2025
TP53‐Mutated Acute Myeloid Leukemia and Blast Phase Myeloproliferative Neoplasm: Distinct Mutation Leads to Poorer Prognosis
Chen D, Cantu M, Siddon A, Weinberg O. TP53‐Mutated Acute Myeloid Leukemia and Blast Phase Myeloproliferative Neoplasm: Distinct Mutation Leads to Poorer Prognosis. European Journal Of Haematology 2025, 115: 57-63. PMID: 40152319, PMCID: PMC12134709, DOI: 10.1111/ejh.14421.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaTP53-mutated acute myeloid leukemiaBlast phase myeloproliferative neoplasmsTP53 mutationsClinical outcomesMPN-BPMyeloproliferative neoplasmsMyeloid leukemiaAssociated with prognostic significanceMissense mutationsLow-risk groupSplice site variantOverall survivalAssociated with relatively better prognosisMyeloid neoplasmsPrognostic significanceBetter prognosisTP53 mutantsTherapeutic responseRisk stratificationRetrospective analysisExon 5TP53Exon 6Poorer PrognosisLILRB3 genetic variation is associated with kidney transplant failure in African American recipients
Sun Z, Yi Z, Wei C, Wang W, Ren T, Cravedi P, Tedla F, Ward S, Azeloglu E, Schrider D, Li Y, Khan A, Zanoni F, Fu J, Ali S, Liu S, Liang D, Liu T, Li H, Xi C, Vy T, Mosoyan G, Sun Q, Kumar A, Zhang Z, Farouk S, Campell K, Ochando J, Lee K, Coca S, Xiang J, Connolly P, Gallon L, O’Connell P, Colvin R, Menon M, Nadkarni G, He J, Kraft M, Jiang X, Zhang X, Kiryluk K, Cherukuri A, Lakkis F, Zhang W, Chen S, Heeger P, Zhang W. LILRB3 genetic variation is associated with kidney transplant failure in African American recipients. Nature Medicine 2025, 31: 1677-1687. PMID: 40065170, DOI: 10.1038/s41591-025-03568-z.Peer-Reviewed Original ResearchSingle-nucelotide polymorphismsAssociated with death-censored graft lossDeath-censored graft lossGenetic variationGraft lossImmunoreceptor tyrosine-based inhibitory motifTyrosine-based inhibitory motifAA individualsApolipoprotein L1Rate of graft lossEnd-stage renal diseaseMissense mutationsInhibitory motifRNA sequencingKidney transplant outcomesKidney transplant failureMultiomics analysisImmune-related diseasesAmino acidsAfrican American recipientsTransplant cohortTransplant failureTransplant outcomesAnalysis of bloodProspective studyIntegrating epidemiology and genomics data to estimate the prevalence of acquired cysteine drug targets in the U.S. cancer patient population
Arun A, Liarakos D, Mendiratta G, Kim J, Goshua G, Olson P, Stites E. Integrating epidemiology and genomics data to estimate the prevalence of acquired cysteine drug targets in the U.S. cancer patient population. The Pharmacogenomics Journal 2025, 25: 5. PMID: 40044654, DOI: 10.1038/s41397-025-00364-3.Peer-Reviewed Original ResearchConceptsGenomic dataEstimates of mutation ratesSomatic missense mutationsGenomic informationPopulation-level estimatesCancer patient populationMissense mutationsNon-epidemiologicallyCancer patientsMutation ratePathogenic mutationsCysteine residuesCancer epidemiologyMutation-specificMutation abundanceDrug targetsMutationsIntegrates epidemiologyAbundancePatient populationEpidemiologyGenomePopulationTargeted therapyResidues
2024
Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation
Guerriero C, Carattino M, Sharp K, Kantz L, Gresko N, Caplan M, Brodsky J. Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation. American Journal Of Physiology - Cell Physiology 2024, 328: c483-c499. PMID: 39714991, PMCID: PMC12168846, DOI: 10.1152/ajpcell.00776.2024.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulum-associated degradationPolycystin-2Autosomal dominant polycystic kidney diseaseEndoplasmic reticulum-associated degradation pathwayMissense mutationsGrowth of yeast strainsDisease-causing missense mutationsDisease-associated mutantsProteasome-dependent degradationHEK293 cellsConsistent with defectsDisease-linked mutationsHEK293 cell modelYeast modelYeast systemYeast strainsGenetic systemTreat autosomal dominant polycystic kidney diseaseMissense variantsProtein misfoldingProtein foldingCellular processesIncreased polyubiquitinationMisfolding phenotypeChemical chaperonesTP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates.
