Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications
Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor...
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Інститут молекулярної біології і генетики НАН України
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nasplib_isofts_kiev_ua-123456789-1568732025-02-09T15:01:12Z Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications Orlovsky, M.A. Reviews Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism. Keywords: glucocorticoid receptors, allelic polymorphism, SNP, NR3C1, GR, stress-induced pathology. Полиморфизм генов, участвующих в реализации стрессорного ответа, является одним из ключевых факторов, определяющих различия в стресс-реактивности и резистентности в человеческой популяции. Среди генов – регуляторов стресса в первую очередь следует выделить гены рецепторов глюкокортикоидов. В обзоре дана детальная характеристика их молекулярной биологии, на основании чего проведен анализ возможной связи наиболее распространенных вариантов SNP с альтерацией стрессорных реакций и развитием клинической патологии. Ключевые слова: глюкокортикоидные рецепторы, аллельный полиморфизм, SNP, NR3C1, GR, болезни адаптации. Поліморфізм генів, які беруть участь у реалізації стресорної відповіді, є одним із ключових факторів, що визначають розбіжності в стрес-реактивності і резистентності в людській популяції. Серед генів – регуляторів стресу у першу чергу варто відзначити гени рецепторів глюкокортикоїдів. В огляді надано детальну характеристику молекулярної біології даних генів, на підставі чого зроблено аналіз можливого зв’язку найрозповсюдженіших варіантів SNP з альтерацією стресорних реакцій та розвитком клінічної патології. Ключові слова: глюкокортикоїдні рецептори, алельний поліморфізм, SNP, NR3C1, GR, захворювання адаптації. 2012 Article Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications / M.A. Orlovsky // Вiopolymers and Cell. — 2012. — Т. 28, № 5. — С. 338-351. — Бібліогр.: 54 назв. — англ., рос. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000061 https://nasplib.isofts.kiev.ua/handle/123456789/156873 577.218 en Вiopolymers and Cell application/pdf application/pdf Інститут молекулярної біології і генетики НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
| language |
English |
| topic |
Reviews Reviews |
| spellingShingle |
Reviews Reviews Orlovsky, M.A. Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications Вiopolymers and Cell |
| description |
Polymorphism of stress-related genes is a key factor determining difference in the stress reactivity and
resistance among humans. Glucocorticoid receptors are important actors of stress responses. This review is
focused on the molecular biology and clinical implications of glucocorticoid receptor gene polymorphism.
Keywords: glucocorticoid receptors, allelic polymorphism, SNP, NR3C1, GR, stress-induced pathology. |
| format |
Article |
| author |
Orlovsky, M.A. |
| author_facet |
Orlovsky, M.A. |
| author_sort |
Orlovsky, M.A. |
| title |
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications |
| title_short |
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications |
| title_full |
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications |
| title_fullStr |
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications |
| title_full_unstemmed |
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR): from molecular biology to clinical implications |
| title_sort |
allelic polymorphism of glucocorticoid receptor nr3c1 (gr): from molecular biology to clinical implications |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2012 |
| topic_facet |
Reviews |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/156873 |
| citation_txt |
Allelic polymorphism of glucocorticoid receptor NR3C1
(GR): from molecular biology to clinical implications / M.A. Orlovsky // Вiopolymers and Cell. — 2012. — Т. 28, № 5. — С. 338-351. — Бібліогр.: 54 назв. — англ., рос. |
| series |
Вiopolymers and Cell |
| work_keys_str_mv |
AT orlovskyma allelicpolymorphismofglucocorticoidreceptornr3c1grfrommolecularbiologytoclinicalimplications |
| first_indexed |
2025-11-27T03:17:15Z |
| last_indexed |
2025-11-27T03:17:15Z |
| _version_ |
1849911874403958784 |
| fulltext |
UDC 577.218
Àëëåëüíûé ïîëèìîðôèçì ðåöåïòîðà
ãëþêîêîðòèêîèäíûõ ãîðìîíîâ NR3C1 (GR):
îò ìîëåêóëÿðíîé áèîëîãèè ê êëèíèêå
Ì. À. Îðëîâñêèé
Èíñòèòóò ôèçèîëîãèè èì. À. À. Áîãîìîëüöà ÍÀÍ Óêðàèíû
Óë. Àêàäåìèêà Áîãîìîëüöà, 4, Êèåâ, Óêðàèíà, 01024
dr.orlovsky@gmail.com
Ïîëèìîðôèçì ãåíîâ, ó÷àñòâóþùèõ â ðåàëèçàöèè ñòðåññîðíîãî îòâåòà, ÿâëÿåòñÿ îäíèì èç êëþ÷åâûõ ôàê-
òîðîâ, îïðåäåëÿþùèõ ðàçëè÷èÿ â ñòðåññ-ðåàêòèâíîñòè è ðåçèñòåíòíîñòè â ÷åëîâå÷åñêîé ïîïóëÿöèè.
Ñðåäè ãåíîâ – ðåãóëÿòîðîâ ñòðåññà â ïåðâóþ î÷åðåäü ñëåäóåò âûäåëèòü ãåíû ðåöåïòîðîâ ãëþêîêîðòè-
êîèäîâ.  îáçîðå äàíà äåòàëüíàÿ õàðàêòåðèñòèêà èõ ìîëåêóëÿðíîé áèîëîãèè, íà îñíîâàíèè ÷åãî ïðîâå-
äåí àíàëèç âîçìîæíîé ñâÿçè íàèáîëåå ðàñïðîñòðàíåííûõ âàðèàíòîâ SNP ñ àëüòåðàöèåé ñòðåññîðíûõ
ðåàêöèé è ðàçâèòèåì êëèíè÷åñêîé ïàòîëîãèè.
Êëþ÷åâûå ñëîâà: ãëþêîêîðòèêîèäíûå ðåöåïòîðû, àëëåëüíûé ïîëèìîðôèçì, SNP, NR3C1, GR, áîëåçíè
àäàïòàöèè.
«Áîëåçíè öèâèëèçàöèè» (àðòåðèàëüíàÿ ãèïåðòåí-
çèÿ, àòåðîñêëåðîç, ñàõàðíûé äèàáåò, èììóíîäåôè-
öèòíûå ñîñòîÿíèÿ, àóòîèììóííàÿ ïàòîëîãèÿ, áèïî-
ëÿðíûå ðàññòðîéñòâà è äåïðåññèÿ) ïðè÷èíÿþò ñóùå-
ñòâåííûé ýêîíîìè÷åñêèé è ãóìàíèòàðíûé óùåðá
ñîâðåìåííîìó ÷åëîâå÷åñòâó.  èõ îñíîâå ëåæàò ñè-
ñòåìíàÿ äèçðåãóëÿöèÿ, âîçíèêàþùàÿ êàê îòâåò íà
àëëîñòàòè÷åñêóþ íàãðóçêó, äèñòðåññ è äåçàäàïòà-
öèþ. Ãëþêîêîðòèêîèäíûå ãîðìîíû êàê ýôôåêòîðû
ñòðåññà è àãåíòû àäàïòàöèè ê ñòðåññó íåïîñðåäñò-
âåííî ó÷àñòâóþò â ðåãóëÿöèè ìåòàáîëèçìà, ãîìåî-
ñòàçà, èììóííûõ ðåàêöèé, ýíäîêðèííîãî ñòàòóñà è
ïñèõè÷åñêèõ ïðîöåññîâ, âëèÿÿ íà íàñòðîåíèå, ïà-
ìÿòü è îáùóþ ïñèõè÷åñêóþ àêòèâíîñòü. Ñðåäè ãå-
íîâ – ðåãóëÿòîðîâ ñòðåññà â ïåðâóþ î÷åðåäü ñëåäó-
åò âûäåëèòü ãåíû ðåöåïòîðîâ ãëþêîêîðòèêîèäîâ. Â
ïðåäñòàâëåííîì îáçîðå ïðîâåäåí àíàëèç ãåíåòèêè
è ìîëåêóëÿðíîé áèîëîãèè ðåöåïòîðîâ ãëþêîêîðòè-
êîèäíûõ ãîðìîíîâ (NR3C1), ñïåêòð ýôôåêòîâ àê-
òèâàöèè êîòîðûõ ðàñïðîñòðàíÿåòñÿ îò ýïèãåíåòè-
÷åñêîé ìîäèôèêàöèè ãåíîìà äî âëèÿíèÿ íà ïñèõè-
÷åñêèå ïðîöåññû.
