{"id":2027,"date":"2018-06-27T19:26:48","date_gmt":"2018-06-27T18:26:48","guid":{"rendered":"http:\/\/slanedeti.sk\/cms\/?p=2027"},"modified":"2018-06-28T07:32:01","modified_gmt":"2018-06-28T06:32:01","slug":"cysticka-fibroza-a-genetika","status":"publish","type":"post","link":"https:\/\/slanedeti.sk\/cms\/cysticka-fibroza-a-genetika\/2027","title":{"rendered":"Cystick\u00e1 fibr\u00f3za a genetika"},"content":{"rendered":"<p><span style=\"font-weight: 400;\">Cystick\u00e1 fibr\u00f3za (CF) sa ozna\u010duje ako genetick\u00e9 ochorenie. Aby pacient mal cystick\u00fa fibr\u00f3zu mus\u00ed nevyhnutne ma\u0165 pr\u00edtomn\u00fa mut\u00e1ciu v CFTR g\u00e9ne (Cystic Fibrosis Transmembrane Regulator). Presnej\u0161ie, mus\u00ed ma\u0165 mut\u00e1cie v oboch alel\u00e1ch g\u00e9nu tak, \u017ee jednu mut\u00e1ciu zded\u00ed od jedn\u00e9ho rodi\u010da a druh\u00fa od druh\u00e9ho (mut\u00e1cie maj\u00fa ancestr\u00e1lny p\u00f4vod). CF je autozom\u00e1lne reces\u00edvne ochorenie. To znamen\u00e1, \u017ee pr\u00edtomnos\u0165 mut\u00e1cie iba v jednej alele nesp\u00f4sob\u00ed ochorenie. Jedinec s mut\u00e1ciou v jednej alele sa ozna\u010duje ako heterozygot, alebo archaicky tie\u017e ako \u201cnosi\u010d\u201c, t.j. m\u00f4\u017ee prenies\u0165 ochorenie na svoje potomstvo. Napr\u00edklad v pr\u00edpade, \u017ee m\u00e1 die\u0165a s in\u00fdm heterozygotom (nosi\u010dom). Bolo objaven\u00fdch mnoho druhov mut\u00e1cii CFTR g\u00e9nu, pri\u010dom druh mut\u00e1cie m\u00e1 vplyv na z\u00e1va\u017enos\u0165 a priebeh ochorenia \u2013 jednotliv\u00e9 mut\u00e1cie maj\u00fa r\u00f4zne klinick\u00e9 d\u00f4sledky.<\/span><\/p>\n<p>&nbsp;<\/p>\n<p><span style=\"font-weight: 400;\">Z Mendelov\u00fdch z\u00e1konov dedi\u010dnosti vypl\u00fdva \u017ee:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Heterozygot (nosi\u010d) a homozygot bez CFTR mut\u00e1ci\u00ed, bud\u00fa ma\u0165 v\u017edy zdrav\u00e9 potomstvo (nebude ma\u0165 CF)<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Pri potomstve dvoch heterozygotov (s jednou mut\u00e1ciou CFTR) je pravdepodobnos\u0165, \u017ee ka\u017ed\u00fd ich potomok bude ma\u0165 CF 25\u00a0%<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Ak by mal homozygot s dvomi CFTR mut\u00e1ciami (pacient s CF) potomstvo s homozygotom bez CFTR mut\u00e1ci\u00ed, v\u0161etci ich potomkovia bud\u00fa zdrav\u00ed (nebud\u00fa ma\u0165 CF)<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Ak by mal homozygot s dvomi CFTR mut\u00e1ciami (pacient s CF) potomstvo s heterozygotom, je pravdepodobnos\u0165 50\u00a0% pre ka\u017ed\u00e9ho ich potomka, \u017ee bude ma\u0165 CF<\/span><\/li>\n<li style=\"font-weight: 400;\"><span style=\"font-weight: 400;\">Ak by mali potomstvo dvaja homozygoti s dvomi CFTR mut\u00e1ciami (pacienti s CF) bude s pravdepodobnos\u0165ou 100\u00a0% tie\u017e ma\u0165 CF <\/span><\/li>\n<\/ul>\n<h4><b>Molekul\u00e1rna genetika a \u0161trukt\u00fara CFTR prote\u00ednu<\/b><\/h4>\n<p><a href=\"https:\/\/www.ensembl.org\/Homo_sapiens\/Gene\/Summary?db=core;g=ENSG00000001626;r=7:117465784-117715971\"><span style=\"font-weight: 400;\">G\u00e9n<\/span><\/a><span style=\"font-weight: 400;\"> sp\u00f4sobuj\u00faci CF bol objaven\u00fd v roku 1989. Jeho poloha bola ur\u010den\u00e1 na \u00faseku 7q31.3, na siedmom chromoz\u00f3me. Pomenovan\u00fd bol CFTR, pri\u010dom niekedy sa v genetick\u00fdch