{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:54:54Z","timestamp":1793040894303,"version":"4.5.0"},"reference-count":25,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>\n                           <jats:italic toggle=\"yes\">DNAJC3<\/jats:italic>, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco\u2013Sjogren and Wolcott\u2013Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in <jats:italic toggle=\"yes\">DNAJC3<\/jats:italic> was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of <jats:italic toggle=\"yes\">DNAJC3<\/jats:italic> [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms <jats:italic toggle=\"yes\">DNAJC3<\/jats:italic> as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose <jats:italic toggle=\"yes\">DNAJC3<\/jats:italic> should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.<\/jats:p>","DOI":"10.1097\/mcd.0000000000000397","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T22:41:37Z","timestamp":1634683297000},"page":"11-17","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":9,"title":["Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation"],"prefix":"10.1097","volume":"31","author":[{"given":"Sharon","family":"Ocansey","sequence":"first","affiliation":[{"name":"Medical Genetics, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Pullen","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Surrey and Sussex Healthcare NHS Trust"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Child Development Centre, Surrey Community NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Clarke","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medard","family":"Hadonou","sequence":"additional","affiliation":[{"name":"St George\u2019s Genomics Service, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlene","family":"Crosby","sequence":"additional","affiliation":[{"name":"St George\u2019s Genomics Service, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Short","sequence":"additional","affiliation":[{"name":"St George\u2019s Genomics Service, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian Christopher","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Department of Paediatric Ophthalmology, Great Ormond Street Children\u2019s Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Smedley","sequence":"additional","affiliation":[{"name":"Genomics England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albanese","family":"Assunta","sequence":"additional","affiliation":[{"name":"Department of Paediatric Endocrinology, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Genomics England Research Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratik","family":"Shah","sequence":"additional","affiliation":[{"name":"Current affiliation: Department of Paediatric Endocrinology and Diabetes, The Royal London Hospital for Children, Barts Health NHS Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriel","family":"McEntagart","sequence":"additional","affiliation":[{"name":"Medical Genetics, St George\u2019s University Hospitals NHS FT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,10,15]]},"reference":[{"key":"R1-20250524","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.bpc.2010.04.001","article-title":"Comparing the functional properties of the Hsp70 chaperones, DnaK and BiP.","volume":"149","author":"Bonomo","year":"2010","journal-title":"Biophys Chem"},{"key":"R2-20250524","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1111\/cge.13069","article-title":"Expanding the phenotype of DNAJC3 mutations: a case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration.","volume":"92","author":"Bublitz","year":"2017","journal-title":"Clin Genet"},{"key":"R3-20250524","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/ana.410130402","article-title":"Neurodegenerative diseases of infancy and childhood.","volume":"13","author":"Dyken","year":"1983","journal-title":"Ann Neurol"},{"key":"R4-20250524","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics.","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol Cell Proteomics"},{"key":"R5-20250524","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1471-2121-10-61","article-title":"Acute ablation of PERK results in ER dysfunctions followed by reduced insulin secretion and cell proliferation.","volume":"10","author":"Feng","year":"2009","journal-title":"BMC Cell Biol"},{"key":"R6-20250524","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1146\/annurev.biochem.70.1.603","article-title":"Folding of newly translated proteins in vivo: the role of molecular chaperones.","volume":"70","author":"Frydman","year":"2001","journal-title":"Annu Rev Biochem"},{"key":"R7-20250524","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1093\/genetics\/162.3.1045","article-title":"Scanning mutagenesis identifies amino acid residues essential for the in vivo activity of the Escherichia coli DnaJ (Hsp40) J-domain.","volume":"162","author":"Genevaux","year":"2002","journal-title":"Genetics"},{"key":"R8-20250524","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.ebiom.2019.03.013","article-title":"Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.","volume":"42","author":"Gregory","year":"2019","journal-title":"EBioMedicine"},{"key":"R9-20250524","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1007\/s00125-014-3230-z","article-title":"The