Ñòðóêòóðà ãåíà è ðåãóëÿöèÿ ýêñïðåññèè. Ãåí
ðåöåïòîðà ãëþêîêîðòèêîèäíûõ ãîðìîíîâ NR3C1
(nuclear receptor subfamily 3, group C, class 1) ïðåä-
ñòàâëåí â ãåíîìå ÷åëîâåêà åäèíñòâåííîé êîïèåé,
ðàñïîëîæåííîé â ëîêóñå 5q31.3 (äëèííîå ïëå÷î 5-é
õðîìîñîìû, 3-é ó÷àñòîê, 1-ÿ ïîëîñà, 3-ÿ ñóá-ïîëî-
ñà). Äëèíà ãåíà ñîñòàâëÿåò 157581 ïàð îñíîâàíèé;
îí ñîäåðæèò äåâÿòü ýêçîíîâ, êîäèðóþùèõ ïîñëåäî-
âàòåëüíîñòè èç 777 àìèíîêèñëîòíûõ îñòàòêîâ [2].
Ñòðóêòóðà ãåíà ïðèâåäåíà íà ðèñ. 1 è 2.
Ýêñïðåññèÿ ãåíà NR3C1 íàõîäèòñÿ ïîä êîíòðî-
ëåì íåñêîëüêèõ àëüòåðíàòèâíûõ ïåðâûõ ýêçîíîâ
(ïî ðàçíûì äàííûì, îò ñåìè äî äåâÿòè), ïðåäâàðÿþ-
ùèõ CpG-áîãàòóþ ïîñëåäîâàòåëüíîñòü (îáëàñòü
ïðîìîòîðà) [3, 4]. Â èíòðîíàõ ìåæäó ýòèìè àëüòåð-
íàòèâíûìè ýêçîíàìè ëîêàëèçîâàíû ñåìü òêàíåñïå-
öèôè÷íûõ ïðîìîòîðîâ, ïîçâîëÿþùèõ èñïîëüçî-
âàòü ðàçëè÷íûå ìåõàíèçìû ãåíåòè÷åñêîãî êîíòðî-
ëÿ ýêñïðåññèè ãåíà â îðãàíàõ è òêàíÿõ [3]. Ìåòèëè-
ðîâàíèå àëüòåðíàòèâíûõ ýêçîíîâ è ïðîìîòîðîâ ÿâ-
338
ISSN 0233–7657. Biopolymers and Cell. 2012. Vol. 28. N 5. P. 338–351
� Institute of Molecular Biology and Genetics, NAS of Ukraine, 2012
339
ÀËËÅËÜÍÛÉ ÏÎËÈÌÎÐÔÈÇÌ NR3C1 (GR): ÎÒ ÌÎËÅÊÓËßÐÍÎÉ ÁÈÎËÎÃÈÈ Ê ÊËÈÍÈÊÅ
ëÿåòñÿ ýïèãåíåòè÷åñêèì ìåõàíèçìîì ðåãóëÿöèè àê-
òèâíîñòè ãåíà [4]. Ïî âñåé âèäèìîñòè, àêòèâíîñòü
ðàçëè÷íûõ ïðîìîòîðîâ âëèÿåò íà âûáîð êîíêðåòíî-
ãî ìåõàíèçìà ñïëàéñèíãà, âåäóùåãî ê îáðàçîâàíèþ
òîé èëè èíîé èçîôîðìû ðåöåïòîðà [4]. Èçâåñòíî,
÷òî ãåíåòè÷åñêèé ïîëèìîðôèçì ðåãóëÿòîðíûõ ó÷à-
ñòêîâ ñâÿçàí ñ ðàçâèòèåì äåïðåññèâíûõ ðàññòðîéñòâ
[5].
Ñïëàéñèíã è òðàíñëÿöèÿ. Èçîôîðìû ðåöåï-
òîðà. Â ðåçóëüòàòå àëüòåðíàòèâíîãî ñïëàéñèíãà
ïðî-ìÐÍÊ, ñ÷èòûâàåìîãî ñ ïîñëåäîâàòåëüíîñòè ãå-
íà NR3C1, âîçìîæíî îáðàçîâàíèå âîñüìè ñïëàéñ-
âàðèàíòîâ, êîäèðóþùèõ ÷åòûðå îñíîâíûå èçîôîð-
ìû ðåöåïòîðà – GR-�, GR-�, GR-�, à òàêæå ìàëîèçó-
÷åííóþ èçîôîðìó GR-P (òàáë. 1). Ïîìèìî ýòîãî â
ðåçóëüòàòå ñäâèãà ðàìêè ñ÷èòûâàíèÿ â ïðîöåññå
èíèöèàöèè òðàíñëÿöèè âîçíèêàåò ðÿä äîïîëíè-
òåëüíûõ èçîôîðì ðåöåïòîðà GR-� (GR-�A, GR-�B,
GR-�C è GR-�D; òàáë. 2). Ïîäîáíûé ìåõàíèçì àëü-
òåðíàòèâíîé èíèöèàöèè òðàíñëÿöèè òèïè÷åí äëÿ
ñèíòåçà ïðîòîîíêîãåíîâ, ðåãóëÿòîðîâ òðàíñêðèï-
öèè, êèíàç è ôàêòîðîâ ðîñòà â êëåòêàõ ýóêàðèîòîâ
[7] è ïîçâîëÿåò óâåëè÷èòü êîëè÷åñòâî áåëêîâûõ
ïðîäóêòîâ îäíîãî è òîãî æå ãåíà, ðàñøèðÿÿ ðåïåð-
òóàð åãî ôèçèîëîãè÷åñêèõ ôóíêöèé è ÷èñëî òêàíå-
ñïåöèôè÷íûõ âàðèàíòîâ îòâåòà [6].
Èçîôîðìû ðåöåïòîðà îòëè÷àþòñÿ C-òåðìèíàëü-
íîé îáëàñòüþ, ÷òî âëèÿåò íà ìåõàíèçìû öèòîïëàç-
ìàòè÷åñêè-íóêëåàðíîãî òðàôèêà è àêòèâàöèè ãåíîâ-
ìèøåíåé [6]. Íàèáîëåå ðàñïðîñòðàíåííîé ôîðìîé
ðåöåïòîðà ÿâëÿåòñÿ GR-� [6], àìèíîêèñëîòíàÿ ïî-
ñëåäîâàòåëüíîñòü êîòîðîé ïïðèâåäåíà íà ðèñ. 1. �-
Èçîôîðìà ïðåäñòàâëåíà ðÿäîì áîëåå êîðîòêèõ ñóá-
èçîôîðì, ó êîòîðûõ îòñóòñòâóþò íåêîòîðûå àìè-
íîêèñëîòû íà C-êîíöå (òàáë. 2), ÷òî íå âëèÿåò íà ñâÿ-
çûâàíèå ñ ãîðìîíîì, íî ìîäèôèöèðóåò ïðîöåññû
òðàíñëîêàöèè àêòèâèðîâàííûõ ðåöåïòîðîâ â ÿäðî [6].
Îñíîâíîå ðàçëè÷èå ìåíåå ðàñïðîñòðàíåííîãî âà-
ðèàíòà GR-�, óðîâåíü ýêñïðåññèè êîòîðîãî ñîñòàâ-
ëÿåò ïîðÿäêà 1 % îò óðîâíÿ GR-� [8], ñîñòîèò â îò-
ñóòñòâèè ñïåöèôè÷åñêîãî ãëþêîêîðòèêîèä-ñâÿçû-
âàþùåãî äîìåíà [9].�-Èçîôîðìà ïðåèìóùåñòâåííî
ëîêàëèçóåòñÿ â ÿäðå è, ïî âñåé âèäèìîñòè, ñëóæèò
äîìèíàíòíî-íåãàòèâíûì ðåãóëÿòîðîì GR-� è MR,
ñ êîòîðûìè îíà ñïîñîáíà êîíêóðèðîâàòü çà ñàéòû
ïðîìîòîðîâ, à òàêæå îáðàçîâûâàòü ãåòåðîäèìåðû
[9, 8]. Òàê, áîëåå íèçêàÿ ÷óâñòâèòåëüíîñòü íåéòðî-
ôèëîâ â ñðàâíåíèè ñ T-ëèìôîöèòàìè ê ãëþêîêîð-
òèêîèä-îïîñðåäîâàííîìó àïîïòîçó, âåðîÿòíî, îáó-
ñëîâëåíà ïîâûøåííîé ýêñïðåññèåé GR-� â ýòèõ
êëåòêàõ [10]. Âìåñòå ñ òåì, ñïîñîáíîñòü GR-� èíãè-
áèðîâàòü ýôôåêòû GR-� â ôèçèîëîãè÷åñêèõ è ïàòî-
Îñíîâíîé ïðîìîòîð
Çîíà ãèïåðìåòèëèðîâàíèÿ
Ýêçîíû
Îáëàñòü àëüòåðíàòèâíûõ ïðîìîòîðîâ è ïåðâûõ ýêçîíîâ
Ïåðâûé àëüòåðíàòèâíûé
ïðîìîòîð
Ðèñ. 1. Ñòðóêòóðà ãåíà
NR3C1
1A 1B 1C 2 3 4 5 6 7 8 9
~ 28 ~ 83 ~ 7 ~ 10 ~ 130 kb Intronic Gap
~ 158 kb
~ 1,5 kb ~ 1,5 kb
1A3
1A1
1A2
9 �
9 �
Ðèñ. 2. Íåòðàíñëèðóå-
ìûå îáëàñòè (áåëûå
áëîêè) è èíòðîííî-ýê-
çîííàÿ ñòðóêòóðà ãåíà
NR3C1 (ñîãëàñíî [31])
340
ÎÐËÎÂÑÊÈÉ Ì. À.