datab\u00e1zach pou\u017e\u00edvaj\u00fa aj synonymn\u00e9 n\u00e1zvy ABCC7, ABC35 (resp. aj niektor\u00e9 \u010fal\u0161ie). G\u00e9n je zlo\u017een\u00fd z 27 ex\u00f3nov, jeho d\u013a\u017eka je pribli\u017ene 250kb. Produktom g\u00e9nu je CFTR prote\u00edn. <\/span><\/p>\n<p><span style=\"font-weight: 400;\">CFTR je membr\u00e1nov\u00fd prote\u00edn, ktor\u00fd patr\u00ed do skupiny \u201cATP-binding cassette\u201c transmembr\u00e1nov\u00fdch transportn\u00fdch prote\u00ednov (ABC transport\u00e9rov). Jeho funkciou je medzimembr\u00e1nov\u00fd transport chloridov\u00fdch i\u00f3nov v epitelov\u00fdch bunk\u00e1ch. CFTR sa sklad\u00e1 z 1480 aminokysel\u00edn, je usporiadan\u00fd do piatich prote\u00ednov\u00fdch dom\u00e9n, pri\u010dom dve dom\u00e9ny s\u00fa transmembr\u00e1nov\u00e9 (TM1, TM2) a \u010fal\u0161ie dve sa ozna\u010duj\u00fa ako nukleotid via\u017e\u00face (NBD1, NBD2). Pre otvorenie i\u00f3nov\u00e9ho kan\u00e1lu je potrebn\u00e1 fosforyl\u00e1cia regula\u010dnej (R) dom\u00e9ny Prote\u00edn kin\u00e1zou A (PKA). Prote\u00edn kin\u00e1za A vyvol\u00e1 fosforyl\u00e1ciu naviazan\u00edm ATP, \u010do vedie k konforma\u010dn\u00fdm zmen\u00e1m CFTR prote\u00ednu. CFTR prote\u00edn je exprimovan\u00fd v tkaniv\u00e1ch, ktor\u00e9 s\u00fa typicky postihnut\u00e9 pri CF: v p\u013e\u00facach, pankrease, potn\u00fdch \u017e\u013eaz\u00e1ch, pohlavn\u00fdch org\u00e1noch. Zauj\u00edmav\u00e9 je, \u017ee CFTR je exprimovan\u00fd aj v obli\u010dk\u00e1ch, ale pri CF sa to klinicky neprejavuje. <\/span><\/p>\n<h4><b>Genetick\u00e9 vy\u0161etrenie<\/b><\/h4>\n<p><span style=\"font-weight: 400;\">Cie\u013eom genetick\u00e9ho vy\u0161etrenia je zisti\u0165 anal\u00fdzou DNA, \u010di m\u00e1 dan\u00fd jedinec h\u013eadan\u00e9 genetick\u00e9 znaky \u2013 v pr\u00edpade CF ur\u010di\u0165, \u010di m\u00e1 mut\u00e1cie v g\u00e9ne pre CFTR a o ktor\u00e9 konkr\u00e9tne mut\u00e1cie sa jedn\u00e1. Na genetick\u00fa anal\u00fdzu je potrebn\u00fd informovan\u00fd s\u00fahlas pacienta, resp. z\u00e1konn\u00e9ho z\u00e1stupcu. Za \u00fa\u010delom vy\u0161etrenia sa odoberie mal\u00e9 mno\u017estvo krvi, pr\u00edpadne je tie\u017e mo\u017en\u00e9 z\u00edska\u0165 vzorku v\u00fdplachom \u00fastnej dutiny. Tie\u017e je mo\u017en\u00e9 prenat\u00e1lne vy\u0161etrenie plodu u tehotnej \u017eeny amniocent\u00e9zou (od. 15. t\u00fd\u017ed\u0148a), alebo choriovou biopsiou (od 13. t\u00fd\u017ed\u0148a). Technika anal\u00fdzy je zalo\u017een\u00e1 na polymer\u00e1zovej re\u0165azovej reakcii (PCR) a rutinne sa vy\u0161etruj\u00fa naj\u010dastej\u0161ie mut\u00e1cie. Napr. 36 naj\u010dastej\u0161\u00edch mut\u00e1ci\u00ed v \u010cR popul\u00e1cii predstavuje 96\u00a0% v\u0161etk\u00fdch pr\u00edpadov CF. Z toho vypl\u00fdva, \u017ee be\u017en\u00e9 genetick\u00e9 diagnostick\u00e9 techniky nezachytia v\u0161etky CFTR mut\u00e1cie. V skuto\u010dnosti napr\u00edklad pri kite obsahuj\u00facom 38 celosvetovo naj\u010dastej\u0161\u00edch mut\u00e1ci\u00ed je z\u00e1chyt v \u010cR popul\u00e1cii okolo 90\u00a0% mut\u00e1ci\u00ed, ke\u010f\u017ee niektor\u00e9 mut\u00e1cie s\u00fa \u0161pecifick\u00e9 pre \u010desk\u00fa popul\u00e1ciu a tie nie s\u00fa obsiahnut\u00e9 v diagnostickom kite. Z toho sa d\u00e1 odvodi\u0165 pribli\u017ene 10\u00a0%-n\u00e1 pravdepodobnos\u0165 falo\u0161ne negat\u00edvneho v\u00fdsledku (pre ka\u017ed\u00fa mut\u00e1ciu). Na druhej strane