Santini V, Stahl M, Sallman D. TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates. American Society Of Clinical Oncology Educational Book 2024, 44: e432650. PMID: 38768424, DOI: 10.1200/edbk_432650.Peer-Reviewed Original ResearchConceptsMissense mutationsResistant to current chemotherapyLoss-of-function effectPhase II trialPhase III trialsAnti-CD47 antibodyAnti-CD123 antibodyResponse to treatmentPressure of chemotherapyApoptosis systemP53 functionChromosome lossTP53 mutationsTruncating mutationsInhibitor therapyMyelodysplastic syndromeOverall survivalII trialIII trialsSelection pressureAnti-CD123Acute leukemiaAML casesDismal diseaseImproved survival
2023
Therapeutic developments for valosin-containing protein mediated multisystem proteinopathy
Boock V, Roy B, Pfeffer G, Kimonis V. Therapeutic developments for valosin-containing protein mediated multisystem proteinopathy. Current Opinion In Neurology 2023, 36: 432-440. PMID: 37678339, DOI: 10.1097/wco.0000000000001184.Peer-Reviewed Original ResearchConceptsInclusion body myopathyPotential therapeutic targetValosin-containing proteinPaget's diseasePreclinical modelsTherapeutic approachesPotential therapyControl trialRare diseaseTherapeutic targetBody myopathyVivo modelFrontotemporal dementiaVCP mutationsMultisystem proteinopathyPathway involvementDiseaseTherapyMitochondrial dysfunctionTherapeutic developmentGene therapyMissense mutationsFunction activityATPase activityRCTsSearch of a genomic sequence database for potential novel blood group antigens: Investigation into why some amino acid substitutions are not immunogenic
Howe J, Stack G. Search of a genomic sequence database for potential novel blood group antigens: Investigation into why some amino acid substitutions are not immunogenic. Transfusion 2023, 63: 1399-1411. PMID: 37386886, DOI: 10.1111/trf.17459.Peer-Reviewed Original ResearchConceptsBlood group antigensGroup antigensB-cell epitopesGenomic sequence databasesLinear B-cell epitopesLow prevalenceSequence databasesAtypical chemokine receptor 1Chemokine receptor 1New blood group antigensExtracellular domainHuman genome sequence databaseMissense mutationsGenome sequence databaseEpitope prediction programsTransfusion practiceProtein structural analysisPoor immunogenicityAmino acid substitutionsReceptor 1Phenotype prevalenceAntigenStudy designBlood groupPrevalenceCFAP45, 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
2022
A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease
Khamirani H, Palicharla VR, Dastgheib SA, Dianatpour M, Imanieh MH, Tabei SS, Besse W, Mukhopadhyay S, Liem KF. A pathogenic variant of TULP3 causes renal and hepatic fibrocystic disease. Frontiers In Genetics 2022, 13: 1021037. PMID: 36276950, PMCID: PMC9585244, DOI: 10.3389/fgene.2022.1021037.Peer-Reviewed Original ResearchTubby-like protein 3Tubby domainPatient variantsC-terminal tubby domainAssociate with phosphoinositidesRecessive deleterious mutationsMembrane-associated proteinsInner medullary collecting duct 3 cellsDuct 3 cellsHomozygous missense mutationConserved domainsProtein traffickingIntraflagellar transportTrafficking proteinsDeleterious mutationsPatient mutationsCritical residuesMissense mutationsTULP3Pathogenic variantsLike protein 3Phenotypic spectrumMutationsCiliary dysfunctionProtein 3A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family
Gauhar Z, Tejwani L, Abdullah U, Saeed S, Shafique S, Badshah M, Choi J, Dong W, Nelson-Williams C, Lifton RP, Lim J, Raja GK. A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family. Cells 2022, 11: 3090. PMID: 36231052, PMCID: PMC9564319, DOI: 10.3390/cells11193090.Peer-Reviewed Original ResearchConceptsAutosomal recessive cerebellar ataxiaCerebellar ataxiaProgressive gait ataxiaMagnetic resonance imagingT mutationHeterogeneous rare disordersNovel homozygous missense mutationWhole-exome sequencingMissense mutationsGait ataxiaMovement disordersDifferential diagnosisRare disorderCerebellar atrophyHomozygous missense mutationConsanguineous Pakistani familyNovel missense mutationResonance imagingBody imbalanceExome sequencingYoung adultsHomozygous mutationPakistani familyAtaxiaType ABRCA2 BRC missense variants disrupt RAD51-dependent DNA repair