ëîãè÷åñêèõ óñëîâèÿõ íåêîòîðûìè àâòîðàìè ñòàâèò-
ñÿ ïîä ñîìíåíèå, ïîñêîëüêó èç-çà íèçêîãî óðîâíÿ
áàçîâîé ýêñïðåññèè GR-�òðåáóåòñÿ ïî ìåíüøåé ìå-
ðå 500-êðàòíîå óñèëåíèå åãî ñèíòåçà äëÿ ïîëó÷åíèÿ
çíà÷èìîãî ýôôåêòà [8]. Ïðè ýòîì óñòàíîâëåíî, ÷òî
GR-� ïîäàâëÿåò ëèøü òðàíñàêòèâàöèîííûå ýôôåê-
òû GR-�, íå âëèÿÿ íà âûçâàííóþ èì òðàíñðåïðåñ-
ñèþ [8]. Ïîìèìî ýòîãî âëèÿíèå GR-�íà áîëåå âûñî-
êîàôôèííûå MR âîçìîæíî è â ôèçèîëîãè÷åñêèõ
óñëîâèÿõ [8]. Ñëåäóåò îòìåòèòü, ÷òî èçîôîðìà GR-�
íå âñòðå÷àåòñÿ ó êðûñ, òàê êàê ó íèõ â ãåíå NR3C1
îòñóòñòâóåò ñîîòâåòñòâóþùèé ñàéò àêòèâíîãî ñïëàé-
ñèíãà [11]. Ôèçèîëîãè÷åñêîå çíà÷åíèå äðóãèõ èçî-
ôîðì ðåöåïòîðà, â ÷àñòíîñòè, GR-� è GR-P îñòàåòñÿ
ìàëîèçó÷åííûì.
Èçîôîðìà GR-� îïèñàíà Ðèâåðñîì è ñîàâò. [12]
â 1999 ã. Îíà ñîäåðæèò äîïîëíèòåëüíûé àðãèíèí â
ñòðóêòóðå ÄÍÊ-ñâÿçûâàþùåãî äîìåíà, âîçíèêàþ-
ùèé â ðåçóëüòàòå àëüòåðíàòèâíîãî ñïëàéñèíãà èíò-
ðîíà ìåæäó 3-ì è 4-ì ýêçîíàìè. Èçâåñòíî, ÷òî òàêàÿ
ìîäèôèêàöèÿ âûçûâàåò ñíèæåíèå òðàíñêðèïöèîí-
íîé àêòèâíîñòè ðåöåïòîðà íà 48 % [13]. GR-� âûñî-
êîýêñïðåññèðîâàí â ðàçëè÷íûõ òêàíÿõ; åãî äîëÿ êî-
ëåáëåòñÿ îò 3,8 äî 8,7 % â îáùåé ïîïóëÿöèè ðåöåïòî-
ðîâ GR [12].
Ñòðóêòóðà ðåöåïòîðà. Ðåöåïòîð ñîñòîèò èç ÷å-
òûðåõ äîìåíîâ, òðè èç êîòîðûõ ïðåäñòàâëåíû âû-
ñîêîêîíñåðâàòèâíûìè ïîñëåäîâàòåëüíîñòÿìè, ïðè-
ñóòñòâóþùèìè â äðóãèõ áåëêàõ (òàáë. 3, ðèñ. 3). Äåé-
ñòâèå GR îñóùåñòâëÿåòñÿ ïîñðåäñòâîì äèìåðîâ,
êîòîðûå ìîãóò ñóùåñòâîâàòü â âèäå ãîìî- è ãåòåðî-
äèìåðîâ ñ MR. Ãîìî- è ãåòåðîäèìåðû èíäóöèðóþò
ðàçëè÷íûå ïîäãðóïïû ãåíîâ, îáåñïå÷èâàÿ òîíêóþ
ðåãóëÿöèþ â çàâèñèìîñòè îò áûñòðîèçìåíÿþùèõñÿ
Èäåíòèôèêàòîð â
êàòàëîãå NCBI RefSeq
Õàðàêòåðèñòèêà Ðåçóëüòèðóþùèé áåëîê Ññûëêà
NM_000176.2 Îñíîâíîé òðàíñêðèïò, êîäèðóþùèé
íàèáîëåå ðàñïðîñòðàíåííóþ èçîôîðìó
ðåöåïòîðà
Èçîôîðìû GR-�, ïîëó÷àåìûå â ðåçóëüòàòå àëü-
òåðíàòèâíûõ âàðèàíòîâ èíèöèàöèè òðàíñëÿöèè ìÐÍÊ:
GR-A, GR-B, GR-C, GR-D è èõ ïîäâèäû
[6]
NM_001204258.1
NM_001204259.1
NM_001204260.1
NM_001204261.1
NM_001204262.1
NM_001204263.1
NM_001204264.1
NM_001018074.1 Âàðèàíòû ñ àëüòåðíàòèâíûìè 5'-íå-
êîäèðóþùèìè ïîñëåäîâàòåëüíîñòÿìè
NM_001018075.1
NM_001018076.1
NM_001018077.1
NM_001020825.1 Îáðàçóåòñÿ â ðåçóëüòàòå ïðèìåíåíèÿ
àëüòåðíàòèâíîãî ñàéòà ñïëàéñ-
àêöåïòîðà â 3'-òåðìèíàëüíîì ýêçîíå
GR-� [9]
NM_001024094.1 Îáðàçóåòñÿ â ðåçóëüòàòå àëüòåðíàòèâ-
íîãî ñïëàéñèíãà â ñàéòå îäíîãî èç êî-
äèðóþùèõ ýêçîíîâ
GR-� [12]
NM_001204265.1 Âàðèàíò áåç äâóõ ýêçîíîâ íà 3'-êîíöå GR-P [40, 41]
Òàáëèöà 1
Ñïëàéñ-âàðèàíòû ìÐÍÊ ãåíà NR3C1 ÷åëîâåêà
óðîâíåé ãîðìîíîâ ïðè ñòðåññå [14, 15]. Âàæíûì àñ-
ïåêòîì â ýòîì ïëàíå ñëóæèò òî, ÷òî õàðàêòåð è ìàã-
íèòóäà GR/MR-îïîñðåäîâàííûõ îòâåòîâ îïðåäåëÿ-
åòñÿ íå òîëüêî ñâÿçûâàíèåì ðåöåïòîðîâ ñ ëèãàíäà-
ìè, íî è íàëè÷èåì íåñòåðîèäíûõ êîðåãóëÿòîðîâ,
êîàêòèâàòîðîâ è êîðåïðåññîðîâ [15]. Äèìåðíàÿ êîí-
ôèãóðàöèÿ ìîëåêóëû GR îòëè÷àåòñÿ îò òàêîâîé ðå-
öåïòîðîâ ïðî÷èõ ñòåðîèäíûõ ãîðìîíîâ è ñîäåðæèò
äîïîëíèòåëüíûé ìåæìîëåêóëÿðíûé �-ñëîé [16].
Àêòèâàöèÿ ðåöåïòîðà. Â áàçîâûõ óñëîâèÿõ â
öèòîïëàçìå êëåòêè ðåöåïòîð ñóùåñòâóåò â ñîñòàâå
ìóëüòèáåëêîâîãî êîìïëåêñà, âêëþ÷àþùåãî îäíó ìî-
ëåêóëó GR, à òàêæå áåëêè òåïëîâîãî øîêà – äâå ìî-
ëåêóëû hsp90, îäíó hsp70, îäíó hsp56 è èììóíîìî-
äóëèí [8]. Ñâÿçûâàíèå ãîðìîíà ñ ðåöåïòîðîì âå-
äåò ê ðÿäó ñîáûòèé, ñðåäè êîòîðûõ äèññîöèàöèÿ áåë-
êîâ òåïëîâîãî øîêà, èììóíîìîäóëèíà, à òàêæå ôîñ-
ôîðèëèðîâàíèÿ GR, âûçûâàþùèå òðàíñïîðòèðîâêó
ãîðìîíî-ðåöåïòîðíîãî êîìïëåêñà â ÿäðî êëåòêè [8].