v pr\u00edpade pozit\u00edvneho v\u00fdsledku (zistenia mut\u00e1cie v CFTR g\u00e9ne) je v\u00fdsledok spo\u013eahliv\u00fd s pravdepodobnos\u0165ou takmer 100\u00a0%. Ak nie je ur\u010den\u00e1 mut\u00e1cia a napriek tomu sa d\u00e1 predpoklada\u0165, \u017ee dan\u00e1 osoba ju m\u00e1, napr\u00edklad v pr\u00edpade, \u017ee ju genetick\u00fd test zalo\u017een\u00fd na PCR nezachytil a jedn\u00e1 sa o pacienta s klinick\u00fdmi prejavmi CF, je mo\u017en\u00e9 pr\u00edtomnos\u0165 mut\u00e1cie dok\u00e1za\u0165 sekvenovan\u00edm DNA. Be\u017ene s\u00fa tak objaven\u00e9 zriedkav\u00e9 mut\u00e1cie, ktor\u00e9 s\u00fa niekedy pop\u00edsan\u00e9 v\u00f4bec prv\u00fd kr\u00e1t. Samozrejme potenci\u00e1lnym probl\u00e9mom m\u00f4\u017ee by\u0165 falo\u0161ne negat\u00edvny v\u00fdsledok najm\u00e4 v pr\u00edpadoch, ke\u010f sa pr\u00edtomnos\u0165 CFTR mut\u00e1cie sk\u00f4r neo\u010dak\u00e1va a preto nie je d\u00f4vod na vy\u0161etrenie sekvenovan\u00edm. Ceny rutinn\u00fdch genetick\u00fdch vy\u0161etren\u00ed sa v poslednom obdob\u00ed v\u00fdrazne zn\u00ed\u017eili, aj ke\u010f napr\u00edklad pri sekvenovan\u00ed ako technicky n\u00e1ro\u010dnej\u0161ej met\u00f3de, nie s\u00fa n\u00edzke. <\/span><\/p>\n<p><span style=\"font-weight: 400;\">Genetick\u00e9 vy\u0161etrenie je \u017eiad\u00face vo viacer\u00fdch pr\u00edpadoch \u2013 spravidla sa pou\u017e\u00edva na \u00a0potvrdenie diagn\u00f3zy po pozit\u00edvnom potnom teste, resp. pozorovan\u00ed klinick\u00fdch prejavov u CF pacienta. Genetick\u00e9 vy\u0161etrenie sa odpor\u00fa\u010da v pr\u00edpade v\u00fdskytu CF aj u pr\u00edbuzn\u00fdch pacienta. Napr\u00edklad zdrav\u00fd s\u00farodenec CF pacienta m\u00e1 pravdepodobnos\u0165 50\u00a0%, \u017ee zdedil mut\u00e1ciu v CFTR g\u00e9ne a m\u00e1 teda v\u00fdrazne vy\u0161\u0161ie riziko, \u017ee jeho potomkovia bud\u00fa ma\u0165 CF, v pr\u00edpade \u017ee aj jeho partner by bol heterozygotom s CFTR mut\u00e1ciou. Anal\u00fdza DNA predstavuje obrovsk\u00fd pokrok v diagnostike, je v\u0161ak potrebn\u00e9 pam\u00e4ta\u0165 aj na niektor\u00e9 jej obmedzenia.<\/span><\/p>\n<h4><b>Popula\u010dn\u00e1 genetika<\/b><\/h4>\n<p><span style=\"font-weight: 400;\">Mut\u00e1cie CFTR g\u00e9nu s\u00fa v \u013eudskej popul\u00e1cii roz\u0161\u00edren\u00e9 dos\u0165 nerovnomerne. Zatia\u013e \u010do CF je naj\u010dastej\u0161\u00edm z\u00e1va\u017en\u00fdm genetick\u00fdm ochoren\u00edm u \u013eud\u00ed eur\u00f3pskeho p\u00f4vodu, je omnoho zriedkavej\u0161ie pri \u010diernej a \u00e1zijskej rase. V Eur\u00f3pe je nosi\u010dom g\u00e9nu pribli\u017ene ka\u017ed\u00fd 25-ty \u010dlovek, u ameri\u010danov hisp\u00e1nskeho p\u00f4vodu je pomer nosi\u010dov 1:45, u \u010dernochov 1:65 a 1:90 u \u00e1zijcov. V r\u00e1mci Eur\u00f3py je najvy\u0161\u0161\u00ed v\u00fdskyt mut\u00e1cii v CFTR g\u00e9ne v \u00cdrsku a smerom na juh kles\u00e1. Slovensko a \u010cesk\u00e1 republika s\u00fa bl\u00edzko eur\u00f3pskeho priemeru s pomerom pribli\u017ene 1:25. Bolo pop\u00edsan\u00fdch viac ako 1800 mut\u00e1cii CFTR g\u00e9nu, pri\u010dom takmer vo v\u0161etk\u00fdch popul\u00e1ci\u00e1ch je naj\u010dastej\u0161ia mut\u00e1cia F508del. Zoznam mut\u00e1ci\u00ed n\u00e1jdete v <\/span><a href=\"https:\/\/www.ensembl.org\/Homo_sapiens\/Gene\/Variation_Gene\/Table?db=core;g=ENSG00000001626;r=7:117465784-117715971\"><span style=\"font-weight: 400;\">Ensembl