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Įtaka Patogenezei Ir Fenotipinei Išraiškai Lietuvos Populiacijoje

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Įtaka Patogenezei Ir Fenotipinei Išraiškai Lietuvos Populiacijoje VILNIAUS UNIVERSITETAS VIOLETA MIKŠTIENĖ ĮGIMTO / PAVELDIMO KLAUSOS SUTRIKIMO GENOMIKA: ĮTAKA PATOGENEZEI IR FENOTIPINEI IŠRAIŠKAI LIETUVOS POPULIACIJOJE Daktaro disertacija Biomedicinos mokslai, Medicina (06 B) Vilnius, 2017 metai 1 Disertacija rengta 2013–2017 metais Vilniaus universitete Mokslinis vadovas – prof. dr. Algirdas Utkus (Vilniaus universitetas, biomedicinos mokslai, medicina – 06 B) Mokslinė konsultantė – prof. dr. Loreta Cimbalistienė (Vilniaus universitetas, biomedicinos mokslai, medicina – 06 B) 2 TURINYS SANTRUMPOS ..................................................................................................... 6 I. ĮVADAS ............................................................................................................ 21 I.1.Tiriamoji problema, jos aktualumas .............................................................. 21 I.2.Tyrimo tikslas ................................................................................................ 23 I.3.Tyrimo uždaviniai .......................................................................................... 23 I.4.Darbo naujumas ir reikšmė ............................................................................ 23 I.5.Ginamieji teiginiai .......................................................................................... 24 I.6.Darbo aprobacija ............................................................................................ 24 II. TYRIMŲ APŽVALGA ................................................................................... 28 II.1. Klausos sutrikimo apibrėžtis ........................................................................ 28 II.2. Klausos sutrikimo klasifikacija .................................................................... 28 II.3. Klausos jutimo organų sistemos ir jos ligų tyrimų istoriniai aspektai ......... 29 II.4. Modernieji klausos sutrikimo genetiniai tyrimai ......................................... 31 II.5. Klausos jutimo organų sistemos vystymasis ............................................... 37 II.6. Garso suvokimo procesas klausos jutimo organų sistemoje........................ 40 II.7. Įgimto / ankstyvo klausos sutrikimo etiologija ............................................ 42 II.8. Paveldimo klausos sutrikimo mechanizmai ................................................. 43 II.9. Klinikiniai paveldimo klausos sutrikimo aspektai ....................................... 56 II.10. Paveldimo klausos sutrikimo genetinė diagnostika ................................... 64 II.11. Klausos sutrikimo gydymo perspektyvos .................................................. 66 II.12. Klausos sutrikimo genomikos reikšmė ...................................................... 69 III. METODAI ..................................................................................................... 70 III.1. Mokslinio tyrimo plano sudarymas ........................................................... 70 3 III.1.1. Tiriamųjų asmenų atrankos kriterijų pasirinkimas ............................... 71 III.1.2. Tiriamųjų asmenų duomenų rinkimas .................................................. 72 III.1.3. Tiriamųjų genetinio tyrimo plano sudarymas ...................................... 72 III.1.4. Duomenų analizės plano ruošimas ....................................................... 74 III.1.5. Genetinės klausos sutrikimo diagnostikos rekomendacijų rengimas ... 74 III.1.6. Mokslinė rezultatų sklaida ................................................................... 75 III.2. Empirinis tyrimas....................................................................................... 75 III.2.1. DEAFGEN biomedicininio tyrimo grupės klinikinių duomenų rinkimas .............................................................................................................. 75 III.2.2. Genetiniai tyrimai DEAFGEN tiriamųjų asmenų grupėje ................... 76 III.2.3. LITGEN tiriamųjų asmenų grupės genetinių tyrimų duomenų rinkimas .............................................................................................................. 84 III.3. Duomenų analizė ....................................................................................... 85 IV. REZULTATAI IR JŲ APTARIMAS .......................................................... 87 Lietuvos populiacijos tiriamųjų asmenų, turinčių klausos sutrikimą, grupė ....... 87 IV.1. Izoliuotą (nesindrominį) klausos sutrikimą turinčių tiriamųjų asmenų pogrupio duomenų analizės rezultatai ................................................................. 88 IV.1.1. Klinikinio ištyrimo rezultatai ............................................................... 