Âðåìÿ ïîëóæèçíè ãîðìîíî-ðåöåïòîðíîãî êîìïëåêñà
äëÿ GR ñîñòàâëÿåò 5 ìèí (â ñðàâíåíèè ñ 45 ìèí äëÿ
MR) [14]; êîíñòàíòà äèññîöèàöèè KD � 0,5 íM [8].
341
ÀËËÅËÜÍÛÉ ÏÎËÈÌÎÐÔÈÇÌ NR3C1 (GR): ÎÒ ÌÎËÅÊÓËßÐÍÎÉ ÁÈÎËÎÃÈÈ Ê ÊËÈÍÈÊÅ
Èçîôîðìà Ñòðóêòóðà Ëîêàëèçàöèÿ è ôóíêöèÿ
GR-� (�-A,
GR-A)
Îñíîâíàÿ èçîôîðìà ðåöåïòîðà, ñîäåðæàùàÿ ÄÍÊ-
è ãîðìîí-ñâÿçûâàþùèå äîìåíû
Íàõîäèòñÿ â öèòîïëàçìå; ïðè ñâÿçûâàíèè ñ ëèãàíäîì òðàíñ-
ïîðòèðóåòñÿ â ÿäðî, ãäå ðåàëèçóåò ñâîè ýôôåêòû. Èçîôîðìû
îòëè÷àþòñÿ ïî ìåõàíèçìàì òðàíñïîðòèðîâêè â ÿäðî [6]
GR-�B Òåðìèíèðîâàí íà 571–573-ì êîäîíå Êîðîòêèå èçîôîðìû ðåöåïòîðà, îòëè÷àþùèåñÿ ïî ìåõàíèçìàì
òðàíñïîðòèðîâêè â ÿäðî [6]
GR-�C1 Òåðìèíèðîâàí íà 748–750-ì êîäîíå
GR-�C2 Òåðìèíèðîâàí íà 760–762-ì êîäîíå
GR-�C3 Òåðìèíèðîâàí íà 784–786-ì êîäîíå
GR-�D1 Òåðìèíèðîâàí íà 1438–1440-ì êîäîíå
GR-�D2 Òåðìèíèðîâàí íà 1483–1485-ì êîäîíå
GR-�D3 Òåðìèíèðîâàí íà 1498–1500-ì êîäîíå
GR-� Áîëåå êîðîòêàÿ, ÷åì GR-�, èçîôîðìà ñ îòëè÷àþ-
ùåéñÿ C-òåðìèíàëüíîé ÷àñòüþ è íå ñîäåðæàùàÿ
ãîðìîí-ñâÿçûâàþùåãî äîìåíà [9]. Íå âñòðå÷àåòñÿ
ó êðûñ [11]
Ïðåèìóùåñòâåííî ëîêàëèçóåòñÿ â ÿäðå è ÿâëÿåòñÿ äî-
ìèíàíòíî-íåãàòèâíûì ðåãóëÿòîðîì äåéñòâèÿ GR-� [9]
GR-� ÄÍÊ-ñâÿçûâàþùèé äîìåí ñîäåðæèò äîïîëíè-
òåëüíóþ àìèíîêèñëîòó (àðãèíèí)
Îáëàäàåò áîëåå íèçêîé àôôèííîñòüþ ê GRE ïî ñðàâíåíèþ ñ
GR-� [12]
GR-P Ñîäåðæèò áîëåå êîðîòêóþ Ñ-òåðìèíàëüíóþ
îáëàñòü, íå âñòðå÷àþùóþñÿ â äðóãèõ èçîôîðìàõ
Ôóíêöèÿ íåèçâåñòíà. Âûñîêîýêñïðåññèðîâàí â
ãëþêîêîðòèêîèä-ðåçèñòåíòíûõ ëèíèÿõ êëåòîê è ìîæåò
âûñòóïàòü ìîäóëÿòîðîì ÷óâñòâèòåëüíîñòè ê
ãëþêîêîðòèêîèäàì [40, 41]
Òàáëèöà 2
Èçîôîðìû ðåöåïòîðà GR ÷åëîâåêà (ïðîäóêòû ãåíà NR3C1)
Ëîêàëèçàöèÿ Äîìåí Ôóíêöèÿ
1–420 Òðàíñàêòèâàöèîííûé Âçàèìîäåéñòâèå ñ ôàêòîðàìè òðàíñêðèïöèè
419–486 ÄÍÊ-ñâÿçûâàþùèé ïî òèïó «öèíêîâûõ ïàëüöåâ» Âçàèìîäåéñòâèå ñ GRE-ïîñëåäîâàòåëüíîñòüþ ÄÍÊ è
ìîäóëÿöèÿ ÷àñòîòû èíèöèàöèè òðàíñêðèïöèè
487–527 Øàðíèðíûé Ïîäâèæíîñòü ìîëåêóëÿðíîé ñòðóêòóðû
528–777 Ëèãàíä-ñâÿçûâàþùèé Ñâÿçûâàíèå ãîðìîíà è òðàíñëîêàöèÿ â ÿäðî
Òàáëèöà 3
Äîìåíû áåëêà GR-�A
Óðîâåíü â êðîâè ãëþêîêîðòèêîèäíûõ ãîðìî-
íîâ, àêòèâèðóþùèõ ðåöåïòîð, ïîäâåðæåí ïóëüñî-
âûì êîëåáàíèÿì íà ïðîòÿæåíèè ñóòîê. Ñðåäíÿÿ äëè-
òåëüíîñòü îäíîãî ïóëüñà ñåêðåöèè ó êðûñ ñîñòàâëÿ-
åò ïîðÿäêà 1 ÷.  âå÷åðíåå âðåìÿ ïèêè ñåêðåöèè áî-
ëåå ÷àñòû, ñëåäóþò äðóã çà äðóãîì ïðàêòè÷åñêè áåç
èíòåðâàëîâ è èìåþò âûñîêóþ àìïëèòóäó; â óòðåí-
íåå âðåìÿ èõ àìïëèòóäà ñíèæåíà è îíè ðàçäåëåíû
ïîëó- è ÷àñîâûìè èíòåðâàëàìè [14, 17].  êðîâè
ãëþêîêîðòèêîèäû âçàèìîäåéñòâóþò ñ êîðòèêîñòå-
ðîèä-ñâÿçûâàþùèì áåëêîì (corticosteroid-binding
protein, CBP) [8]; èõ ïðîíèêíîâåíèå ÷åðåç ãåìàòî-
ýíöåôàëè÷åñêèé áàðüåð ðåãóëèðóåòñÿ P-ãëèêîïðî-
òåèíîì mdr1A (áåëîê ìíîæåñòâåííîé ëåêàðñòâåí-
íîé ðåçèñòåíòíîñòè, multiple drug resistance) [18].
Ïèêîâûå êîíöåíòðàöèè ãëþêîêîðòèêîèäîâ â
êðîâè âûçûâàþò àêòèâàöèþ è òðàíñëîêàöèþ ìîëå-
êóë GR â ÿäðî óæå ïî èñòå÷åíèè 30 ìèí (â áàçîâûõ
óñëîâèÿõ ðåöåïòîðû GR â ÿäðå ïðàêòè÷åñêè íå ïðè-
ñóòñòâóþò) [14, 19]. Ïîñëå ýòîãî ïðîèñõîäèò îòíî-
ñèòåëüíî áûñòðîå (íà ïðîòÿæåíèè 90 ìèí) óìåíü-
øåíèå èõ óðîâíÿ äî èñõîäíûõ çíà÷åíèé [14, 19].
Òàêèì îáðàçîì, îáùàÿ äëèòåëüíîñòü öèêëà àêòèâà-
öèè ðåöåïòîðîâ, èõ òðàíñëîêàöèè è ýëèìèíàöèè èç
ÿäðà ñîñòàâëÿåò 120 ìèí. Ýëèìèíàöèÿ ðåöåïòîðîâ
èç ÿäðà ïðîèñõîäèò âñëåäñòâèå èõ ïðîòåàñîìíîé
äåãðàäàöèè íåïîñðåäñòâåííî â ÿäðå è áëîêèðóåòñÿ
èíãèáèòîðàìè 26S-ñóáúåäèíèöû ïðîòåàñîìû [14].