browseri<\/span><\/a><span style=\"font-weight: 400;\"> alebo v <\/span><a href=\"http:\/\/www.genet.sickkids.on.ca\/cftr\/Home.html\"><span style=\"font-weight: 400;\">Cystic Fibrosis Mutation Database<\/span><\/a><span style=\"font-weight: 400;\">. Zast\u00fapenie jednotliv\u00fdch mut\u00e1ci\u00ed je v jednotliv\u00fdch \u013eudsk\u00fdch popul\u00e1ci\u00e1ch rozdielne. Mnoh\u00e9 s\u00fa \u0161pecifick\u00e9 pre konkr\u00e9tne popul\u00e1cie ako napr\u00edklad mut\u00e1cia G551D pre z\u00e1padn\u00fa Eur\u00f3pu, W1282X u etnick\u00fdch \u017eidov, G542X v stredomor\u00ed. Pri niektor\u00fdch \u010fal\u0161\u00edch mut\u00e1ci\u00e1ch bol ale preuk\u00e1zan\u00fd nez\u00e1visl\u00fd p\u00f4vod a vyskytuj\u00fa sa v nepr\u00edbuzn\u00fdch popul\u00e1ci\u00e1ch, ako napr. R553X, R117H, R334W. \u00a0V Slovenskej popul\u00e1cii, podobne ako vo v\u00e4\u010d\u0161ine Eur\u00f3py dominuje mut\u00e1cia F508del. Jej zast\u00fapenie je v\u0161ak relat\u00edvne ni\u017e\u0161ie \u2013 okolo 55 %. Oproti \u010cR je ni\u017e\u0161ie zast\u00fapenie typicky slovansk\u00fdch mut\u00e1cii CFTRdele2,3, 2143delT a vy\u0161\u0161ie je zast\u00fapen\u00e1 stredomorsk\u00e1 mut\u00e1cia G542X.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Z genetick\u00e9ho v\u00fdskumu vypl\u00fdva, \u017ee jedin\u00fdm sp\u00f4sobom ako sa mohli mut\u00e1cie CFTR tak roz\u0161\u00edri\u0165 v popul\u00e1cii je, \u017ee poskytuj\u00fa (alebo v minulosti poskytovali) ur\u010dit\u00fa evolu\u010dn\u00fa v\u00fdhodu pre pre\u017eitie jedincov s jednou mut\u00e1ciou CFTR g\u00e9nu \u2013 heterozygotov. Podobn\u00fd efekt bol op\u00edsan\u00fd aj pri niektor\u00fdch \u010fal\u0161\u00edch genetick\u00fdch ochoreniach (najzn\u00e1mej\u0161ie pri kos\u00e1\u010dikovitej an\u00e9mii, kde s\u00fa heterozygoti odolnej\u0161\u00ed proti mal\u00e1rii), pri\u010dom \u010dastou heterozygotnou v\u00fdhodou v t\u00fdchto zn\u00e1mych pr\u00edpadoch je zv\u00fd\u0161en\u00e1 odolnos\u0165 vo\u010di niektor\u00fdm infek\u010dn\u00fdm ochoreniam. Bolo zisten\u00e9, \u017ee bakt\u00e9rie cholery (<\/span><i><span style=\"font-weight: 400;\">Vibrio cholerae<\/span><\/i><span style=\"font-weight: 400;\">) a bru\u0161n\u00e9ho t\u00fdfusu (<\/span><i><span style=\"font-weight: 400;\">Salmonella typhi<\/span><\/i><span style=\"font-weight: 400;\">) vyu\u017e\u00edvaj\u00fa pri infikovan\u00ed buniek CFTR prote\u00edn, \u010do viedlo k predpokladom, \u017ee heterozygoti s CFTR mut\u00e1ciou by mohli ma\u0165 zv\u00fd\u0161en\u00fa odolnos\u0165 vo\u010di t\u00fdmto ochoreniam. Tieto predpoklady neboli zatia\u013e vedecky potvrden\u00e9, naopak objavilo sa viacero te\u00f3rii o in\u00fdch zdrojoch CFTR heterozygotnej v\u00fdhody a t\u00e1to t\u00e9ma je st\u00e1le otvoren\u00e1. <\/span><\/p>\n<p><a href=\"https:\/\/slanedeti.sk\/cms\/wp-content\/uploads\/2018\/06\/DNA_2.jpg\"><img loading=\"lazy\" decoding=\"async\" class=\"aligncenter wp-image-2028 \" src=\"https:\/\/slanedeti.sk\/cms\/wp-content\/uploads\/2018\/06\/DNA_2.jpg\" alt=\"DNA2\" width=\"693\" height=\"289\" \/><\/a><\/p>\n<h4><b>Klinick\u00e1 genetika, modifikuj\u00face g\u00e9ny, lie\u010dba, g\u00e9nov\u00e1 terapia<\/b><\/h4>\n<p><span style=\"font-weight: 400;\">V r\u00e1mci CF pacientskej popul\u00e1cie s\u00fa zna\u010dn\u00e9 rozdiely v z\u00e1va\u017enosti a priebehu ochorenia, pri\u010dom podstatn\u00fd vplyv na t\u00fato