{"id":"https://openalex.org/W4381337772","doi":"https://doi.org/10.2337/db23-1750-p","title":"1750-P: Differential Impacts of Two Novel HNF1A Variants Associated with Familial Young-Onset Diabetes on Protein Function and Insulin Secretion In Vitro","display_name":"1750-P: Differential Impacts of Two Novel HNF1A Variants Associated with Familial Young-Onset Diabetes on Protein Function and Insulin Secretion In Vitro","publication_year":2023,"publication_date":"2023-06-20","ids":{"openalex":"https://openalex.org/W4381337772","doi":"https://doi.org/10.2337/db23-1750-p"},"language":"en","primary_location":{"id":"doi:10.2337/db23-1750-p","doi":"https://doi.org/10.2337/db23-1750-p","is_oa":false,"landing_page_url":"https://doi.org/10.2337/db23-1750-p","pdf_url":null,"source":{"id":"https://openalex.org/S129060628","display_name":"Diabetes","issn_l":"0012-1797","issn":["0012-1797","1939-327X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-140","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320274","host_organization_name":"American Diabetes Association","host_organization_lineage":["https://openalex.org/P4310320274"],"host_organization_lineage_names":["American Diabetes Association"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Diabetes","raw_type":"journal-article"},"volume":null,"type":"article","indexed_in":["crossref"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5026400444","display_name":"Ines Cherkaoui","orcid":"https://orcid.org/0009-0000-3844-4932","observed_orcids":["https://orcid.org/0009-0000-3844-4932"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"INES CHERKAOUI","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5101514225","display_name":"Qian Du","orcid":"https://orcid.org/0000-0002-5074-0395","observed_orcids":["https://orcid.org/0000-0002-5074-0395"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"QIAN DU","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5056650920","display_name":"Camille Dion","orcid":"https://orcid.org/0000-0003-1299-1772","observed_orcids":["https://orcid.org/0000-0003-1299-1772"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"CAMILLE DION","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5065332242","display_name":"Harry G. Leitch","orcid":"https://orcid.org/0000-0002-3486-8962","observed_orcids":["https://orcid.org/0000-0002-3486-8962"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"HARRY LEITCH","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5088435331","display_name":"PAULINE L. CHABOSSEAU","orcid":"https://orcid.org/0000-0003-4048-0902","observed_orcids":["https://orcid.org/0000-0003-4048-0902"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"PAULINE L. CHABOSSEAU","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5052062552","display_name":"Dietrich Egli","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"DIETRICH M. EGLI","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5092383188","display_name":"Dilshad Sachedina","orcid":"https://orcid.org/0000-0002-0878-6664","observed_orcids":["https://orcid.org/0000-0002-0878-6664"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"DILSHAD SACHEDINA","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5018524091","display_name":"Jules Wastin","orcid":null,"observed_orcids":[]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"JULES WASTIN","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5028705245","display_name":"Shivani Misra","orcid":"https://orcid.org/0000-0003-2886-0726","observed_orcids":["https://orcid.org/0000-0003-2886-0726"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"SHIVANI MISRA","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5015737554","display_name":"Guy A. Rutter","orcid":"https://orcid.org/0000-0001-6360-0343","observed_orcids":["https://orcid.org/0000-0001-6360-0343"]},"institutions":[],"countries":[],"is_corresponding":false,"raw_author_name":"GUY A. RUTTER","raw_affiliation_strings":["Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Montr\u00e9al, QC, Canada, New York, NY, London, United Kingdom","institution_ids":[]}]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":0.0,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":{"value":0.13980771,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":null,"biblio":{"volume":"72","issue":"Supplement_1","first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10839","display_name":"Pancreatic function and diabetes","score":0.9901999831199646,"subfield":{"id":"https://openalex.org/subfields/2746","display_name":"Surgery"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T10839","display_name":"Pancreatic function and