{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T22:43:48Z","timestamp":1776984228486,"version":"3.51.4"},"reference-count":18,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (<jats:italic>HADH<\/jats:italic>) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). <jats:italic>HADH<\/jats:italic> encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial \u03b2-oxidation of fatty acids. Mutations in <jats:italic>GLUD1<\/jats:italic> encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with <jats:italic>HADH<\/jats:italic> mutations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>An oral leucine tolerance test was conducted in controls and nine patients with <jats:italic>HADH<\/jats:italic> mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Patients demonstrated severe HH (glucose range 1.7\u20133.2\u2009mmol\/l; insulin range 4.8-63.8\u2009mU\/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity and half maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with <jats:italic>HADH<\/jats:italic> mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with <jats:italic>GLUD1<\/jats:italic> mutations).<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1750-1172-7-25","type":"journal-article","created":{"date-parts":[[2012,5,14]],"date-time":"2012-05-14T12:16:23Z","timestamp":1336997783000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase"],"prefix":"10.1186","volume":"7","author":[{"given":"Amanda J","family":"Heslegrave","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ritika R","family":"Kapoor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Eaton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernadette","family":"Chadefaux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teoman","family":"Akcay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enver","family":"Simsek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah E","family":"Flanagan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sian","family":"Ellard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalid","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2012,5,14]]},"reference":[{"key":"383_CR1","first-page":"169","volume":"3","author":"A Agren","year":"1977","unstructured":"Agren A, Borg K, Brolin SE, Carlman J, Lundqvist G: Hydroxyacyl CoA dehydrogenase, an enzyme important in fat metabolism in different cell types in the islets of Langerhans. Diabete Metab. 1977, 3: 169-172.","journal-title":"Diabete Metab"},{"key":"383_CR2","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1210\/me.2006-0411","volume":"21","author":"OT Hardy","year":"2007","unstructured":"Hardy OT, Hohmeier HE, Becker TC, Manduchi E, Doliba NM, Gupta RK, White P, Stoeckert CJ Jr, Matschinsky FM, Newgard CB, Kaestner KH: Functional genomics of the beta-cell: short-chain 3-hydroxyacyl-coenzyme A dehydrogenase regulates insulin secretion independent of K\u2009+\u2009currents. Mol Endocrinol. 2007, 21: 765-773.","journal-title":"Mol Endocrinol"},{"key":"383_CR3","doi-asserted-by":"publisher","first-page":"21134","DOI":"10.1074\/jbc.M700083200","volume":"282","author":"GA Martens","year":"2007","unstructured":"Martens GA, Vervoort A, Van de CM, Stange G, Hellemans K, Van Thi HV, Schuit F, Pipeleers D: Specificity in beta cell expression of L-3-hydroxyacyl-CoA dehydrogenase, short chain, and potential role in down-regulating insulin release. J Biol Chem. 2007, 282: 21134-21144. 10.1074\/jbc.M700083200.","journal-title":"J Biol Chem"},{"key":"383_CR4","doi-asserted-by":"publisher","first-page":"2221","DOI":"10.1210\/jc.2009-0423","volume":"94","author":"RR Kapoor","year":"2009","unstructured":"Kapoor RR, James C, Flanagan SE, Ellard S, Eaton S, Hussain K: 3-Hydroxyacyl-coenzyme A dehydrogenase deficiency and hyperinsulinemic hypoglycemia: characterization of a novel mutation and severe dietary protein sensitivity. J Clin Endocrinol Metab. 2009, 94: 2221-2225. 10.1210\/jc.2009-0423.","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"383_CR5","doi-asserted-by":"publisher","first-page":"3724","DOI":"10.1210\/jcem.86.8.7755","volume":"86","author":"A Kelly","year":"2001","unstructured":"Kelly A, Ng D, Ferry RJ Jr, Grimberg A, Koo-McCoy S, Thornton PS, Stanley CA: Acute insulin responses to leucine in children with the hyperinsulinism\/ hyperammonemia syndrome. J Clin Endocrinol Metab. 2001, 86 (8): 3724-3728. 10.1210\/jc.86.8.3724.","journal-title":"J Clin Endocrinol Metab"},{"key":"383_CR6","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.bbrc.2007.10.188","volume":"368","author":"C Filling","year":"2008","unstructured":"Filling C, Keller B, Hirschberg D, Marschall HU, Jornvall H, Bennett MJ, Oppermann U: Role of short-chain hydroxyacyl CoA dehydrogenases in SCHAD deficiency. Biochem Biophys Res Commun. 2008, 368: 6-11. 10.1016\/j.bbrc.2007.10.188.","journal-title":"Biochem Biophys Res Commun"},{"key":"383_CR7","doi-asserted-by":"publisher","first-page":"31806","DOI":"10.1074\/jbc.M110.123638","volume":"285","author":"C Li","year":"2010","unstructured":"Li C, Chen P, Palladino A, Narayan S, Russell LK, Sayed S, Xiong G, Chen J, Stokes D, Butt YM, Jones PM, Collins HW, Cohen NA, Cohen AS, NissimI , Smith TJ, Strauss AW, Matschinsky FM, Bennett MJ, Stanley CA: Mechanism of hyperinsulinism in short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency involves activation of glutamate dehydrogenase. J Biol Chem. 2010, 285: 31806-31818. 