variabilitu maj\u00fa genetick\u00e9 faktory \u2013 niektor\u00e9 CFTR mut\u00e1cie s\u00fa klinicky z\u00e1va\u017enej\u0161ie, resp. s\u00fa zn\u00e1me aj mut\u00e1cie CFTR g\u00e9nu, ktor\u00e9 neved\u00fa k prejavom CF. Mut\u00e1cie boli najprv rozde\u013eovan\u00e9 ako \u201cz\u00e1va\u017en\u00e9\u201c (pr\u00edznaky pankreatickej insuficiencie, ochorenia pe\u010dene, diabetes) a \u201cmierne\u201c (bez po\u0161kodenia pankreasu, atypick\u00e9 formy CF, CBAVD). Z patofyziologick\u00e9ho h\u013eadiska je d\u00f4le\u017eit\u00e9, \u010di je pri danej mut\u00e1cii \u010diasto\u010dne (rezidu\u00e1lne) zachovan\u00e1 funk\u010dnos\u0165 CFTR. Aj pacienti ktor\u00ed maj\u00fa iba jednu miernu mut\u00e1ciu maj\u00fa priaznivej\u0161\u00ed klinick\u00fd stav. Z pop\u00edsan\u00fdch mut\u00e1ci\u00ed patr\u00ed k miernym (s rezidu\u00e1lnou funkciou) iba asi 10 %. Niektor\u00e9 (zriedkav\u00e9) mut\u00e1cie CFTR g\u00e9nu neved\u00fa ku klinick\u00fdm prejavom CF, s\u00fa zn\u00e1me ako jedna z mo\u017en\u00fdch pr\u00ed\u010din mu\u017eskej neplodnosti (CBAVD \u2013 Congenital Bilateral Absence of the Vas Deferens). Mu\u017esk\u00e1 neplodnos\u0165 sa prejavuje prakticky v\u017edy aj pri z\u00e1va\u017en\u00fdch mut\u00e1ci\u00e1ch. Nesk\u00f4r bola navrhnut\u00e1 klasifik\u00e1cia mut\u00e1cii do tried, pod\u013ea toho ak\u00fd je ich patofyziologick\u00fd mechanizmus.<\/span><\/p>\n<p>&nbsp;<\/p>\n<table>\n<tbody>\n<tr>\n<td><b>Trieda<\/b><\/td>\n<td><b>Patofyziologick\u00fd defekt (pr\u00edklad)<\/b><\/td>\n<\/tr>\n<tr>\n<td><span style=\"font-weight: 400;\">I<\/span><\/td>\n<td><span style=\"font-weight: 400;\">Naru\u0161en\u00e1 synt\u00e9za CFTR prote\u00ednu, ktor\u00fd je \u00faplne nepr\u00edtomn\u00fd na apik\u00e1lnej membr\u00e1ne (G542X, R553X, R1162X, W1282X)<\/span><\/td>\n<\/tr>\n<tr>\n<td><span style=\"font-weight: 400;\">II<\/span><\/td>\n<td><span style=\"font-weight: 400;\">Abnorm\u00e1lna posttransla\u010dn\u00e1 glykozyl\u00e1cia a intracelul\u00e1rny transport, spojen\u00fd s nepr\u00edtomnos\u0165ou na apik\u00e1lnej membr\u00e1ne (F508del)<\/span><\/td>\n<\/tr>\n<tr>\n<td><span style=\"font-weight: 400;\">III<\/span><\/td>\n<td><span style=\"font-weight: 400;\">Porucha regul\u00e1cie CFTR prote\u00ednu, ktor\u00fd je pr\u00edtomn\u00fd na apik\u00e1lnej membr\u00e1ne (G551D, G551S)<\/span><\/td>\n<\/tr>\n<tr>\n<td><span style=\"font-weight: 400;\">IV<\/span><\/td>\n<td><span style=\"font-weight: 400;\">Zn\u00ed\u017een\u00e1 vodivos\u0165 chloridov\u00e9ho kan\u00e1lu s norm\u00e1lnym mno\u017estvom CFTR prote\u00ednu, ktor\u00fd je pr\u00edtomn\u00fd na apik\u00e1lnej membr\u00e1ne a zachov\u00e1va sa rezidu\u00e1lnu funkciu (R117H, R334W, R347P)<\/span><\/td>\n<\/tr>\n<tr>\n<td><span style=\"font-weight: 400;\">V<\/span><\/td>\n<td><span style=\"font-weight: 400;\">Redukovan\u00e1 synt\u00e9za, zhor\u0161en\u00fd intracelul\u00e1rny transport a zn\u00ed\u017een\u00e9 mno\u017estvo plne funk\u010dn\u00e9ho CFTR prote\u00ednu na apik\u00e1lnej membr\u00e1ne (2489+5G\u2192A, A455E)<\/span><\/td>\n<\/tr>\n<tr>\n<td><span style=\"font-weight: 400;\">VI<\/span><\/td>\n<td><span style=\"font-weight: 400;\">Zn\u00ed\u017een\u00e1 stabilita funk\u010dn\u00e9ho CFTR prote\u00ednu na apik\u00e1lnej membr\u00e1ne (N287Y, 4279insA)<\/span><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p>&nbsp;<\/p>\n<p><span style=\"font-weight: 