Öèòîïëàçìàòè÷åñêàÿ êîíöåíòðàöèÿ ðåöåïòîðîâ â
õîäå ýòîãî öèêëà çíà÷èìî íå ñíèæàåòñÿ, ÷òî ñâèäå-
òåëüñòâóåò î ïðîõîæäåíèè â êàæäîì öèêëå ðåêðó-
òèíãà ëèøü íåáîëüøîé ÷àñòè ðåöåïòîðîâ [14].
Ïîñòòðàíñëÿöèîííàÿ ìîäèôèêàöèÿ. Â íàñòî-
ÿùåå âðåìÿ äëÿ ìîëåêóëû GR ÷åëîâåêà îïèñàíû 14
ðàçëè÷íûõ âàðèàíòîâ ïîñòòðàíñëÿöèîííîé ìîäè-
ôèêàöèè, âêëþ÷àÿ ôîñôîðèëëèðîâàíèå, ñóìîèëÿ-
öèþ è ó áèêâèòèíèçàöèþ (òàáë. 4). Ôîñôîðèëèðî-
âàíèå è äåôîñôîðèëèðîâàíèå GR îêàçûâàþò ñóùå-
ñòâåííîå âëèÿíèå íà ôóíêöèþ ðåöåïòîðà, åãî âíóò-
ðèêëåòî÷íûé òðàôèê è àôôèííîñòü ê ëèãàíäàì
[20]. Â ñâîáîäíîì ñîñòîÿíèè ðåöåïòîð ôîñôîðèëè-
ðîâàí (ñàéòû Tre171 è Ser246 â GR êðûñû [21]),
îäíàêî ñâÿçûâàíèå ãîðìîíà (íî íå àíòàãîíèñòîâ)
âåäåò ê åãî äàëüíåéøåìó ôîñôîðèëèðîâàíèþ, íå-
îáõîäèìîìó, ïî âñåé âèäèìîñòè, äëÿ ïðîÿâëåíèÿ
ôèçèîëîãè÷åñêîé àêòèâíîñòè [22]. Òàêîå ôîñôîðè-
ëèðîâàíèå, ñêîðåå âñåãî, ïðîèñõîäèò â ñàéòàõ Ser
203 è Ser211 ïðè ó÷àñòèè öèêëèí-çàâèñèìûõ êèíàç
[20, 22]. Ýòè æå ñàéòû ôîñôîðèëèðîâàíèÿ ñâÿçàíû
ñ ðåãóëÿöèåé òðàôèêà àêòèâèðîâàííîãî ðåöåïòîðà
â ðàçëè÷íûå êëåòî÷íûå êîìïàðòìåíòû: GR-Ser211-
P îáíàðóæèâàåòñÿ â ÿäðå êëåòêè, â òî âðåìÿ êàê GR-
Ser203-P è äâàæäû ôîñôîðèëèðîâàííûå GR-Ser
203/Ser211-P – èñêëþ÷èòåëüíî â öèòîçîëå [22]. Ôîñ-
ôîðèëèðîâàíèå ñàéòà Ser226 ïðè ó÷àñòèè JNK, à
òàêæå MAPK ïðèâîäèò ê óñêîðåííîìó âûâåäåíèþ
ðåöåïòîðà èç ÿäðà, ïîäàâëÿÿ òðàíñêðèïöèþ ãëþêî-
êîðòèêîèä-çàâèñèìûõ ãåíîâ [23, 21]. Çàìåíà â ýòîì
ëîêóñå ñåðèíà íà àëàíèí (Ser266Ala) âûçûâàåò ïî-
òåðþ ÷óâñòâèòåëüíîñòè ðåöåïòîðà GR ê äåéñòâèþ
JNK [23]. Àêòèâàöèÿ JNK ïðîèñõîäèò ïðè äåéñòâèè
öèòîêèíîâ, ëèïîïîëèñàõàðèäîâ è îñìîòè÷åñêèõ
ñòèìóëîâ [23], è ôîñôîðèëèðîâàíèå ïî îñòàòêó Ser
226 ìîæåò áûòü ìåõàíèçìîì êîíòððåãóëÿöèè àêòèâ-
íîñòè ñèñòåìíîãî èììóííîãî è ñòðåññîðíîãî îòâåòà.
Ïîìèìî ôîñôîðèëèðîâàíèÿ áåëîê GR ïîäâåð-
ãàåòñÿ íåäàâíî îòêðûòîìó ïðîöåññó ñóìîèëÿöèè,
êîíúþãèðîâàííîìó ñî ñïåöèôè÷åñêèì ìàëûì óáè-
êâèòèí-ïîäîáíûì ìîäèôèêàòîðîì (SUMO-1) [24].
Ïðîöåññ êàòàëèçèðóåòñÿ E3-ëèãàçàìè, êîòîðûå ïðè
ýòîì îòëè÷íû îò ëèãàç, ó÷àñòâóþùèõ â óáèêâèòè-
íèçàöèè. Ñóìîèëÿöèÿ ìîäèôèöèðóåò òðàôèê è àê-
òèâíîñòü ðÿäà áåëêîâ. GR ìîãóò áûòü ñóìîèëèðîâà-
íû â òðåõ ëîêóñàõ, îòíîñÿùèõñÿ ê òðàíñàêòèâàöèîí-
íîìó äîìåíó (Lys277 è Lys293) è ëèãàíä-ñâÿçûâà-
þùåìó äîìåíó â C-òåðìèíàëüíîé îáëàñòè (Lys703),
÷òî âåäåò ê ìîäèôèêàöèè òðàíñêðèïöèîííîé àêòèâ-
íîñòè ðåöåïòîðà, ïðè÷åì íàáëþäàåìûé ýôôåêò ÿâ-
ëÿåòñÿ ïðîìîòîð-çàâèñèìûì [24]. Ñàéòû òðàíñàê-
òèâàöèîííîãî äîìåíà áîëåå ïîäâåðæåíû ýòîìó òè-
ïó ìîäèôèêàöèè â ñðàâíåíèè ñ ñàéòîì ëèãàíä-ñâÿ-
342
ÎÐËÎÂÑÊÈÉ Ì. À.
Ðèñ. 3. ÄÍÊ-ñâÿçûâàþùèé äîìåí ãëþêîêîðòèêîèäíîãî ðåöåïòîðà
çûâàþùåãî äîìåíà. Ãëþêîêîðòèêîèäíûå ãîðìîíû,
ïî-âèäèìîìó, ñòèìóëèðóþò ñóìîèëÿöèþ ðåöåïòîðà
÷åðåç åãî òðàíñëîêàöèþ â ÿäðî, ãäå è ðàñïîëàãàåòñÿ
ñîîòâåòñòâóþùàÿ E3-ëèãàçà (Ubc9) [24].
Ðåöåïòîð ãëþêîêîðòèêîèäîâ ìîæåò ôóíêöèî-
íèðîâàòü â äâóõ ðåæèìàõ: êàê ôàêòîð òðàíñêðèï-
öèè, ñâÿçûâàþùèéñÿ ñ ãëþêîêîðòèêîèä-÷óâñòâè-
òåëüíûìè ó÷àñòêàìè ÄÍÊ (glucocorticoid-responsi-
ve elements, GRE), è êàê ðåãóëÿòîð àêòèâíîñòè äðó-
ãèõ òðàíñêðèïöèîííûõ ôàêòîðîâ. Â 2009 óñòàíîâ-
ëåíî, ÷òî ðàçëè÷íûå íóêëåîòèäíûå ïîñëåäîâàòåëü-
íîñòè ÄÍÊ, ñâÿçûâàþùèåñÿ ñ GR, ñëóæàò êî-ôàê-
òîðîì â àêòèâíîñòè ðåöåïòîðà, ñïåöèôè÷åñêè è
äèôôåðåíöèðîâàííî ìåíÿÿ åãî êîíôîðìàöèþ è òåì
ñàìûì âëèÿÿ íà ýêñïðåññèþ òåõ èëè èíûõ ãåíîâ [25].
Äåãðàäàöèÿ ðåöåïòîðà. GR, êàê è áîëüøèíñò-
âî èíûõ ÿäåðíûõ ðåöåïòîðîâ, ÿâëÿåòñÿ ñóáñòðàòîì
óáèêâèòèí-çàâèñèìîé ïðîòåàñîìíîé äåãðàäàöèè
[14, 26, 27]. Â ïðîöåññàõ ïðîòåàñîìíîé äåãðàäàöèè
ðåöåïòîðîâ ó÷àñòâóþò êîìïëåêñû CHIP [26] è áå-
ëîê Mdm2 (E3-ëèãàçà) [28].