Jimenez-Sainz J, Mathew J, Moore G, Lahiri S, Garbarino J, Eder JP, Rothenberg E, Jensen RB. BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair. ELife 2022, 11: e79183. PMID: 36098506, PMCID: PMC9545528, DOI: 10.7554/elife.79183.Peer-Reviewed Original ResearchConceptsHomology-directed repairDNA double-strand breaksFork protectionReplication fork protectionRad51 nucleoprotein filamentsMissense mutationsSingle amino acid substitutionRad51-ssDNA complexesDouble-strand breaksUnknown functional consequencesBRCA2 VUSAmino acid substitutionsGenome stabilityNucleoprotein filamentDNA repairRepeat regionSpacer regionBRCA2 proteinBenign allelesCellular responsesAcid substitutionsFunctional consequencesFrameshift mutationGene predisposeBRC2Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM
Tuysuz B, Department of Pediatric Genetics I, Sencicek A, Ozer E, Goc N, Yalcinkaya C, Bilguvar K, Department of Neurosurgery P, Department of Neurology I. Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM. Turkish Archives Of Pediatrics 2022, 57: 521-525. PMID: 35950747, PMCID: PMC9524456, DOI: 10.5152/turkarchpediatr.2022.22070.Peer-Reviewed Original ResearchWhole-exome sequencingL1 syndromeSevere phenotypeMissense mutationsHemizygous missense mutationClinical characteristicsDifferential diagnosisIndex patientsPatientsCarrier mothersPathogenic missense mutationsMale childrenL1CAM mutationsPathogenic variantsMild formHydrocephalusSpeech delaySyndromeExon 18Truncating mutationsGenetic etiologyIntellectual disabilityL1CAML1CAM geneFamily membersDe novo mutations in the BMP signaling pathway in lambdoid craniosynostosis
Timberlake AT, Kiziltug E, Jin SC, Nelson-Williams C, Loring E, Allocco A, Marlier A, Banka S, Stuart H, Passos-Buenos M, Rosa R, Rogatto S, Tonne E, Stiegler A, Boggon T, Alperovich M, Steinbacher D, Staffenberg D, Flores R, Persing J, Kahle K, Lifton R. De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. Human Genetics 2022, 142: 21-32. PMID: 35997807, DOI: 10.1007/s00439-022-02477-2.Peer-Reviewed Original ResearchConceptsDe novo mutationsDamaging de novo mutationsSingle-cell RNA sequencing analysisTranscriptional co-repressorTarget sequence recognitionRNA sequencing analysisTranscription factor NfixNovo mutationsEnrichment of mutationsBMP receptorsCo-repressorParent-offspring triosTranscription factorsGenetic gainImplicating perturbationsOsteoblast precursorsPremature suture fusionSequencing analysisMolecular etiologySequence recognitionMissense mutationsMutationsExome sequencingGenetic etiologyOsteoprogenitor cellsComplex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder
Grosso B, Kramer A, Tyagi S, Bennett D, Tifft C, D’Souza P, Wangler M, Macnamara E, Meza U, Bannister R. Complex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder. Scientific Reports 2022, 12: 9186. PMID: 35655070, PMCID: PMC9163077, DOI: 10.1038/s41598-022-12789-y.Peer-Reviewed Original ResearchConceptsCongenital ataxiaQ-type Ca2Function mutationsSevere neurodevelopmental disorderTsA-201 cellsCerebral edemaFocal seizuresCaV2.1 channelsCentral synapsesChannel dysfunctionNeurological disordersNeuromuscular junctionCACNA1A variantsNeurotransmitter releaseΑ1A subunitAction potential-like stimuliReversal potentialNeurodevelopmental disordersComplex functional effectsFunctional effectsDisordersAtaxiaMissense mutationsCa2Channel gatingConformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants
Kots E, Mlynarczyk C, Melnick A, Khelashvili G. Conformational transitions in BTG1 antiproliferative protein and their modulation by disease mutants. Biophysical Journal 2022, 121: 3753-3764. PMID: 35459639, PMCID: PMC9617077, DOI: 10.1016/j.bpj.2022.04.023.Peer-Reviewed Original ResearchConceptsB-cell translocation gene 1Antiproliferative proteinAssociate with transcriptional cofactorsFamily of antiproliferative proteinsWild-typeFunctional interactionsDisease-linked mutationsSomatic missense mutationsCell cycle progressionMarkov state model analysisConformational transitionBinding partnersTranscriptional cofactorCellular partnersCellular processesProtein regionsDisease mutantsMissense mutationsCycle progressionBinding hotspotsBinding proteinFunctional associationEnsemble of conformationsMolecular mechanismsA2-A4Lymphocyte Cytosolic Protein 1 (L-plastin) I232F Mutation Impairs Granulocytic Proliferation and Causes Neutropenia
