2024
CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow
Kim A, Sakin I, Viviano S, Tuncel G, Aguilera S, Goles G, Jeffries L, Ji W, Lakhani S, Kose C, Silan F, Oner S, Kaplan O, Group M, Ergoren M, Mishra-Gorur K, Gunel M, Sag S, Temel S, Deniz E. CC2D1A causes ciliopathy, intellectual disability, heterotaxy, renal dysplasia, and abnormal CSF flow. Life Science Alliance 2024, 7: e202402708. PMID: 39168639, PMCID: PMC11339347, DOI: 10.26508/lsa.202402708.Peer-Reviewed Original ResearchConceptsDevelopmental disabilitiesIntellectual disabilityPatient-derived fibroblastsMidbrain regionsBrain developmentDefective ciliogenesisCSF circulationDisabilityCSF flowAbnormal CSF flowNervous system developmentMutant tadpolesCiliated tissuesMultiple model systemsVariant functionPronephric ductUnrelated familiesCC2D1AExpression patternsCiliogenesisRenal dysplasiaLeft-right organizerFunctional analysisDisease mechanismsBrain
2023
CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability
Deniz E, Pasha M, Guerra M, Viviano S, Ji W, Konstantino M, Jeffries L, Lakhani S, Medne L, Skraban C, Krantz I, Khokha M. CFAP45, a heterotaxy and congenital heart disease gene, affects cilia stability. Developmental Biology 2023, 499: 75-88. PMID: 37172641, PMCID: PMC10373286, DOI: 10.1016/j.ydbio.2023.04.006.Peer-Reviewed Original ResearchConceptsLeft-right organizerCilia stabilityLeft-right patterningCongenital heart disease genesApical surfaceCell apical surfaceLive confocal imagingLeftward fluid flowHeart disease genesRecessive missense mutationLethal birth defectMotile monociliaProtein familyEarly embryogenesisMulticiliated cellsCiliary axonemeDisease genesFrog embryosGenetic underpinningsWhole-exome sequencingMissense mutationsConfocal imagingEmbryosCiliaCongenital heart disease
2021
Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons
Runge K, Mathieu R, Bugeon S, Lafi S, Beurrier C, Sahu S, Schaller F, Loubat A, Herault L, Gaillard S, Pallesi-Pocachard E, Montheil A, Bosio A, Rosenfeld JA, Hudson E, Lindstrom K, Mercimek-Andrews S, Jeffries L, van Haeringen A, Vanakker O, Van Hecke A, Amrom D, Küry S, Ratner C, Jethva R, Gamble C, Jacq B, Fasano L, Santpere G, Lorente-Galdos B, Sestan N, Gelot A, Giacuzz S, Goebbels S, Represa A, Cardoso C, Cremer H, de Chevigny A. Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons. Molecular Psychiatry 2021, 26: 6125-6148. PMID: 34188164, PMCID: PMC8760061, DOI: 10.1038/s41380-021-01179-x.Peer-Reviewed Original ResearchConceptsLayer 5 neuronsKO miceForebrain glutamatergic neuronsTranscription factor NeuroD2Forebrain excitatory neuronsNeurodevelopmental disordersAutism spectrum disorderCortical projection neuronsPatch-clamp recordingsIntellectual disabilitySocial interaction deficitsSpontaneous seizuresCerebral cortexGlutamatergic neuronsSpine densityProjection neuronsIntrinsic excitabilityNervous system developmentNeuronal excitabilityExcitatory neuronsJuvenile miceBulk RNA sequencingSynaptic functionNeurobehavioral featuresDysregulated expressionExpansion of NEUROD2 phenotypes to include developmental delay without seizures
Mis EK, Sega AG, Signer RH, Cartwright T, Ji W, Martinez‐Agosto J, Nelson SF, Palmer CGS, Lee H, Mitzelfelt T, Konstantino M, Network U, Jeffries L, Khokha MK, Marco E, Martin MG, Lakhani SA. Expansion of NEUROD2 phenotypes to include developmental delay without seizures. American Journal Of Medical Genetics Part A 2021, 185: 1076-1080. PMID: 33438828, PMCID: PMC8212414, DOI: 10.1002/ajmg.a.62064.Peer-Reviewed Original ResearchConceptsDevelopmental delayEarly-onset seizuresDe novo heterozygous variantsNovo heterozygous variantsDifferentiation factor 2Xenopus laevis tadpolesHeterozygous variantsSeizuresNeuronal differentiationParental studiesFunctional testingMissense variantsPatient variantsFunctional evidenceFactor 2Vivo assaysLaevis tadpolesVariant pathogenicityFunction effectsAdolescentsVariants
2020
DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes
Marquez J, Mann N, Arana K, Deniz E, Ji W, Konstantino M, Mis EK, Deshpande C, Jeffries L, McGlynn J, Hugo H, Widmeier E, Konrad M, Tasic V, Morotti R, Baptista J, Ellard S, Lakhani SA, Hildebrandt F, Khokha MK. DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes. Journal Of Medical Genetics 2020, 58: 453-464. PMID: 32631816, PMCID: PMC7785698, DOI: 10.1136/jmedgenet-2019-106805.Peer-Reviewed Original ResearchConceptsLoss of ciliaPatient tissuesPatient variantsCongenital heart diseaseMultiple organ systemsMultiple congenital anomaliesDLG5 variantsVariety of pathologiesNephrotic syndromeHeart diseaseCongenital anomaliesRespiratory tractKidney tissueOrgan systemsCystic kidneysPatient phenotypesKidneyDiseaseLimb abnormalitiesUnrelated familiesRescue experimentsCraniofacial malformationsCilia dysfunctionTissue-specific manifestationsTissue
2018
De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy
Sega AG, Mis EK, Lindstrom K, Mercimek-Andrews S, Ji W, Cho MT, Juusola J, Konstantino M, Jeffries L, Khokha MK, Lakhani SA. De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy. Journal Of Medical Genetics 2018, 56: 113. PMID: 30323019, DOI: 10.1136/jmedgenet-2018-105322.Peer-Reviewed Original ResearchConceptsEarly infantile epileptic encephalopathyInfantile epileptic encephalopathyEpileptic encephalopathyPatient variantsDe novo pathogenic variantsNovel de novo variantNovo pathogenic variantsEarly-onset refractory seizuresDifferentiation factor 2Whole-exome sequencingNeuronal differentiation factorRefractory seizuresSignificant developmental delaySpontaneous seizuresUnderlying etiologyEctopic neuronsDe novo variantsPatient's conditionEncephalopathyPathogenic variantsSevere disordersDevelopmental delayUnrelated childrenExome sequencingGene mutations