400;\">\u010eal\u0161\u00ed genetick\u00fd v\u00fdskum uk\u00e1zal, \u017ee ani genetick\u00e1 variabilita CFTR (spolu s enviroment\u00e1lnymi faktormi) \u00faplne nevysvet\u013euje fenotypick\u00fa variabilitu a bol vysloven\u00fd predpoklad tzv. <\/span><a href=\"http:\/\/perspectivesinmedicine.cshlp.org\/content\/2\/12\/a009548.full\"><span style=\"font-weight: 400;\">CF modifikuj\u00facich g\u00e9nov<\/span><\/a><span style=\"font-weight: 400;\">. Nieko\u013eko tak\u00fdchto g\u00e9nov bolo identifikovan\u00fdch asocia\u010dn\u00fdmi genetick\u00fdmi \u0161t\u00fadiami a niektor\u00e9 \u010fal\u0161ie m\u00f4\u017eu ma\u0165 v\u00fdznam, ale ich vplyv zatia\u013e nebol jednozna\u010dne potvrden\u00fd. Jedn\u00fdm z g\u00e9nov, ktor\u00fd m\u00e1 vplyv na priebeh CF je MBL2 (Mannose Binding Lectin). MBL2 ovplyv\u0148uje imunitn\u00e9 procesy a m\u00e1 vplyv na to ako \u00faspe\u0161ne dok\u00e1\u017ee organizmus \u010deli\u0165 bakteri\u00e1lnym a v\u00edrusov\u00fdm infekci\u00e1m, ktor\u00e9 s\u00fa naj\u010dastej\u0161ou komplik\u00e1ciou CF. Zn\u00ed\u017een\u00e1 funkcia MBL2 vedie k hor\u0161ej progn\u00f3ze CF. \u00a0\u010eal\u0161\u00edm zn\u00e1mym g\u00e9nom je EDNRA (Endothelial receptor type A), ktor\u00fd ovplyv\u0148uje \u010dinnos\u0165 hladk\u00fdch svalov d\u00fdchac\u00edch ciest. G\u00e9n TGF-\u03b21 (Transforming Growth Factor \u03b21) m\u00e1 v\u00fdznam pri astme a COPD t\u00fdm, \u017ee reguluje z\u00e1pal a remodul\u00e1ciu d\u00fdchac\u00edch ciest. Viacero \u0161t\u00fadii potvrdilo, \u017ee m\u00e1 v\u00fdznam aj pri CF. G\u00e9n T2DM by mohol ma\u0165 vplyv na riziko pre rozvoj diabetu pri CF (CFRD), alebo MSRA (Methionine Sulfoxide Reductase A) pre riziko mek\u00f3niov\u00e9ho ileu. Tieto (a niektor\u00e9 \u010fal\u0161ie) vz\u0165ahy s\u00fa predmetom prebiehaj\u00faceho v\u00fdskumu. <\/span><\/p>\n<p><span style=\"font-weight: 400;\">Modern\u00e9 lieky na CF \u2013 <\/span><a href=\"https:\/\/slanedeti.sk\/cms\/kalydeco-a-orkambi-prichadzaju-do-europy\/1853\"><span style=\"font-weight: 400;\">Kalydeco, Orkambi<\/span><\/a><span style=\"font-weight: 400;\">, Symdeko \u00fa\u010dinkuj\u00fa na \u00farovni CFTR prote\u00ednu a prin\u00e1\u0161aj\u00fa kauz\u00e1lnu lie\u010dbu, ozna\u010duj\u00fa sa aj ako CFTR modul\u00e1tory. St\u00e1le v\u0161ak nie s\u00fa dostato\u010dne \u00fa\u010dinn\u00e9 na to, aby dok\u00e1zali \u00faplne odstr\u00e1ni\u0165 sympt\u00f3my CF, iba ich zmier\u0148uj\u00fa t\u00fdm, \u017ee <\/span><a href=\"https:\/\/www.jscimedcentral.com\/Pulmonology\/pulmonology-4-1038.pdf\"><span style=\"font-weight: 400;\">\u010diasto\u010dne zvy\u0161uj\u00fa funk\u010dnos\u0165 defektn\u00e9ho CFTR<\/span><\/a><span style=\"font-weight: 400;\">. Tieto lieky s\u00fa indikovan\u00e9 na z\u00e1klade pr\u00edtomnosti konkr\u00e9tnej mut\u00e1cie v CFTR g\u00e9ne. Kalydeco je ur\u010den\u00e9 pre pacientov s mut\u00e1ciami G551D, G1244E, G1349D, G178R, G551S, S1251N, S549N, S549R, R117H a Orkambi u pacientov s dvomi mut\u00e1ciami F508del. Symdeko je ur\u010den\u00e9 pre pacientov s dvomi mut\u00e1ciami F508del (rovnako ako Orkambi, najm\u00e4 v pr\u00edpade,\u017ee sa u dan\u00e9ho pacienta pri Orkambi vyskytn\u00fa ne\u017eiad\u00face \u00fa\u010dinky) a tie\u017e pre pacientov s jednou mut\u00e1ciou F508del a \u010fal\u0161ou, ktor\u00e1 je responz\u00edvna na kombin\u00e1ciu tezacaftoru a ivacaftoru. K t\u00fdmto liekom m\u00e1 v Eur\u00f3pe v s\u00fa\u010dasnosti kv\u00f4li ich vysokej cene pr\u00edstup iba mal\u00e1 \u010das\u0165 pacientov.