diabetes","score":0.9901999831199646,"subfield":{"id":"https://openalex.org/subfields/2746","display_name":"Surgery"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11171","display_name":"Diabetes and associated disorders","score":0.008299999870359898,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11642","display_name":"Genomics and Rare Diseases","score":0.00019999999494757503,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/monogenic-diabetes","display_name":"monogenic diabetes","score":0.8220000267028809},{"id":"https://openalex.org/keywords/variant-pathogenicity","display_name":"variant pathogenicity","score":0.7889999747276306},{"id":"https://openalex.org/keywords/calcium-dynamics","display_name":"calcium dynamics","score":0.675000011920929},{"id":"https://openalex.org/keywords/dna-binding","display_name":"DNA binding","score":0.5910000205039978},{"id":"https://openalex.org/keywords/transactivation-activity","display_name":"transactivation activity","score":0.7310000061988831},{"id":"https://openalex.org/keywords/nuclear-localization","display_name":"nuclear localization","score":0.8769999742507935}],"concepts":[{"id":"https://openalex.org/C126322002","wikidata":"https://www.wikidata.org/wiki/Q11180","display_name":"Internal medicine","level":1,"score":0.673388659954071},{"id":"https://openalex.org/C134018914","wikidata":"https://www.wikidata.org/wiki/Q162606","display_name":"Endocrinology","level":1,"score":0.6714461445808411},{"id":"https://openalex.org/C1292079","wikidata":"https://www.wikidata.org/wiki/Q3817769","display_name":"Transactivation","level":4,"score":0.6679990887641907},{"id":"https://openalex.org/C161600633","wikidata":"https://www.wikidata.org/wiki/Q18031867","display_name":"HNF1A","level":3,"score":0.6370625495910645},{"id":"https://openalex.org/C2779306644","wikidata":"https://www.wikidata.org/wiki/Q2002370","display_name":"Insulin","level":2,"score":0.6318168640136719},{"id":"https://openalex.org/C555293320","wikidata":"https://www.wikidata.org/wiki/Q12206","display_name":"Diabetes mellitus","level":2,"score":0.5536493062973022},{"id":"https://openalex.org/C202751555","wikidata":"https://www.wikidata.org/wiki/Q221681","display_name":"In vitro","level":2,"score":0.4897804260253906},{"id":"https://openalex.org/C107459253","wikidata":"https://www.wikidata.org/wiki/Q674925","display_name":"Induced pluripotent stem cell","level":4,"score":0.4734237492084503},{"id":"https://openalex.org/C188997412","wikidata":"https://www.wikidata.org/wiki/Q1640386","display_name":"Proband","level":4,"score":0.4471752643585205},{"id":"https://openalex.org/C501734568","wikidata":"https://www.wikidata.org/wiki/Q42918","display_name":"Mutation","level":3,"score":0.3567952513694763},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.34666678309440613},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.34536248445510864},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.30883049964904785},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.20699623227119446},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.14325934648513794},{"id":"https://openalex.org/C150194340","wikidata":"https://www.wikidata.org/wiki/Q26972","display_name":"Gene expression","level":3,"score":0.12048453092575073},{"id":"https://openalex.org/C145103041","wikidata":"https://www.wikidata.org/wiki/Q1151519","display_name":"Embryonic stem cell","level":3,"score":0.0}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.2337/db23-1750-p","doi":"https://doi.org/10.2337/db23-1750-p","is_oa":false,"landing_page_url":"https://doi.org/10.2337/db23-1750-p","pdf_url":null,"source":{"id":"https://openalex.org/S129060628","display_name":"Diabetes","issn_l":"0012-1797","issn":["0012-1797","1939-327X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-140","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320274","host_organization_name":"American Diabetes Association","host_organization_lineage":["https://openalex.org/P4310320274"],"host_organization_lineage_names":["American Diabetes Association"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Diabetes","raw_type":"journal-article"}],"best_oa_location":null,"sustainable_development_goals":[{"display_name":"Good health and well-being","id":"https://metadata.un.org/sdg/3","score":0.98580002784729}],"study_designs":[],"awards":[{"id":"https://openalex.org/G1800554090","display_name":"Genetic and nutritional control of pancreatic beta cell identity.","funder_award_id":"MR/R022259/1","funder_id":"https://openalex.org/F4320334626","funder_display_name":"Medical Research Council"},{"id":"https://openalex.org/G2021752256","display_name":"Roles of GWA genes in controlling pancreatic beta cell function and