biostudies-literatureMoulton MJUniversity of Texas Southwestern Medical CenterNIA NIH HHSNIH Office of the DirectorNIANHGRINHGRI NIH HHSBaylor College of MedicineNINDS NIH HHSNational Institutes of HealthNIH HHSNINDS101174https://www.ebi.ac.uk/biostudies/studies/S-EPMC12358889biostudies-literatureUnknown26(9)<h4>Purpose</h4>We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.<h4>Methods</h4>We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function.<h4>Results</h4>WeGenetics in medicine : official journal of the American College of Medical GeneticsDominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities.PMC12358889U01 NS134354R01 AG073260OD R24 OD022005T32 NS043124-19U01 HG007703U01 NS13454U54D083092U01 AG072439T32 NS043124R24 OD022005U54 NS093793U01 HG010215Douglas JDasari SCole FSUndiagnosed Diseases NetworkEmrick LTRios JWener MNovacic DTaylor HMalicdan MCVWorley KSutton SCunningham MJobanputra VWalker MButte MJStoler JMEzell KJean-Marie OBonner DGropman ALoo SKSeto ECoakley TRPallais JCFieg ELAtala KPapp JCBellen HJAcosta MTPosey JELanza IRRebelo ASilverman EKMiller DDayal JGJarvik GPVogel TPAdams DRKrakow DKratz LByers PMartin MGShelkowitz EFisher PGBale JFogel BLMahoney RRenteria GSinsheimer JSLanpher BCScott DAIzumi KSmith CAMcCray ATWhitlock JPhillips JAPetcharet LSweetser DAAlvey JTran AAMacnamara EFCobban LARaper ADavis JWegner DJTarakad AMarth GCogan JDMaghiro ASCBivona STabor HKWenger TGonzalez JMPusey Swerdzewski BNBejerano GJarvik JCraigen WJMight MWangler MFPak SZuchner SHisama FMBayrak-Toydemir PMartin BALongo NHayes NKetkar SRosenfeld JAMao RLiu PSullivan KMamounas LAWambach JLalani SRAlvarez RLDutta DDorrani NParker NHWise CABlue EWambach JAOrengo JPThorson WWheeler MTHing AHorike-Pyne MMartinez-Agosto JAKilich GBennett JBamshad MCorona RZhang ZTekin MEng CMD'Souza PHom JKravets EPeart LHanchard NNelson SFHalley MCSmith KSSheppeard SSybert VLatchman KDelgado MKrasnewich DMIntrone WUrv TKBohnsack JTifft CJWan JBaldridge DLewis RAHolm IASolomon BSolnica-Krezel LClark GDZheng YRodan LHAfzali BKohane ISByrd WENieves-Rodriguez SBeck AKhanshour APotocki LMoretti POxendine ICrouse ABGlass IMikati MWegner DDoss ALHutchison SRives LCoggins MLin WWAndrews AKiley DKohler JNShashi VBehrens ETan ALMBotto LAshley EABacino CAChanprasert SEckstein DJBarbouth DBriere LCQuinlan ARuzhnikov MWood HBeggs AHMarwaha SNakano-Okuno MHuang YHamid RFu JReuter CMDai HSpillmann RCGoddard PCSisco KDuker ALVanderver AGlanton EBalasubramanyam ABurrage LCMorimoto MShin JSchoch KMarom RUngar RAManolio TAToro CPace LLee BHChao HTCassini TOglesbee DHuang AGrange DKVelinder MMcConkie-Rosell AStergachis AMorava EMaduro VVYamamoto SBober MBMoulton MJViskochil DCarey JSampson JBBademci GFalk MHigh FBernstein JABerry GTBurke EABican AKobren SNLeBlanc KWalley NMRossignol FLam CRobertson AKHassey KWard PAEarl DMcGee EHubshman MWMacRae CAKaitryn ERosenthal EChinn IDoherty DMirzaa GCorner BAllworth AMaas RLLoscalzo JColley HAMulvihill JJGahl WASchedl TRao DAJayadev SKanca ODipple KNeumann SWolfe LAKorrick SRaskind WDell'Angelica ECBorja NTan QKWesterfield MWahl CESabaii MDouine EDfalseDominant missense variants in SREBF2 are associated with complex dermatological, neurological, and skeletal abnormalities.<h4>Purpose</h4>We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation.<h4>Methods</h4>We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function.<h4>Results</h4>We2024-01-01T00:00:00Z2024 Sep2026-05-29T17:08:53.635Z2026-04-08T05:28:23.759ZS-EPMC123588893884719310.1016/j.gim.2024.101174