Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.
Laura BryantDong LiSamuel G CoxDylan MarchioneEvan F JoinerKhadija WilsonKevin JanssenPearl LeeMichael E MarchDivya NairElliott H SherrBrieana FregeauKlaas J WierengaAlexandrea WadleyGrazia M S ManciniNina Powell-HamiltonJiddeke van de KampTheresa GrebeJohn DeanAlison RossHeather P CrawfordZoe PowisMegan T ChoMarcia C WillingLinda ManwaringRachel SchotCaroline NavaAlexandra AfenjarDavor LesselMatias WagnerFlorentine RadelfahrJuliane WinkelmannClaudia B CatarinoKyle RettererJane L SchuetteJeffrey W InnisAmy PizzinoSabine LüttgenJonas DeneckeTim M StromKristin G Monaghannull nullZuo-Fei YuanHolly DubbsRenee BendJennifer A LeeMichael J LyonsJulia HoefeleRoman GünthnerHeiko ReutterBoris KerenKelly RadtkeOmar SherbiniCameron MrokseKatherine L HelbigSylvie OdentBenjamin CogneSandra MercierStephane BezieauThomas BesnardSébastien KüryRichard RedonKarit ReinsonMonica H WojcikKatrin ÕunapPilvi IlvesA Micheil InnesKristin D Kernohannull nullGregory CostainM Stephen MeynDavid ChitayatElaine ZackaiAnna LehmanHilary Kitsonnull nullMartin G MartinJulian A Martinez-Agostonull nullStan F NelsonChristina G S PalmerJeanette C PappNeil H ParkerJanet S SinsheimerEric VilainJijun WanAmanda J YoonAllison ZhengElise BrimbleGiovanni Battista FerreroFrancesca Clementina RadioDiana CarliSabina BarresiAlfredo BruscoMarco TartagliaJennifer Muncy ThomasLuis UmanaMarjan M WeissGarrett GotwayK E StuurmanMichelle L ThompsonKirsty McWalterConstance T R M StumpelServi J C StevensAlexander P A StegmannKristian TvetenArve VølloTrine PrescottChristina FagerbergLone Walentin LaulundMartin J LarsenMelissa BylerRobert Roger LebelAnna C HurstJoy DeanSamantha A Schrier VerganoJennifer NormanSaadet Mercimek-AndrewsJuanita NeiraMargot I Van AllenNicola LongoElizabeth SellarsRaymond J LouieSara S CatheyElly BrokampDelphine HeronMolly SnyderAdeline VanderverCeleste SimonXavier de la CruzNatália PadillaJ Gage CrumpWendy ChungBenjamin GarciaHakon H HakonarsonElizabeth Joyce BhojPublished in: Science advances (2020)
Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
Keyphrases
- dna methylation
- gene expression
- end stage renal disease
- cell proliferation
- single cell
- ejection fraction
- newly diagnosed
- copy number
- peritoneal dialysis
- prognostic factors
- stem cells
- oxidative stress
- machine learning
- transcription factor
- mesenchymal stem cells
- patient reported outcomes
- cell therapy
- electronic health record
- deep learning
- big data
- bone marrow
- childhood cancer