mass.","funder_award_id":"MR/K001981/1","funder_id":"https://openalex.org/F4320334626","funder_display_name":"Medical Research Council"},{"id":"https://openalex.org/G8459268062","display_name":"Roles of the type 2 diabetes (T2D)-associated gene C2cd4a in regulating glucose homeostasis in the mouse","funder_award_id":"MR/R014329/1","funder_id":"https://openalex.org/F4320334626","funder_display_name":"Medical Research Council"}],"funders":[{"id":"https://openalex.org/F4320334626","display_name":"Medical Research Council","ror":"https://ror.org/03x94j517"}],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W6945715351","https://openalex.org/W4405307880","https://openalex.org/W6991695291","https://openalex.org/W2902254549","https://openalex.org/W2948875194","https://openalex.org/W4380878292","https://openalex.org/W2937163338","https://openalex.org/W2156093494","https://openalex.org/W4388523802","https://openalex.org/W7038757243"],"abstract_inverted_index":{"Introduction:":[0],"Mutations":[1],"in":[2,18,132,150,179,198,227],"the":[3,46,50,84,222],"HNF1A":[4,26,34,40,118,121,234,282],"are":[5,12],"a":[6,31,38,124,250,271],"cause":[7],"of":[8,141,155,188,224,274,281],"monogenic":[9],"diabetes":[10],"and":[11,20,37,71,105,138],"usually":[13],"dominantly":[14],"inherited.":[15],"We":[16,43,220],"report":[17],"vitro":[19,228],"clinical":[21],"studies":[22,230],"on":[23,245],"two":[24],"novel":[25,233,272],"variants":[27],"to":[28,93,116,231,249],"determine":[29],"pathogenicity:":[30],"recessive":[32,238],"(homozygous)":[33],"variant":[35,41,52,86,235,240],"(p.A251T)":[36],"dominant":[39,251],"(p.S19L).":[42],"also":[44],"investigated":[45],"mechanisms":[47],"by":[48,110,278],"which":[49],"former":[51],"affects":[53],"insulin":[54,106,175,264],"secretion":[55,107,176,265],"using":[56,76],"beta":[57],"cells":[58,64,91,165,200,210],"derived":[59,259],"from":[60,81],"induced":[61],"pluripotent":[62],"stem":[63],"(iPSCs).":[65],"Methods:":[66],"Nuclear":[67],"localization,":[68],"DNA":[69,144],"binding,":[70],"transactivation":[72,133],"activity":[73,134],"were":[74,87,101,148,196],"examined":[75],"standard":[77,279],"techniques.":[78],"iPSC":[79,258],"lines":[80],"proband":[82,257],"carrying":[83],"p.A251T":[85,122,239],"differentiated":[88],"into":[89],"beta-like":[90],"according":[92],"Sui":[94],"et":[95],"al,":[96],"CPHG,":[97],"2018.":[98],"Ca2+":[99,194,268],"dynamics":[100],"monitored":[102],"with":[103,136,183],"Cal-520,":[104],"was":[108,169,177],"measured":[109],"homogeneous":[111],"time-resolved":[112],"fluorescence":[113],"assay":[114],"compared":[115,135,182,248],"wild-type":[117],"(WT).":[119],"Results:":[120],"showed":[123],"mild":[125,243],"(10.4%":[126],"\u00b1":[127,204,213],"7.3,":[128],"p=":[129,216],"0.16)":[130],"decrease":[131],"WT,":[137,142,156,167],"decreased":[139,178],"(48%":[140],"p=0.12)":[143],"binding.":[145],"These":[146],"reductions":[147],"significant":[149],"p.S19L":[151,252],"(DNA":[152],"binding":[153],"57%":[154],"p=0.049).":[157],"Significant":[158],"impaired":[159],"nuclear":[160],"uptake":[161],"(63%":[162],"vs":[163],"90%":[164],"for":[166,172],"p<0.0001)":[168],"only":[170],"apparent":[171],"p.S19L.":[173],"Glucose-stimulated":[174],"A251T":[180,261],"iPSCs":[181],"WT":[184],"(0.29%":[185],"vs.":[186,211],"0.46%":[187],"total":[189],"insulin).":[190],"In":[191],"contrast,":[192],"glucose-induced":[193],"increases":[195],"increased":[197],"mutant":[199],"(arbitrary":[201],"units:":[202],"7.39":[203],"1.23,":[205],"mean":[206],"+/\u2212":[207],"SD,":[208],"n=725":[209],"4.58":[212],"0.77,":[214],"n=724,":[215],"<":[217],"0.001)":[218],"Conclusion:":[219],"demonstrate":[221],"value":[223],"combining":[225],"multiple":[226],"functional":[229],"decipher":[232],"pathogenicity.":[236],"The":[237],"has":[241],"relatively":[242],"effects":[244],"protein":[246],"function":[247],"variant.":[253],"However,":[254],"when":[255],"studying":[256],"beta-cell":[260],"impairs":[262],"glucose-stimulated":[263],"despite":[266],"preserved":[267],"entry,":[269],"suggesting":[270],"mechanism":[273],"action":[275],"not":[276],"captured":[277],"tests":[280],"function.":[283],"Disclosure":[284],"I.Cherkaoui:":[285],"None.":[286,294,296,298,300,302,304,306],"G.A.Rutter:":[287],"Consultant;":[288],"Sun":[289],"Pharmaceutical":[290],"Industries":[291],"Ltd.":[292],"Q.Du:":[293],"C.Dion:":[295],"H.Leitch:":[297],"P.L.Chabosseau:":[299],"D.M.Egli:":[301],"D.Sachedina:":[303],"J.Wastin:":[305],"S.Misra:":[307],"Research":[308],"Support;":[309],"Dexcom,":[310],"Inc.":[311],"Funding":[312],"Diabetes":[313],"UK":[314]},"counts_by_year":[],"updated_date":"2026-11-03T10:50:19.383937","created_date":"2023-06-21T00:00:00"}