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">G\u00e9nov\u00e1 terapia je medic\u00ednsky koncept, ktor\u00fd predpoklad\u00e1 n\u00e1hradu nefunk\u010dn\u00e9ho g\u00e9nu, v pr\u00edpade CF nahradenie mutovan\u00e9ho CFTR funk\u010dn\u00fdm g\u00e9nom v organizme pacienta. Predpoklad\u00e1 sa, \u017ee \u00a0nahradenie 5-10 % mutovan\u00fdch CFTR g\u00e9nov v p\u013e\u00facach pacienta vedie k odstr\u00e1neniu p\u013e\u00facnych klinick\u00fdch prejavov CF. Najoptimistickej\u0161\u00ed poh\u013ead bol na g\u00e9nov\u00fa terapiu okolo roku 2000, ke\u010f sa predpokladalo, \u017ee po zosekvenovan\u00ed \u013eudsk\u00e9ho gen\u00f3mu (Human Genome Project) \u00a0bude mo\u017en\u00e9 relat\u00edvne jednoducho lie\u010di\u0165 genetick\u00e9 defekty. Tejto oblasti sa n\u00e1sledne za\u010dalo venova\u0165 mno\u017estvo laborat\u00f3rnych \u0161t\u00fadii. R\u00fdchlo v\u0161ak za\u010dalo by\u0165 jasn\u00e9, \u017ee dopravenie a integr\u00e1cia funk\u010dn\u00e9ho g\u00e9nu do organizmu pacienta bude problematick\u00e1. Prv\u00e1 (2b) <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4673100\/\"><span style=\"font-weight: 400;\">klinickck\u00e1 \u0161t\u00fadia<\/span><\/a><span style=\"font-weight: 400;\"> g\u00e9novej terapie pri CF prebiehala a\u017e v roku 2012 a jej v\u00fdsledkom bolo iba ve\u013emi mierne zlep\u0161enie klinick\u00fdch parametrov. V s\u00fa\u010dasnosti g\u00e9nov\u00e1 terapia u\u017e nepatr\u00ed medzi hlavn\u00e9 oblasti v\u00fdskumu lie\u010dby CF a nepredpoklad\u00e1 sa, \u017ee by v bl\u00edzkej dobe zabezpe\u010dila spo\u013eahliv\u00fa lie\u010dbu. Ur\u010dit\u00fd rozruch a nov\u00fa n\u00e1dej priniesol v\u00fdskum g\u00e9novej technol\u00f3gie CRISPR\/Cas9 po roku 2010. \u0160t\u00fadia z roku 2013 preuk\u00e1zala, \u017ee v laborat\u00f3rnych podmienkach je mo\u017en\u00e9 vyu\u017ei\u0165 CRIPSR\/Cas9 aj na opravu CFTR g\u00e9nu a v tejto oblasti prebieha \u010fal\u0161\u00ed v\u00fdskum. Z poh\u013eadu klinick\u00e9ho \u00a0aj genetick\u00e9ho v\u00fdskumu maj\u00fa pri CF v\u00fdznam tie\u017e zvieracie modely ochorenia. Za \u00fa\u010delom \u0161t\u00fadia CF boli vytvoren\u00e9 modely CF u <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3596000\/\"><span style=\"font-weight: 400;\">my\u0161i, prasa\u0165a a fretky<\/span><\/a><span style=\"font-weight: 400;\"> \u2013 CFTR g\u00e9n bol integrovan\u00fd do gen\u00f3mu t\u00fdchto druhov pokusn\u00fdch zvierat.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Cystick&aacute; fibr&oacute;za (CF) sa ozna&#269;uje ako genetick&eacute; ochorenie. Aby pacient mal cystick&uacute; fibr&oacute;zu mus&iacute; nevyhnutne ma&#357; pr&iacute;tomn&uacute; mut&aacute;ciu v CFTR g&eacute;ne (Cystic Fibrosis Transmembrane Regulator). Presnej&scaron;ie, mus&iacute; ma&#357; mut&aacute;cie v oboch alel&aacute;ch g&eacute;nu tak, &#382;e jednu mut&aacute;ciu zded&iacute; od jedn&eacute;ho &hellip; <a href=\"https:\/\/slanedeti.sk\/cms\/cysticka-fibroza-a-genetika\/2027\">Continued<\/a><\/p>\n","protected":false},"author":7,"featured_media":2029,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"kt_blocks_editor_width":"","footnotes":""},"categories":[3,253],"tags":[],"class_list":["post-2027","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-lieky-a-liecba","category-o-cystickej-fibroze"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.4 