10.1074\/jbc.M110.123638.","journal-title":"J Biol Chem"},{"key":"383_CR8","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1172\/JCI200111294","volume":"108","author":"PT Clayton","year":"2001","unstructured":"Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE: Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest. 2001, 108: 457-465.","journal-title":"J Clin Invest"},{"key":"383_CR9","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1016\/j.jpeds.2005.01.032","volume":"146","author":"K Hussain","year":"2005","unstructured":"Hussain K, Clayton PT, Krywawych S, Chatziandreou I, Mills P, Ginbey DW, Geboers AJ, Berger R, van den Berg IE, Eaton S: Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene. J Pediatr. 2005, 146: 706-708. 10.1016\/j.jpeds.2005.01.032.","journal-title":"J Pediatr"},{"key":"383_CR10","doi-asserted-by":"publisher","first-page":"E498","DOI":"10.1210\/jc.2010-1906","volume":"96","author":"SE Flanagan","year":"2011","unstructured":"Flanagan SE, Patch AM, Locke JM, Akcay T, Simsek E, Alaei M, Yekta Z, Desai M, Kapoor RR, Hussain K, Ellard S: Genome-Wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinaemic-hypoglycaemia in consanguineous pedigrees. J Clin Endocrinol Metab. 2011, 96: E498-E502. 10.1210\/jc.2010-1906.","journal-title":"J Clin Endocrinol Metab"},{"key":"383_CR11","doi-asserted-by":"publisher","first-page":"11544","DOI":"10.1021\/bi00204a017","volume":"33","author":"KO Wrzeszczynski","year":"1994","unstructured":"Wrzeszczynski KO, Colman RF: Activation of bovine liver glutamate dehydrogenase by covalent reaction of adenosine 5'-O-[S-(4-bromo-2,3-dioxobutyl)thiophosphate] with arginine-459 at an ADP regulatory site. Biochemistry. 1994, 33: 11544-11553. 10.1021\/bi00204a017.","journal-title":"Biochemistry"},{"key":"383_CR12","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976, 72: 248-254. 10.1016\/0003-2697(76)90527-3.","journal-title":"Anal Biochem"},{"key":"383_CR13","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1007\/s004390050990","volume":"104","author":"T Yorifuji","year":"1999","unstructured":"Yorifuji T, Muroi J, Uematsu A, Hiramatsu H, Momoi T: Hyperinsulinism-hyperammonemia syndrome caused by mutant glutamate dehydrogenase accompanied by novel enzyme kinetics. Hum Genet. 1999, 104: 476-479. 10.1007\/s004390050990.","journal-title":"Hum Genet"},{"key":"383_CR14","doi-asserted-by":"publisher","first-page":"667","DOI":"10.2337\/diabetes.49.4.667","volume":"49","author":"CA Stanley","year":"2000","unstructured":"Stanley CA, Fang J, Kutyna K, Hsu BY, Ming JE, Glaser B, Poncz M: Molecular basis and characterization of the hyperinsulinism\/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. Diabetes. 2000, 49: 667-673. 10.2337\/diabetes.49.4.667.","journal-title":"Diabetes"},{"key":"383_CR15","doi-asserted-by":"crossref","first-page":"13610","DOI":"10.1016\/S0021-9258(18)68285-7","volume":"263","author":"LA Fahien","year":"1988","unstructured":"Fahien LA, MacDonald MJ, Kmiotek EH, Mertz RJ, Fahien CM: Regulation of insulin release by factors that also modify glutamate dehydrogenase. J Biol Chem. 1988, 263: 13610-13614.","journal-title":"J Biol Chem"},{"key":"383_CR16","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1067\/mpd.2001.111818","volume":"138","author":"BY Hsu","year":"2001","unstructured":"Hsu BY, Kelly A, Thornton PS, Greenberg CR, Dilling LA, Stanley CA: Protein-sensitive and fasting hypoglycemia in children with the hyperinsulinism\/hyperammonemia syndrome. J Pediatr. 2001, 138: 383-389. 10.1067\/mpd.2001.111818.","journal-title":"J Pediatr"},{"key":"383_CR17","doi-asserted-by":"publisher","first-page":"E1219","DOI":"10.1152\/ajpendo.00028.2010","volume":"298","author":"JR Treberg","year":"2010","unstructured":"Treberg JR, Clow KA, Greene KA, Brosnan ME, Brosnan JT: Systemic activation of glutamate dehydrogenase increases renal ammoniagenesis: implications for the hyperinsulinism\/hyperammonemia syndrome. Am J Physiol Endocrinol Metab. 2010, 298: E1219-E1225. 10.1152\/ajpendo.00028.2010.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"383_CR18","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jpeds.2006.02.033","volume":"149","author":"SH Fourtner","year":"2006","unstructured":"Fourtner SH, Stanley CA, Kelly A: Protein-sensitive hypoglycemia without leucine sensitivity in hyperinsulinism caused by K(ATP) channel mutations. J Pediatr. 2006, 149: 47-52. 10.1016\/j.jpeds.2006.02.033.","journal-title":"J Pediatr"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1750-1172-7-25.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T19:37:21Z","timestamp":1630525041000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/1750-1172-7-25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,14]]},"references-count":18,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["383"],"URL":"https:\/\/doi.org\/10.1186\/1750-1172-7-25","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,14]]},"assertion":[{"value":"23 January 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"25"}}