Ðåêðóòèíã ðàçëè÷íûõ ñóáúåäèíèö ïðîòåàñîìû
è E3-ëèãàç â çîíó ïðîìîòîðà ïðè àêòèâàöèè ðåöåï-
òîðîâ ñòåðîèäíûõ ãîðìîíîâ ÿâëÿåòñÿ íåîáõîäè-
ìûì óñëîâèåì ðåàëèçàöèè èõ ýôôåêòà, è áëîêàäà
ïðîòåàñîìíîãî ïðîòåîëèçà ìîæåò áûòü ïðè÷èíîé
âîçíèêíîâåíèÿ àññîöèàöèè ðåöåïòîðîâ è õðîìàòè-
íà [26]. Ñ äðóãîé ñòîðîíû, ïîäàâëåíèå ïðîòåàñîì-
íîé äåãðàäàöèè áåëêîâ âåäåò ê óñèëåíèþ òðàíñ-
êðèïöèîííîé àêòèâíîñòè â òêàíÿõ, ÷òî ìîæåò áûòü
ñâÿçàíî ñ íàðóøåííîé äåãðàäàöèåé è ïåðñèñòåíò-
íîé àêòèâíîñòüþ ôàêòîðîâ òðàíñêðèïöèè â ÿäðå.
Åùå îäíèì ìåõàíèçìîì ó÷àñòèÿ ïðîòåàñîìíîé äå-
ãðàäàöèè â ðåãóëÿöèè àêòèâíîñòè ðåöåïòîðîâ ãëþ-
êîêîðòèêîèäîâ ñëóæèò ñòèìóëèðóþùåå âëèÿíèå
ðàçëè÷íûõ àãåíòîâ, â ÷àñòíîñòè ýñòðîãåíîâ, íà ýêñ-
ïðåññèþ ñïåöèôè÷åñêîé E3-ëèãàçû Mdm2, ïðèâî-
äÿùóþ ê ñíèæåíèþ àêòèâíîñòè GR [28]. Òàêèì îá-
ðàçîì, àêòèâíîñòü ïðîòåàñîìû ÿâëÿåòñÿ êëþ÷åâûì
ýëåìåíòîì â äèíàìè÷åñêîé ðåãóëÿöèè äåéñòâèÿ
ñòåðîèäíûõ ãîðìîíîâ.
Ãåíåòè÷åñêèé ïîëèìîðôèçì ãåíà NR3C1. Ïî-
ëèìîðôèçì ãåíîâ, ó÷àñòâóþùèõ â ðåàëèçàöèè ñòðåñ-
ñîðíîãî îòâåòà, ïî âñåé âèäèìîñòè, èãðàåò ðîëü êëþ-
÷åâîãî ôàêòîðà, îïðåäåëÿþùåãî ðàçëè÷èÿ â ñòðåññ-
ðåàêòèâíîñòè è ðåçèñòåíòíîñòè âíóòðè ÷åëîâå÷åñ-
êîé ïîïóëÿöèè [1]. Â íàñòîÿùåå âðåìÿ, ñîãëàñíî
äàííûì Íàöèîíàëüíîãî èíñòèòóòà çäîðîâüÿ ÑØÀ,
èçâåñòåí 2571 ïîëèìîðôèçì ãåíà NR3C1 ÷åëîâåêà
ïî òèïó «çàìåíû åäèíè÷íîãî íóêëåîòèäà» (single nuc-
leotide polymorphism, SNP, ðèñ. 4), èç êîòîðûõ 161
èìååò ÷àñòîòó âñòðå÷àåìîñòè ìèíîðíîãî àëëåëÿ âû-
343
ÀËËÅËÜÍÛÉ ÏÎËÈÌÎÐÔÈÇÌ NR3C1 (GR): ÎÒ ÌÎËÅÊÓËßÐÍÎÉ ÁÈÎËÎÃÈÈ Ê ÊËÈÍÈÊÅ
¹ Ïîçèèÿ Àìèíîêèñëîòà Ìîäèôèêàöèÿ Êèíàçà Çíà÷åíèå Ññûëêà
1 8 Òðåîíèí Ôîñôîðèëèðîâàíèå – – –
2, 4 45, 134 Ñåðèí Ôîñôîðèëèðîâàíèå – – –
3, 5 133, 141 Ñåðèí Ôîñôîðèëèðîâàíèå – – [20, 42]
7, 8 203, 211 Ñåðèí Ôîñôîðèëèðîâàíèå Cdk Àêòèâèðóåò ðåöåïòîð ïîñëå ñâÿçûâàíèÿ
ñ ãîðìîíîì
[22]
9 226 Ñåðèí Ôîñôîðèëèðîâàíèå ERK2, MAPK-8,
JNK
Ñíèæàåò àêòèâíîñòü ðåöåïòîðà [21, 23]
10 234, 267 Ñåðèí Ôîñôîðèëèðîâàíèå – – –
11 277, 293 Ëèçèí Ñóìîèëÿöèÿ Ubc9 (E3-ëèãàçà) – [24]
12 419 Ëèçèí Óáèêâèòèíèçàöèÿ â
ÄÍÊ-ñâÿçûâàþùåì
äîìåíå
CHIP, Mdm2
(E3-ëèãàçà)
Âîçìîæíûé PEST-ìàðêåð äåãðàäàöè [26–28]
13 508 Ñåðèí Ôîñôîðèëèðîâàíèå
øàðíèðíîãî äîìåíà
DNA-dependent
protein kinase
Âëèÿåò íà òðàíñêðèïöèîííóþ
àêòèâíîñòü
[43]
14 703 Ëèçèí Ñóìîèëÿöèÿ Ubc9 (E3-ëèãàçà) – [24]
Òàáëèöà 4
Ñàéòû ïîñòòðàíñëÿöèîííîé ìîäèôèêàöèè GR-�A
øå 10 % è åùå 127 — âûøå 1 %. Ñðåäè âñåõ SNP íà-
ìè âûÿâëåíû 42 ìèññåíñ-ìóòàöèè, âåäóùèå ê çàìå-
íå òîé èëè èíîé àìèíîêèñëîòû â ñòðóêòóðå ðàçëè÷-
íûõ èçîôîðì ðåöåïòîðîâ GR. Ïîìèìî SNP â ëèòå-
ðàòóðå îïèñàíà ñåìåéíàÿ ìóòàöèÿ ãåíà NR3C1 ñ äå-
ëåöèåé ÷åòûðåõ íóêëåîòèäîâ, çàòðàãèâàþùàÿ èíò-
ðîííûé è ýêçîííûé ó÷àñòêè è âåäóùàÿ ê ïðåêðàùå-
íèþ ýêñïðåññèè ïîâðåæäåííîãî ãåíà [29].
Ìèññåíñíûå ïîëèìîðôèçìû. Èçâåñòíû 42
ìèññåíñíûå SNP, ïðèñóòñòâóþùèå â êàæäîì èç ÷å-
òûðåõ äîìåíîâ áåëêà (òàáë. 5). Ïðè ýòîì, êàê âèä-
íî èç äàííûõ ýòîé òàáëèöû, íàèáîëüøåå êëèíè-
÷åñêîå çíà÷åíèå èìåþò ïîëèìîðôèçìû, çàòðàãè-
âàþùèå òðàíñàêòèâàöèîííûé è ëèãàíä-ñâÿçûâàþ-
ùèé äîìåíû. Îñíîâíûìè âèäàìè íàðóøåíèÿ ôóíê-
öèè ðåöåïòîðà ïðè ýòèõ ïîëèìîðôèçìàõ ñëóæàò:
1) çàìåäëåíèå òðàíñëîêàöèè àêòèâèðîâàííîãî
ðåöåïòîðà â ÿäðî (äîêàçàíî äëÿ rs104893912, rs121
909727 è rs104893908);
2) ñíèæåííàÿ àôôèííîñòü ê ãîðìîíó (äîêàçàíî
äëÿ rs121909727, rs104893908) èëè êîàêòèâàòîðàì
(äîêàçàíî äëÿ rs104893912, rs121909727);
3) íåñòàáèëüíîñòü ðåöåïòîðà (äîêàçàíî äëÿ rs
104893908);
4) ñíèæåíèå òðàíñàêòèâàöèîííîé àêòèâíîñòè (äî-
êàçàíî äëÿ rs104893912, rs121909727 è rs104893914;
ïðåäïîëàãàåòñÿ äëÿ rs148967394).