88 IV.1.2. Genetinio tyrimo rezultatai ................................................................... 89 IV.1.3. Klausos sutrikimo etiologinė struktūra .............................................. 123 IV.1.4. Nustatytų genetinių pokyčių koreliacijos su tiriamųjų fenotipu tyrimo rezultatai ........................................................................................................ 128 IV.2. Sindrominio klausos sutrikimo pogrupio charakterizavimas .................. 135 IV.2.1. Klinikinio ištyrimo rezultatai ............................................................. 135 IV.2.2. Klausos sutrikimo etiologinė struktūra .............................................. 136 4 IV.2.3. Retas (pirmas Lietuvoje) sindrominio klausos sutrikimo atvejis ....... 141 IV.3. Genetinio tyrimo rezultatai sveikų lietuvių populiacijos asmenų grupėje (LITGEN) .......................................................................................................... 149 IV.3.1. AR paveldėjimo KS genų tyrimo rezultatai ....................................... 149 IV.3.2. XR paveldėjimo KS genų tyrimo rezultatai ....................................... 152 IV.3.3. AR paveldėjimo klausos sutrikimo dažnis lietuvių populiacijoje ...... 156 IV.4. Įgimto / paveldimo klausos sutrikimo genetinio ištyrimo gairės ............ 158 V. IŠVADOS ....................................................................................................... 166 LITERATŪRA ................................................................................................... 168 PRIEDAI ............................................................................................................. 202 5 SANTRUMPOS 1000genomes_all – 1000 genomų projekto visų tirtų populiacijų duomenys A – adeninas AAV – su adenovirusu susijęs virusas (angl. adeno-associated virus) ABR – klausos sukeltų smegenų kamieno potencialų tyrimas (angl. auditory brainstem response) ACMG – Amerikos medicinos genetikos ir genomikos kolegija (angl. American College of Medical Genetics and Genomics) ACTG1 – gama aktino genas 1 (angl. actin, gamma 1) AD – autosominis dominantinis paveldėjimas Ala – alaninas AntiGAD65 – antikūnai prieš kasos beta ląstelių glutamino rūgšties dekarboksilazę (angl. anti glutamic acid decarboxylase) Anti-IA2 – antikūnai prieš kasos beta ląstelių tirozino fosfatazę (angl. anti tyrosine phosphatase) AR – autosominis recesyvus paveldėjimas Arg – argininas Asn – asparaginas Asp – aspartatas ASSR – stabilios būsenos sukeltųjų potencialų tyrimas (angl. Auditory steady state response) Atoh1 – transkripcijos veiksnį koduojantis genas pelių genome (angl. atonal, drosophila, homolog of, 1) ATOH1 – transkripicijos veiksnys žmogaus ląstelėse (angl. atonal, drosophila, homolog of, 1) ATP – adenozino trifosfatas AUNA1 – autosominio dominantinio paveldėjimo klausos neuropatija 1 (angl. Auditory neuropathy, autosomal dominant, 1) BAM – binarinio sekoskaitos duomenų formato failas (angl. binary file format) 6 BTD – biotinidazės genas BMP – kaulų morfogenetinis baltymas (angl. bone morphogenetic protein) BOR – branchiootorenalinis sindromas Bp – bazių poros C – citozinas CATSPER2 – spermatozoidų katijonų kanalo genas 2 (angl. Cation channel, sperm-associated, 2) CCDC50 – baltymo, turinčio susisukusią spiralę, genas 50 (angl. Coiled-coil domain-containing protein 50) CDH23 – kadherinų šeimos baltymo 23 genas (angl. Cadherin-related family, member 23) CEBPE – transkripcijos veiksnys (angl. CCAAT/enhancer-binding protein, epsilon) CEACAM16 – su karcinogeniniu antigenu susijusios 16-os ląstelės adhezijos molekulės genas (angl. Carcinoembryonic antigen-related cell adhesion molecule 16) CHARGE sindromas – akies koloboma, širdies ydos, choanų atrezija, raidos atsilikimas, genitalijų anomalijos, ausų anomalijos ir (ar) kurtumas (angl. CHARGE association: coloboma of the eye; heart anomaly; atresia, choanal; retardation of mental and somatic development; microphallus; ear abnormalities and/or deafness) CHD7 – transkripcijos veiksnio genas (angl. Chromodomain helicase DNA- binding protein 7) Chr – chromosoma CHREBP (MLX) – transkripcijos veiksnys (angl. Carbohydrate response element- binding protein, rat, homolog of) CLDN14 – klaudino 14 genas (angl. Claudin 14) ClinVAR – NCBI duomenų bazė, kurioje kaupiami duomenys apie genomo variantų patogeniškumą 7 CMV – citomegaloviruso infekcija COCH – kochlino genas (angl. Cochlin) COL2A1 – 2-o tipo kolageno α1 grandinės genas (angl. Collagen, type II, alpha-1) COL4A3 – 4-o tipo kolageno α3 grandinės genas (angl. Collagen, type IV, α-3) COL4A4 – 4-o tipo kolageno α4 grandinės genas (angl. Collagen, type IV, α-4) COL4A5 – 4-o tipo kolageno α5 grandinės genas (angl. Collagen, type IV, α-5) COL11A1 – 11-o tipo kolageno α1 grandinės genas (angl. Collagen, type XI, α-1) COL11A2 - 11-o tipo kolageno α1 grandinės genas (angl. Collagen, type XI, α-2) Cys –
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