nucleotide exchange factor SIL1 is required for glucose-stimulated insulin secretion from mouse pancreatic beta cells in vivo.","volume":"57","author":"Ittner","year":"2014","journal-title":"Diabetologia"},{"key":"R10-20250524","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1111\/j.1651-2227.2004.tb02748.x","article-title":"Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature.","volume":"93","author":"Iyer","year":"2004","journal-title":"Acta Paediatr"},{"key":"R11-20250524","first-page":"531210","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans.","author":"Karczewski","year":"2020","journal-title":"bioRxiv"},{"key":"R12-20250524","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.2337\/diabetes.49.8.1325","article-title":"Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy.","volume":"49","author":"Kassem","year":"2000","journal-title":"Diabetes"},{"key":"R13-20250524","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1515\/bmc-2018-0009","article-title":"Small heat shock proteins and neurodegeneration: recent developments.","volume":"9","author":"Kourtis","year":"2018","journal-title":"Biomol Concepts"},{"key":"R14-20250524","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.2337\/diabetes.54.4.1074","article-title":"Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK.","volume":"54","author":"Ladiges","year":"2005","journal-title":"Diabetes"},{"key":"R15-20250524","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s12079-014-0243-9","article-title":"Heat shock proteins in neurodegenerative disorders and aging.","volume":"8","author":"Leak","year":"2014","journal-title":"J Cell Commun Signal"},{"key":"R16-20250524","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1530\/EJE-20-0636","article-title":"DNAJC3 deficiency induces \u03b2-cell mitochondrial apoptosis and causes syndromic young-onset diabetes.","volume":"184","author":"Lytrivi","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"R17-20250524","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1111\/pedi.13098","article-title":"Novel insights into diabetes mellitus due to DNAJC3-defect: einvolution of neurological and endocrine phenotype in the pediatric age group.","volume":"21","author":"Ozon","year":"2020","journal-title":"Pediatr Diabetes"},{"key":"R18-20250524","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1006\/jmbi.1996.0395","article-title":"NMR structure of the J-domain and the Gly\/Phe-rich region of the Escherichia coli DnaJ chaperone.","volume":"260","author":"Pellecchia","year":"1996","journal-title":"J Mol Biol"},{"key":"R19-20250524","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1136\/archdischild-2012-302840","article-title":"Neurodegenerative disorders and metabolic disease.","volume":"98","author":"Pierre","year":"2013","journal-title":"Arch Dis Child"},{"key":"R20-20250524","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1038\/ng1678","article-title":"Mutations in SIL1 cause Marinesco-Sj\u00f6gren syndrome, a cerebellar ataxia with cataract and myopathy.","volume":"37","author":"Senderek","year":"2005","journal-title":"Nat Genet"},{"key":"R21-20250524","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S2213-8587(16)30323-0","article-title":"Hyperinsulinaemic hypoglycaemia in children and adults.","volume":"5","author":"Shah","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"R22-20250524","doi-asserted-by":"crossref","first-page":"331","DOI":"10.33549\/physiolres.933689","article-title":"Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome.","volume":"67","author":"Stanik","year":"2018","journal-title":"Physiol Res"},{"key":"R23-20250524","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.ajhg.2014.10.013","article-title":"Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.","volume":"95","author":"Synofzik","year":"2014","journal-title":"Am J Hum Genet"},{"key":"R24-20250524","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/sj.embor.7400172","article-title":"The J-protein family: modulating protein assembly, disassembly and translocation.","volume":"5","author":"Walsh","year":"2004","journal-title":"EMBO Rep"},{"key":"R25-20250524","doi-asserted-by":"crossref","first-page":"eaau6520","DOI":"10.1126\/science.aau6520","article-title":"Germline selection shapes human mitochondrial DNA diversity.","volume":"364","author":"Wei","year":"2019","journal-title":"Science (New York, N.Y.)"}],"container-title":["Clinical Dysmorphology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/MCD.0000000000000397","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:01:35Z","timestamp":1748131295000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/MCD.0000000000000397"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,15]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1097\/mcd.0000000000000397","relation":{},"ISSN":["0962-8827"],"issn-type":[{"value":"0962-8827","type":"print"}],"subject":[],"published":{"date-parts":[[2021,10,15]]}}}