Ñðåäè ïîëèìîðôèçìîâ, ïðèâåäåííûõ â òàáë. 5,
ó ëþäåé êëèíè÷åñêè èññëåäîâàíû rs121909726,
rs56149945, rs104893909, rs104893910, rs104893911,
rs104893912, rs104893913, rs104893914, rs121909727.
Âñå îíè ÿâëÿþòñÿ ñëåäñòâèÿìè ìèññåíñíûõ ìóòà-
öèé, íàðóøàþùèõ ñòðóêòóðó áåëêà, è êàæäàÿ èç
íèõ âåäåò ê ðàçâèòèþ ãåíåðàëèçîâàííûõ ñåìåéíûõ
ôîðì ãëþêîêîðòèêîèäíîé ðåçèñòåíòíîñòè. Â ñëó-
÷àå rs104893911 ðåçèñòåíòíîñòü ñî÷åòàåòñÿ ñ ãèïî-
êàëèåìèåé è ïñåâäîãåðìàôðîäèòèçìîì [30]. Îñ-
íîâíûìè ñèìïòîìàìè ãëþêîêîðòèêîèäíîé ðåçè-
ñòåíòíîñòè âûñòóïàåò âûñîêèé óðîâåíü êîðòèçîëà
è ÀÊÒÃ â ïëàçìå êðîâè, ÷òî ìîæåò áûòü àññîöèèðî-
âàíî ñ óâåëè÷åíèåì êîíöåíòðàöèè ìèíåðàëîêîðòè-
êîèäíûõ ãîðìîíîâ è ïîëîâûõ ñòåðîèäîâ [30].
Áîëüøàÿ ÷àñòü ìèññåíñíûõ ïîëèìîðôèçìîâ, èçó-
÷åííûõ â ÷åëîâå÷åñêîé ïîïóëÿöèè, èìååò äîñòàòî÷-
íî íèçêóþ ÷àñòîòó ðàñïðîñòðàíåíèÿ; ïðè ýòîì ãîìî-
çèãîòû ïî ìóòàíòíûì àëëåëÿì ïðàêòè÷åñêè íå âñòðå-
÷àþòñÿ, âåðîÿòíî, èç-çà ñâîåé íåæèçíåñïîñîáíîñòè
(òàáë. 5). Íèçêàÿ ÷àñòîòà ãåòåðîçèãîò â ñâîþ î÷åðåäü
óêàçûâàåò íà ñóùåñòâåííîå äåéñòâèå îòðèöàòåëüíî-
ãî åñòåñòâåííîãî îòáîðà ïî îòíîøåíèþ ê ìóòàöèÿì
ãåíà NR3C1 [31], ÷òî ìîæåò áûòü ñâÿçàíî ñ åãî âàæ-
íîé ðîëüþ ïðè ñòðåññå è â ïðîöåññàõ àäàïòàöèè.
Ïîëèìîðôèçìû íåêîäèðóþùèõ îáëàñòåé ãå-
íà è äðóãèå ôîðìû íåìèññåíñíûõ ìóòàöèé. Áîëü-
øàÿ ÷àñòü SNP, âñòðå÷àþùèõñÿ ñðåäè ëþäåé, îòíî-
ñèòñÿ ê èíòðîííûì ïîñëåäîâàòåëüíîñòÿì ãåíà, íå-
ïîñòðåäñòâåííî ïðèëåãàþùèì ê ýêçîíàì [31]. Ïî-
ìèìî ýòîãî èçâåñòíû ìóòàöèè â àëüòåðíàòèâíûõ ýê-
çîíàõ, êîäèðóþùèõ èçîôîðìó GR-� ðåöåïòîðà; ìó-
òàöèè, äîáàâëÿþùèå äîïîëíèòåëüíûå àìèíîêèñëî-
òû â ñóùåñòâóþùèõ ýêçîíàõ. Îáùàÿ õàðàêòåðèñòè-
êà ýòèõ SNP äàíà â òàáë. 6.
Èç âñåõ ïîëèìîðôèçìîâ, ïåðå÷èñëåííûõ â òàáë.
6, ñëåäóåò îñîáî îñòàíîâèòüñÿ íà äâóõ, îáëàäàþ-
ùèõ íàèáîëüøèì êëèíè÷åñêèì çíà÷åíèåì: rs6198 è
rs41423247.
Ïîëèìîðôèçì rs6198 ïðåäñòàâëÿåò ñîáîé çàìå-
íó íóêëåîòèäà A íà G â ïîçèöèè 3669 (ýêçîí 9�)
[31]. Ìóòàíòíûé âàðèàíò âåäåò ê èçìåíåíèþ ñòà-
áèëüíîñòè âàðèàíòà GR-� ìÐÍÊ è, ñëåäîâàòåëüíî,
óñèëåíèþ åãî ñèíòåçà. Ýòà èçîôîðìà GR âûïîëíÿåò
ðîëü äîìèíàíòíîãî èíãèáèòîðà àêòèâíîé àëüôà-
ôîðìû ðåöåïòîðà, âûçûâàÿ ñíèæåíèå îòâåòà íà ãëþ-
êîêîðòèêîèäû. Òàêèì îáðàçîì, ìóòàíòíàÿ ôîðìà
ãåíà ïðîÿâëÿåòñÿ â áîëåå íèçêîì áàçàëüíîì óðîâíå
àðòåðèàëüíîãî äàâëåíèÿ [31], à òàêæå â ïîâûøåííîì
344
ÎÐËÎÂÑÊÈÉ Ì. À.
Îñíîâíîé ïðîìîòîð
Çîíà ãèïåðìåòèëèðîâàíèÿ
Ýêçîíû
Îáëàñòü àëüòåðíàòèâíûõ ïðîìîòîðîâ è ïåðâûõ ýêçîíîâ
Ïåðâûé àëüòåðíàòèâíûé
ïðîìîòîð
Ðèñ. 4. Ðåãèîíàëüíàÿ ïëîò-
íîñòü SNPs â ðàçëè÷íûõ çî-
íàõ ãåíà NR3C1
345
ÀËËÅËÜÍÛÉ ÏÎËÈÌÎÐÔÈÇÌ NR3C1 (GR): ÎÒ ÌÎËÅÊÓËßÐÍÎÉ ÁÈÎËÎÃÈÈ Ê ÊËÈÍÈÊÅ
dbSNP ID Çàìåíà
Ïîçèöèÿ â
áåëêå GR-�
Äîìåí
áåëêà
×àñòîòû (äèêèé/
ãåòåðî/ìóòàíòíûé)
Êëèíè÷åñêîå ñîñòîÿíèå Ìåõàíèçì
1 2 3 4 5 6 7
rs61759024 Pro � Ser 9 TAD 99,9/0,1/0; N = 4428 í/ä Âáëèçè ñàéòà ôîñôî-
ðèëèðîâàíèÿ Tre8
rs6190
ER22/23EK
Arg � Lys 23 TAD 90,3/9,7/0; N = 226
(åâðîï.)