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Cystick\u00e1 fibr\u00f3za a genetika - Slan\u00e9 deti<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/slanedeti.sk\/cms\/cysticka-fibroza-a-genetika\/2027\" \/>\n<meta property=\"og:locale\" content=\"sk_SK\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Cystick\u00e1 fibr\u00f3za a genetika - Slan\u00e9 deti\" \/>\n<meta property=\"og:description\" content=\"Cystick&aacute; fibr&oacute;za (CF) sa ozna&#269;uje ako genetick&eacute; ochorenie. Aby pacient mal cystick&uacute; fibr&oacute;zu mus&iacute; nevyhnutne ma&#357; pr&iacute;tomn&uacute; mut&aacute;ciu v CFTR g&eacute;ne (Cystic Fibrosis Transmembrane Regulator). Presnej&scaron;ie, mus&iacute; ma&#357; mut&aacute;cie v oboch alel&aacute;ch g&eacute;nu tak, &#382;e jednu mut&aacute;ciu zded&iacute; od jedn&eacute;ho &hellip; Continued\" \/>\n<meta property=\"og:url\" content=\"https:\/\/slanedeti.sk\/cms\/cysticka-fibroza-a-genetika\/2027\" \/>\n<meta property=\"og:site_name\" content=\"Slan\u00e9 deti\" \/>\n<meta property=\"article:publisher\" content=\"http:\/\/www.facebook.com\/slanedeti\" \/>\n<meta property=\"article:published_time\" content=\"2018-06-27T18:26:48+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2018-06-28T06:32:01+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/slanedeti.sk\/cms\/wp-content\/uploads\/2018\/06\/DNA_1.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"270\" \/>\n\t<meta property=\"og:image:height\" content=\"270\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Gallagher\" \/>\n<meta name=\"twitter:label1\" content=\"Autor\" \/>\n\t<meta name=\"twitter:data1\" content=\"Gallagher\" \/>\n\t<meta name=\"twitter:label2\" content=\"Predpokladan\u00fd \u010das \u010d\u00edtania\" \/>\n\t<meta name=\"twitter:data2\" content=\"13 min\u00fat\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/cysticka-fibroza-a-genetika\\\/2027#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/cysticka-fibroza-a-genetika\\\/2027\"},\"author\":{\"name\":\"Gallagher\",\"@id\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/#\\\/schema\\\/person\\\/05d1c3faf9ab837ae66dc01f490cedaa\"},\"headline\":\"Cystick\u00e1 fibr\u00f3za a genetika\",\"datePublished\":\"2018-06-27T18:26:48+00:00\",\"dateModified\":\"2018-06-28T06:32:01+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/cysticka-fibroza-a-genetika\\\/2027\"},\"wordCount\":2592,\"image\":{\"@id\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/cysticka-fibroza-a-genetika\\\/2027#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/wp-content\\\/uploads\\\/2018\\\/06\\\/DNA_1.jpg\",\"articleSection\":[\"Lieky a lie\u010dba\",\"O cystickej fibr\u00f3ze\"],\"inLanguage\":\"sk-SK\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/cysticka-fibroza-a-genetika\\\/2027\",\"url\":\"https:\\\/\\\/slanedeti.sk\\\/cms\\\/cysticka-fibroza-a-genetika\\\/2027\",\"name\":\"Cystick\u00e1 fibr\u00f3za a genetika - 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Aby pacient mal cystick&uacute; fibr&oacute;zu mus&iacute; nevyhnutne ma&#357; pr&iacute;tomn&uacute; mut&aacute;ciu v CFTR g&eacute;ne (Cystic Fibrosis Transmembrane Regulator). 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