Mustafa Khokha, MD
Professor AdjunctCards
About
Titles
Professor Adjunct
Biography
We are interested in the molecular mechanisms that cause critical illness in infants and children. We enroll patients with birth defects or other critical illness that cannot be explained by an acquired illness and perform exome sequencing in order to identify candidate genes that may explain the child's disease. Then we model the candidate gene in order to understand its function. In the context of birth defects, we employ the high-throughput human disease model, Xenopus tropicalis in which we can knockout desired genes and examine phenotypes in just three days.
Traditionally gene discovery in these patients was very challenging, but now not only is candidate gene discovery efficient but we can rapidly model the human disease and understand gene function in model organisms or patient cells.
Appointments
Obstetrics, Gynecology & Reproductive Sciences
ProfessorSecondary
Other Departments & Organizations
- Khokha Lab
- Obstetrics, Gynecology & Reproductive Sciences
- Pediatric Critical Care Transport Program
- Pediatric Genomics Discovery Program (PGDP)
- Program in Translational Biomedicine (PTB)
- Yale Center for Genomic Health
- Yale Medicine
- Yale Ventures
Education & Training
- Fellow
- Molecular & Cell Biology, University of California, Berkeley (2006)
- Fellow
- Pediatric Critical Care, University of California, San Francisco (2002)
- Resident
- Resident Pediatrics, St. Louis Children's Hospital, 1995-98 (1998)
- MD
- Northwestern University Medical School (1995)
- BS
- Northwestern University (1991)
Research
Overview
My laboratory is interested in the problem of birth defects that occur when embryonic patterning fails to occur properly. A fertilized egg must activate a complex genetic program in order to form functional adult structures. Failure to do so correctly leads to congenital malformations in children, the main cause of infant mortality in the US. We are particularly interested in cellular signals and transcriptional regulation that lead to particular fate changes that specify new tissue types during development. We are also interested in morphogenesis that provides shape to the developing embryo.
Our main approach is to analyze genes identified in infants and children that have birth defects.
We focus on Xenopus as a model system because it is the most closely related human model that is easily and rapidly manipulated. Also there are many congenital malformation genes to analyze and the low cost of Xenopus allows us to study many of these genes by engaging in high-throughput screens. Our main focus is:
- Analysis of human mutations using Xenopus We have identified a number of genes that are mutated in patients that have congenital heart disease, a failure to properly pattern the heart. We have validated a number of these genes by showing that they also cause abnormal development of frog hearts and are now analyzing the mechanisms of their development. Many of these genes are novel and identifying their mechanisms of cardiac morphogenesis will lead to new understanding of congenital malformations and the underlying developmental biology. We are looking to expand to other organ systems as well including the patterning of the face and other organ systems.
Medical Research Interests
Publications
Featured Publications
Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR
Sempou E, Kostiuk V, Zhu J, Cecilia Guerra M, Tyan L, Hwang W, Camacho-Aguilar E, Caplan M, Zenisek D, Warmflash A, Owens N, Khokha M. Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR. Nature Communications 2022, 13: 6681. PMID: 36335122, PMCID: PMC9637099, DOI: 10.1038/s41467-022-34363-w.Peer-Reviewed Original ResearchConceptsPluripotent cellsAdult tissue homeostasisCell fate commitmentDifferentiated cell fatesLeft-right patterningPluripotent embryonic cellsHuman embryonic stem cellsTemporal transcriptome analysisGene regulatory networksExpense of differentiationEmbryonic stem cellsGerm layer differentiationMembrane depolarizationFate commitmentPluripotent stateCell fateTranscriptome analysisRegulatory networksMyogenic lineageEmbryonic developmentTissue homeostasisDifferentiated fateEmbryonic cellsCandidate genesPluripotencyKap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling
Hwang WY, Kostiuk V, González DP, Lusk CP, Khokha M. Kap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling. ELife 2022, 11: e70495. PMID: 36300792, PMCID: PMC9665845, DOI: 10.7554/elife.70495.Peer-Reviewed Original ResearchConceptsNuclear transport receptorsΒ-catenin nuclear transportNuclear transportΒ-cateninExcessive WntΒ-catenin nuclear importHeterologous model systemsΒ-catenin accumulatesPrimary embryonic axisNuclear transport machineryRan-dependent mannerNuclear localization signalTCF/LEF reporterPY-NLSNuclear importLocalization signalTransport machineryTransport receptorsResponsive genesEmbryonic developmentEmbryonic axisWnt signalingKey effectorsDirect bindingHuman diseasesMechanical stretch scales centriole number to apical area via Piezo1 in multiciliated cells
Kulkarni S, Marquez J, Date P, Ventrella R, Mitchell B, Khokha M. Mechanical stretch scales centriole number to apical area via Piezo1 in multiciliated cells. ELife 2021, 10: e66076. PMID: 34184636, PMCID: PMC8270640, DOI: 10.7554/elife.66076.Peer-Reviewed Original ResearchConceptsCentriole numberMulticiliated cellsCentriole amplificationHundreds of centriolesOptimal cell functionTension-dependent mannerMechanosensitive ion channelsEmbryonic elongationOrganelle numberCell biologyNumber controlIon channelsCentriolesMost cellsPiezo1Multiple ciliaCell functionMCC functionMechanical forcesApical areaCiliaCellsPotential roleAmplificationFundamental questionsWDR5 Stabilizes Actin Architecture to Promote Multiciliated Cell Formation
Kulkarni SS, Griffin JN, Date PP, Liem KF, Khokha MK. WDR5 Stabilizes Actin Architecture to Promote Multiciliated Cell Formation. Developmental Cell 2018, 46: 595-610.e3. PMID: 30205038, PMCID: PMC6177229, DOI: 10.1016/j.devcel.2018.08.009.Peer-Reviewed Original ResearchConceptsMulticiliated cellsF-actinBasal bodiesHundreds of ciliaApical actin networkApical F-actinApical actinChromatin modificationsChromatin modifiersTissue morphogenesisActin cytoskeletonActin architectureActin networkWDR5Intracellular organellesG-actinCell surfaceCell formationCellsCytoskeletonMorphogenesisOrganellesRegulatorActinBindsRAPGEF5 Regulates Nuclear Translocation of β-Catenin
Griffin JN, del Viso F, Duncan AR, Robson A, Hwang W, Kulkarni S, Liu KJ, Khokha MK. RAPGEF5 Regulates Nuclear Translocation of β-Catenin. Developmental Cell 2017, 44: 248-260.e4. PMID: 29290587, PMCID: PMC5818985, DOI: 10.1016/j.devcel.2017.12.001.Peer-Reviewed Original ResearchConceptsLeft-right patterningNuclear transportΒ-cateninNuclear transport pathwaysΒ-catenin nuclear transportNuclear translocationRap1a/bExchange factorCytoplasmic stabilizationEmbryonic developmentNuclear localizationCanonical WntRAPGEF5WntPathway activationNew targetsTransport pathwaysTranslocationPatterningDisease statesTransport systemGTPasesIntensive investigationGuanineCommon diseaseCongenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia
del Viso F, Huang F, Myers J, Chalfant M, Zhang Y, Reza N, Bewersdorf J, Lusk CP, Khokha MK. Congenital Heart Disease Genetics Uncovers Context-Dependent Organization and Function of Nucleoporins at Cilia. Developmental Cell 2016, 38: 478-492. PMID: 27593162, PMCID: PMC5021619, DOI: 10.1016/j.devcel.2016.08.002.Peer-Reviewed Original ResearchConceptsNuclear pore complexPore complexCiliary pore complexLeft-right patterningBarrel-like structureNPC functionEmbryonic developmentCandidate genesNup188Human genomicsNanoscale organizationNucleoporinsDirect roleSuper-resolution imagingCiliaLoss of ciliaNup93GenomicsComplexesGenesKnockdownDuplicationPatterningMechanismThe heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality
Boskovski MT, Yuan S, Pedersen NB, Goth CK, Makova S, Clausen H, Brueckner M, Khokha MK. The heterotaxy gene GALNT11 glycosylates Notch to orchestrate cilia type and laterality. Nature 2013, 504: 456-459. PMID: 24226769, PMCID: PMC3869867, DOI: 10.1038/nature12723.Peer-Reviewed Original Research
2025
CACNA1G, A Heterotaxy Candidate Gene, Plays a Role in Ciliogenesis and Left‐Right Patterning in Xenopus tropicalis