Mahat U, Garg B, Yang CY, Mehta H, Hanna R, Rogers HJ, Flagg A, Ivanov AI, Corey SJ. Lymphocyte Cytosolic Protein 1 (L-plastin) I232F Mutation Impairs Granulocytic Proliferation and Causes Neutropenia. Blood Advances 2022, 6: 2581-2594. PMID: 34991157, PMCID: PMC9043934, DOI: 10.1182/bloodadvances.2021006398.Peer-Reviewed Original ResearchConceptsLymphocyte cytosolic protein 1Impaired cell motilityDiffuse intracellular localizationUnfolded protein responseCytosolic protein 1Level of genesCell cycle arrestActin regulationG2/M phaseNew genesActin cytoskeletonActin dynamicsCell motilityProtein responseSubcellular fractionationMutant formsF-actinIntracellular localizationWhole-exome sequencingCycle arrestHeLa cellsMissense mutationsHeterozygous missense mutationM phaseLCP1A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism
Fadiga L, Lavrador M, Vicente N, Barros L, Gonçalves C, Al-Naama A, Saraiva L, Lemos M. A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism. International Journal Of Molecular Sciences 2022, 23: 4423. PMID: 35457241, PMCID: PMC9026826, DOI: 10.3390/ijms23084423.Peer-Reviewed Original ResearchConceptsCongenital hypogonadotropic hypogonadismMissense mutationsFibroblast growth factor receptor 1Sequence-based prediction methodsPathogenesis of CHHFailure of pubertal developmentIdentified missense mutationsFibroblast growth factor receptor 1 geneHypogonadotropic hypogonadismWhole-exome sequencingNormosmic congenital hypogonadotropic hypogonadismHeterozygous missense mutationExome sequencingGenetic studiesGrowth factor receptor 1Mutation spectrumFibroblast growth factor receptor 1 proteinIncomplete penetranceGonadotropin-releasing hormoneReproductive endocrine disordersAffected siblingsAmino acidsMutationsGenetic defectsGenesBiallelic BICD2 variant is a novel candidate for Cohen-like syndrome
Caglayan AO, Tuysuz B, Gül E, Alkaya DU, Yalcinkaya C, Gleeson JG, Bilguvar K, Gunel M. Biallelic BICD2 variant is a novel candidate for Cohen-like syndrome. Journal Of Human Genetics 2022, 67: 553-556. PMID: 35338243, PMCID: PMC9420744, DOI: 10.1038/s10038-022-01032-1.Peer-Reviewed Original ResearchConceptsWhole-exome sequencing analysisTruncal obesityJoint hypermobilityLower extremitiesHomozygous missense mutationSevere formBICD2 mutationsType 2BHeterozygous mutationsSpeech delayType 2AIntellectual disabilityPatientsSyndromeConsanguineous unionsMissense mutationsNovel candidatesSequencing analysisFirst reportMutationsDominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis
Cornière N, Thomson RB, Thauvin S, Villoutreix BO, Karp S, Dynia DW, Burlein S, Brinkmann L, Badreddine A, Dechaume A, Derhourhi M, Durand E, Vaillant E, Froguel P, Chambrey R, Aronson PS, Bonnefond A, Eladari D. Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis. Journal Of Medical Genetics 2022, 59: 1035-1043. PMID: 35115415, PMCID: PMC9346097, DOI: 10.1136/jmedgenet-2021-108256.Peer-Reviewed Original ResearchConceptsRare heterozygous missense mutationsWild-type proteinStrong dominant-negative effectDominant negative effectDominant negative mutationMembrane surface expressionOxalate transporter SLC26A6Calcium oxalate nephrolithiasisCotransfection studiesOxalate transporterSilico analysisNegative mutationTransport activityMissense mutationsHeterozygous missense mutationEnteric hyperoxaluriaComplex multifactorial diseaseMutationsOxalate nephrolithiasisHuman populationSurface expressionCell culturesUrinary oxalate excretionMajor risk factorGenetic factorsA novel c.1937T>C (p.Leu646Pro) missense mutation in a patient with Leber congenital amaurosis
Kaur S, Sukhija J, Kaur A, Srivastava P, Katoch D, Singh S, Chaudhary K. A novel c.1937T>C (p.Leu646Pro) missense mutation in a patient with Leber congenital amaurosis. Journal Of American Association For Pediatric Ophthalmology And Strabismus 2022, 26: 34-35. PMID: 35101627, DOI: 10.1016/j.jaapos.2021.08.300.Peer-Reviewed Original ResearchConceptsLeber congenital amaurosisCongenital amaurosisComprehensive genotype-phenotype correlationMissense mutationsSluggish pupillary reactionInherited Retinal DystrophiesGenotype-phenotype correlationNormal fundusRetinal dystrophyTyrosine kinase domainGUCY2D geneExon 9Pupillary reactionExome sequencingPatientsLow visionAmaurosisLeberMutationsGenetic studiesHyperopiaGUCY2DKinase domainFundusNystagmus
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