{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:36:57Z","timestamp":1762004217327},"reference-count":16,"publisher":"Wiley","issue":"S3","license":[{"start":{"date-parts":[[2010,6,3]],"date-time":"2010-06-03T00:00:00Z","timestamp":1275523200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In <jats:italic>Npc1<\/jats:italic> null mice, a model for Niemann Pick Disease Type C1, it has been reported that hepatocyte insulin receptor function is significantly impaired, consistent with growing evidence that membrane fluidity and microdomain structure have an important role in insulin signal transduction. However, whether insulin receptor function is also compromised in human Niemann Pick disease Type C1 is unclear. We now report a girl who developed progressive dementia, ataxia and opthalmoplegia from 9 years old, followed by severe acanthosis nigricans, hirsutism and acne at 11 years old. She was diagnosed with Niemann Pick Disease type C1 (OMIM#257220) based on positive filipin staining and reduced cholesterol\u2010esterifying activity in dermal fibroblasts, and homozygosity for the p.Ile1061Thr <jats:italic>NPC1<\/jats:italic> mutation. Further analysis revealed her also to be heterozygous for a novel trinucleotide deletion (c.3659\u2009+\u20091_3659\u2009+\u20093delGTG) at the end of exon 20 of <jats:italic>INSR<\/jats:italic>, encoding the insulin receptor, leading to deletion of Trp1193 in the intracellular tyrosine kinase domain. INSR mRNA and protein levels were normal in dermal fibroblasts, consistent with a primary signal transduction defect in the mutant receptor. Although the proband was significantly more insulin resistant than her father, who carried the <jats:italic>INSR<\/jats:italic> mutation but was only heterozygous for the <jats:italic>NPC1<\/jats:italic> variant, their respective degrees of IR were very similar to those previously reported in a father\u2013daughter pair with the closely related p.Trp1193Leu <jats:italic>INSR<\/jats:italic> mutation. This suggests that loss of NPC1 function, with attendant changes in membrane cholesterol composition, does not significantly modify the IR phenotype, even in the context of severely impaired INSR function.<\/jats:p>","DOI":"10.1007\/s10545-010-9107-5","type":"journal-article","created":{"date-parts":[[2010,6,2]],"date-time":"2010-06-02T15:22:42Z","timestamp":1275492162000},"page":"227-232","source":"Crossref","is-referenced-by-count":2,"title":["Loss of <i>NPC1<\/i> function in a patient with a co\u2010inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance"],"prefix":"10.1002","volume":"33","author":[{"given":"J.","family":"Kirk","sequence":"first","affiliation":[{"name":"Department of Endocrinology Birmingham Children's Hospital Steelhouse Lane Birmingham B4 6NH United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. M.","family":"Porter","sequence":"additional","affiliation":[{"name":"Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital University of Cambridge Cambridge CB2 0QQ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.","family":"Parker","sequence":"additional","affiliation":[{"name":"Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital University of Cambridge Cambridge CB2 0QQ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.","family":"Barroso","sequence":"additional","affiliation":[{"name":"The Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton Cambridge CB10 1SA United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"O'Rahilly","sequence":"additional","affiliation":[{"name":"Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital University of Cambridge Cambridge CB2 0QQ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Hendriksz","sequence":"additional","affiliation":[{"name":"Clinical Inherited Metabolic Disorders Birmingham Children's Hospital Steelhouse Lane Birmingham B4 6NH United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. K.","family":"Semple","sequence":"additional","affiliation":[{"name":"Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital University of Cambridge Cambridge CB2 0QQ UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2010,6,3]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.06.013"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00402277"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2007.09.002"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-1702"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.07.007"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1086\/302626"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000133625.73570.54"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0350033"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2544998"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0166"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.14.5217"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-13-3-566"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20050460"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.13.6.576"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-080508-141205"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/414782a"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-010-9107-5","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T06:23:56Z","timestamp":1694759036000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-010-9107-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,6,3]]},"references-count":16,"journal-issue":{"issue":"S3","published-print":{"date-parts":[[2010,12]]}},"alternative-id":["10.1007\/s10545-010-9107-5"],"URL":"https:\/\/doi.org\/10.1007\/s10545-010-9107-5","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,6,3]]}}}