Kostiuk V, Kabir R, Akbari R, Rushing A, González D, Kim A, Kim A, Zenisek D, Khokha M. CACNA1G, A Heterotaxy Candidate Gene, Plays a Role in Ciliogenesis and Left‐Right Patterning in Xenopus tropicalis. Genesis 2025, 63: e70009. PMID: 40008628, PMCID: PMC11867209, DOI: 10.1002/dvg.70009.Peer-Reviewed Original ResearchConceptsCongenital heart diseaseCACNA1GLow-voltage-activated calcium channelsExpression of Cacna1gCalcium channelsPatient cohortCardiac functionLR patterningHeterotaxyLR organizerChannel familyCACNA1SHeart diseaseLeft-rightG expressionXenopus tropicalisAbnormal expressionProcess of cilia formationCardiac loopingMultiple organsSignaling cascadesLR asymmetryPatientsT-typeEmbryonic developmentNup107 contributes to the maternal-to-zygotic transition by preventing the premature nuclear export of pri-miR427
Kostiuk V, Kabir R, Levangie K, Empke S, Morgan K, Owens N, Lusk C, Khokha M. Nup107 contributes to the maternal-to-zygotic transition by preventing the premature nuclear export of pri-miR427. Development 2025, 152: dev202865. PMID: 39791357, PMCID: PMC11829755, DOI: 10.1242/dev.202865.Peer-Reviewed Original ResearchConceptsMaternal transcriptsMaternal-to-zygotic transitionMaternal RNA clearanceZinc-finger transcription factorDegradation of maternal transcriptsEctodermal cell fatesMaternal-zygotic transitionNuclear pore complexNucleoporin functionZygotic transcriptionNuclear exportTranscript stabilityCell fateNuclear retentionTranscription factorsPore complexNup107TranscriptionEarly embryosRecognition sitesRNA clearanceGastrulationGerm layersTime courseThe Alia Camel of Jordan: a genetically distinct dromedary breed
Haddad N, Al-Araishi M, Awabdeh S, Patidar R, Bell R, Jawasreh K, Alhurani H, Elharbid L, Sweidan R, Al-Anaswah E, Brake M, Sadder M, Blanco O, Sbeih L, Uduman M, Lakhani S, Khokha M, Weir A. The Alia Camel of Jordan: a genetically distinct dromedary breed. Journal Of Heredity 2025, esae076. PMID: 39761336, DOI: 10.1093/jhered/esae076.Peer-Reviewed Original Research
Clinical Trials
Current Trials
Pediatric Genomics Discovery Program (PGDP)
HIC ID1411014977RolePrincipal InvestigatorPrimary Completion Date12/31/2023Recruiting ParticipantsGenderBoth
Academic Achievements & Community Involvement
Clinical Care
Overview
When he began his career as a pediatrician, Mustafa Khokha, MD, remembers treating many newborns and infants suffering from infections. He finds it notable that developments in the medical field have evolved to the point where such infections have now become quite rare. For example, where some of his tiny patients used to suffer from meningococcemia, a blood infection caused by bacteria, vaccines have largely stopped these bacterial illnesses. Pneumonia and septic shock cases are also on the decline, he says. “What’s striking to me now is the different kinds of cases I deal with today,” notes Dr. Khokha.
Now, as a physician-researcher specializing in developmental biology, Dr. Khokha is interested in birth defects and identifying the genes that may cause them. “I get great satisfaction from telling parents and their children about the research we’ve done with genetic sequencing to understand why their child is sick. This is something we could not have done even a few years ago.” In addition to running a laboratory, Dr. Khokha is director of the Pediatric Genomics Discovery Program. This program enlists a team of experts to study young patients with unknown or undiagnosed diseases, with the goal of identifying the cause of each of these mysterious conditions.
At Yale School of Medicine, Dr. Khokha is professor of critical care pediatrics and of genetics and Director of the Pediatric Genomics Discovery Program.
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Media
- Multiciliated cell as a model for ciliopathies from Xenopus (frog) embryonic epidermis.
- Secondary axis induced by the overexpression of Wnt signal in the Xenopus embryo
News
- September 10, 2024
NIH Recognizes Yale’s Expertise in the Genetics of Rare Diseases
- September 15, 2023
Mitochondrial Function: Beyond Serving as the ‘Powerhouse of the Cell’
- May 22, 2023
Racing to solve rare diseases
- April 05, 2022
100 Years of Pediatrics at Yale
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Contacts
Pediatric Critical Care Medicine
PO Box 208064
New Haven, CT 06520-8064
United States
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Locations
Khokha Lab
Lab
Laboratory for Surgery, Obsterics & Gynecology
375 Congress Avenue, Ste LSOG 402
New Haven, CT 06519
Appointments
203.785.2333Office - Mustafa Khokha
Academic Office
Laboratory for Surgery, Obsterics & Gynecology
375 Congress Avenue, Ste LSOG 405C
New Haven, CT 06519
Appointments
203.785.4650Patient Care Locations
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