecia - genetics</subject><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Binding Sites</subject><subject>Calcitriol - metabolism</subject><subject>Calcitriol - pharmacology</subject><subject>Cesarean Section</subject><subject>COS Cells</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>European Continental Ancestry Group</subject><subject>Genotype</subject><subject>Humans</subject><subject>Hypophosphatemia, Familial - genetics</subject><subject>Infant, Newborn</subject><subject>Male</subject><subject>Mutation</subject><subject>Polymorphism, Restriction Fragment Length</subject><subject>Receptors, Calcitriol - chemistry</subject><subject>Receptors, Calcitriol - genetics</subject><subject>Receptors, Calcitriol - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>Steroid Hydroxylases - genetics</subject><subject>steroid receptor coactivator 1</subject><subject>Transcriptional Activation</subject><subject>United States</subject><subject>vitamin D 24-hydroxylase</subject><subject>vitamin D receptor-interacting protein</subject><subject>Vitamin D3 24-Hydroxylase</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNp1kcFuEzEQhi0EoiFw44x8ope62F4nax-jFNpKBaQIuFpee1Zx2V0vtjc0T8Rr4jRBXOA0mtGnTzPzI_Sa0UvGGX3XwyWnlBPKFvwJmjElBFGK1U_RjEopiZRUnaEXKd1TysRCsufojHFBKymqGfq1wp_CDjr8ccom-zBgP-Ab6PwDZhyHFuct4G8-m77Mr_AGLIw5RHzbj8bHhNfB2Ox35nE2ZIiHtljM4PDaTAlSsUVwxRD3mF3wBbny272L4WG_-6MlG0g-ZTNkvPH2O-SEf_q8DVPGqy6MYL15iZ61pkvw6lTn6OuH91_WN-Tu8_XtenVHrFAyk0Y1DpiUlVOVgMpxJ2RNW1czZVXNl1zWjW2WrJZKcNtaaRqqhGE1dUI0S1fN0dujd4zhxwQp694nC11nBghT0kxxKmh53RxdHEEbQ0oRWj1G35cjNaP6EIzuQR-C0YdgCv7m5J2aHtxf-JREAc6PQJjG_6nISVUdSRhcsNEPMEZISd-HKQ7lN_9e4Dd-x6dP</recordid><startdate>200211</startdate><enddate>200211</enddate><creator>Malloy, Peter J</creator><creator>Xu, Rong</creator><creator>Peng, Lihong</creator><creator>Clark, Pamela A</creator><creator>Feldman, David</creator><general>Endocrine Society</general><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>200211</creationdate><title>A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia</title><author>Malloy, Peter J ; Xu, Rong ; Peng, Lihong ; Clark, Pamela A ; Feldman, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-b9bde1883d934e3d2d4870fd719c9726287bcb6178942cfc8ab094a170d44b6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Alopecia - genetics</topic><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Binding Sites</topic><topic>Calcitriol - metabolism</topic><topic>Calcitriol - pharmacology</topic><topic>Cesarean Section</topic><topic>COS Cells</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>European Continental Ancestry Group</topic><topic>Genotype</topic><topic>Humans</topic><topic>Hypophosphatemia, Familial - genetics</topic><topic>Infant, Newborn</topic><topic>Male</topic><topic>Mutation</topic><topic>Polymorphism, Restriction Fragment Length</topic><topic>Receptors, Calcitriol - chemistry</topic><topic>Receptors, Calcitriol - genetics</topic><topic>Receptors, Calcitriol - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>Steroid Hydroxylases - genetics</topic><topic>steroid receptor coactivator 1</topic><topic>Transcriptional Activation</topic><topic>United States</topic><topic>vitamin D 24-hydroxylase</topic><topic>vitamin D receptor-interacting protein</topic><topic>Vitamin D3 24-Hydroxylase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Malloy, Peter J</creatorcontrib><creatorcontrib>Xu, Rong</creatorcontrib><creatorcontrib>Peng, Lihong</creatorcontrib><creatorcontrib>Clark, Pamela A</creatorcontrib><creatorcontrib>Feldman, David</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Malloy, Peter J</au><au>Xu, Rong</au><au>Peng, Lihong</au><au>Clark, Pamela A</au><au>Feldman, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2002-11</date><risdate>2002</risdate><volume>16</volume><issue>11</issue><spage>2538</spage><epage>2546</epage><pages>2538-2546</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)2D3]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [3H]1,25-(OH)2D3 in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)2D3 or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)2D3-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>12403843</pmid><doi>10.1210/me.2002-0152</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford Journals |
| subjects | Alopecia - genetics Amino Acid Sequence Amino Acid Substitution Animals Base Sequence Binding Sites Calcitriol - metabolism Calcitriol - pharmacology Cesarean Section COS Cells Cytochrome P-450 Enzyme System - genetics European Continental Ancestry Group Genotype Humans Hypophosphatemia, Familial - genetics Infant, Newborn Male Mutation Polymorphism, Restriction Fragment Length Receptors, Calcitriol - chemistry Receptors, Calcitriol - genetics Receptors, Calcitriol - metabolism RNA, Messenger - genetics Steroid Hydroxylases - genetics steroid receptor coactivator 1 Transcriptional Activation United States vitamin D 24-hydroxylase vitamin D receptor-interacting protein Vitamin D3 24-Hydroxylase |
| title | A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia |
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