Àññîöèèðîâàí ñ ãëþêîêîðòèêîèäíîé ðåçèñòåíòíî-
ñòüþ ïðè áîëåçíè Êðîíà [44]; â îäíîé ðàáîòå ïîêà-
çàíà ñâÿçü ïðîäóêöèè êîðòèçîëà ïðè ñîöèàëüíîì
ñòðåññå [45], â äðóãîé – åå íå âûÿâëåíî [46]
rs72481829 Asp � Asn 25 TAD 0,6/0/99,4; N = 356 í/ä í/ä
rs148102613 Phe � Leu 29 TAD 100/0/0; N = 4550 í/ä í/ä
rs143711342 Tyr � His 30 TAD 99,0/0,1/0; N = 4550 í/ä í/ä
rs148967394 Ser � Pro 44 TAD 100/0/0; N = 4550 í/ä Ïðèìûêàåò ê ñàéòó ôîñôî-
ðèëèðîâàíèÿ Ser45, â ñâÿçè
ñ ÷åì âîçìîæíî ñíèæåíèå
òðàíñàêòèâàöèîííîé ñïîñîá-
íîñòè ðåöåïòîðà
rs79138720 Val � Gly 50 TAD Íåêëèíè÷åñêèé
èñòî÷íèê
í/ä í/ä
rs6192 Phe � Val 65 TAD 99,2/0,8/0; N = 4450 Îòñóòñòâóåò âëèÿíèå íà áàçàëüíûé óðîâåíü
àðòåðèàëüíîãî äàâëåíèÿ [31]
rs145020010 Met � Val 98 TAD 100/0/0; N = 4222 í/ä í/ä
rs72542740 Gly � Arg 99 TAD 99,8/0,2/0; N = 526 í/ä í/ä
rs72481830 Asn � Ser 130 TAD 99,4/0,6; N = 360 í/ä í/ä
rs141093427 Phe � Leu 156 TAD 100/0/0; N = 4548 í/ä í/ä
rs186831584 Val � Ile 163 TAD î/í í/ä í/ä
rs146524172 Asn � Ser 180 TAD 100/0/0; N = 4550 í/ä í/ä
rs140309412 Asn � Ile 222 TAD 100/0/0; N = 4224 í/ä í/ä
rs72542742 Ala � Thr 229 TAD 99,7/0,3/0; N = 4132 í/ä í/ä
rs183372229 Leu � Phe 286 TAD î/í í/ä í/ä
rs72542743 Ile � Val 292 TAD Àëëåëè: 99,8/0,2;
N = 526
Âáëèçè ñàéòà ñóìîèëÿöèè Lys419
rs72542745 Ser � Gly 325 TAD Àëëåëè: 99,8/0,2;
N = 526
í/ä í/ä
rs72558022 Asp � His 346 TAD 94,4/5,6/0; N = 18 í/ä í/ä
rs148470701 Gln � Glu 347 TAD î/í í/ä í/ä
rs6195N363S Asn � Ser 363 TAD 95,8/4,2/0; N = 48
rs56149945 Asn � Ser
Asn � Ile
363 TAD 95,9/4,0/0/0; N =
4550
Èçâåñòåí êëèíè-
÷åñêèé ñëó÷àé
rs1800445 Asn � Ser 365 TAD î/í í/ä í/ä
Òàáëèöà 5
Èçâåñòíûå ìèññåíñíûå SNPs
ðèñêå ðåâìàòîèäíîãî àðòðèòà è ñèñòåìíîé êðàñíîé
âîë÷àíêè [32], ïî âñåé âèäèìîñòè, âñëåäñòâèå óñè-
ëåííîãî ïðîâîñïàëèòåëüíîãî îòâåòà, âûçâàííîãî
ñíèæåííîé ÷óâñòâèòåëüíîñòüþ ê ãëþêîêîðòèêîè-
äàì [31]. Ïîìèìî ýòîãî, ñîâìåñòíî ñ rs10482605
SNP ôîðìèðóåò ãàïëîòèï, ñâÿçàííûé ñ óâåëè÷åí-
íûì ðèñêîì ðàçâèòèÿ áîëüøîé äåïðåññèè [5]. Âñå-
ãî â ïîïóëÿöèè åâïðîïåîèäîâ â ÑØÀ ÷àñòîòà ìó-
òàíòíîé ôîðìû ñîñòàâëÿåò 19 %. SNP íîñèò äîìè-
íàíòíûé õàðàêòåð, ÷òî ïîçâîëÿåò ðàññìàòðèâàòü ãå-
òåðîçèãîòû â êà÷åñòâå ãðóïïû ðèñêà ïî îïèñàííûì
çàáîëåâàíèÿì.
346
ÎÐËÎÂÑÊÈÉ Ì. À.
1 2 3 4 5 6 7
rs147136661 Ser � Phe 370 TAD 100/0/0; N = 4544 í/ä í/ä
rs145046100 Thr � Ala 413 TAD î/í í/ä í/ä
rs113048309 Ser � Pro 425 DBD î/í í/ä í/ä
rs104893913 Arg � His 477 DBD î/í í/ä í/ä
rs72542747 Thr � Ser 504 HD î/í í/ä í/ä
rs72481843 Gly � Ala 516 HD Åäèíè÷íûé ñëó÷àé í/ä í/ä
rs33391 Asn � Lys 517 HD Âîñåìü ñëó÷àåâ, â
ïîïóëÿöèè íå
âûÿâëåí
rs104893911 Val � Ala 571 LBD ? Âîçìîæíà ïàòîãåííîñòü
rs104893909 Ile � Asn 559 LBD Åäèíè÷íûé ñëó÷àé í/ä í/ä
rs104893908 Asp � Val 641 LBD Åäèíè÷íûé ñëó÷àé ÏÃÐ Ñíèæåííàÿ àôôèííîñòü ê ãîð-
ìîíó, íàðóøåííûé òðàíñïîðò
â ÿäðî, íåñòàáèëüíîñòü ðåöåï-
òîðà [39]
rs113100205 Val � Ile 658 LBD Îäíà ñåìüÿ í/ä í/ä
rs104893914 Gly � Ser 679 LBD î/í ÏÃÐ
Ñíèæåííîå òðàíñàêòèâà-
öèîííîå äåéñòâèå [47]
rs68012717 Asp � Glu 687 LBD î/í
rs121909727 Phe � Leu 737 LBD Åäèíè÷íûé ñëó÷àé ÎÃÐ Ñíèæåííàÿ àôôèííîñòü ê ãîð-
ìîíó, çàäåðæêà â ÿäåðíîé
òðàíñëîêàöèè è íàðóøåííîå
âçàèìîäåéñòâèå ñ NCOA2
(GR-interacting protein-1 co-
activator) [48]
rs104893910 Ile � Met 747 LBD ?
rs121909726 Leu � Phe 753 LBD î/í
rs186936077 Asn � Asp 766 LBD î/í
rs104893912 Leu � Pro 773 LBD Åäèíè÷íûé ñëó÷àé ÎÃÐ Äâóêðàòíîå ñíèæåíèå òðàíñ-
àêòèâàöèîííîé ñïîñîáíîñòè,
äîìèíàíòíî-íåãàòèâíîå âëèÿ-
íèå íà äèêèé òèï ðåöåïòîðà,
çàìåäëåííûé ïåðåíîñ â ÿäðî,
íàðóøåííîå âçàèìîäåéñòâèå ñ
NCOA2 [49]
Îêîí÷àíèå òàáë. 5
Ñëåäóþùèé ðàñïðîñòðàíåííûé ïîëèìîðôèçì
rs41423247, èìåíóåìûé òàêæå BclI, ñâÿçàí ñ çàìå-
íîé C íà G â ïîçèöèè 41503, ñîîòâåòñòâóþùåé èí-
òðîííîé çîíå ãåíà [33]. Ýòî ïîçâîëÿåò ïðåäïîëî-
æèòü ñâÿçü ìóòàöèè ñ ìåõàíèçìàìè àëüòåðíàòèâíî-
ãî ñïëàéñèíãà ìÐÍÊ è èçìåíåííîé ïðîäóêöèåé èçî-
ôîðì ðåöåïòîðà. ×àñòîòà ìèíîðíîãî àëëåëÿ ñîñòàâ-
ëÿåò 26,4 %, ÷òî äåëàåò äàííûé ïîëèìîðôèçì îä-
íèì èç íàèáîëåå âñòðå÷àþùèõñÿ âàðèàíòîâ ãåíà
NR3C1 â ÷åëîâå÷åñêîé ïîïóëÿöèè. SNP âûçûâàåò
ïîâûøåííóþ ÷óâñòâèòåëüíîñòü ê ãëþêîêîðòèêîèä-
íûì ãîðìîíàì [33]. Âî ìíîãèõ èññëåäîâàíèÿõ ó íî-
ñèòåëåé BclI ïîêàçàí ïîâûøåííûé ðèñê ïðèâû÷-
íîãî íåâûíàøèâàíèÿ áåðåìåííîñòè [34], áðîíõè-
àëüíîé àñòìû [35], íåáëàãîïðèÿòíîãî òå÷åíèÿ þâå-
íèëüíîãî àðòðèòà [36], ÷òî ìîæåò ÿâëÿòñÿ ðåçóëüòà-
347
ÀËËÅËÜÍÛÉ ÏÎËÈÌÎÐÔÈÇÌ NR3C1 (GR): ÎÒ ÌÎËÅÊÓËßÐÍÎÉ ÁÈÎËÎÃÈÈ Ê ÊËÈÍÈÊÅ
dbSNP ID Òèï SNP ×àñòîòà ìèíîðíîãî àëëåëÿ Îáëàñòü ìóòàöèè Êëèíè÷åñêîå çíà÷åíèå
rs7701443 A/G G: 46,8 %; N = 1022 Èíòðîí Ðåçèñòåíòíîñòü ê êîðòèêîñòåðîèäàì ó äåòåé ñ áîëåçíüþ
Êðîíà [44]
rs9324924 G/T T: 44,8 %; N = 978 Èíòðîí Äàííûõ î ñâÿçè ñ ãëþêîêîðòèêîèäíîé ðåçèñòåíòíîñòüþ íå
âûÿâëåíî [50]
rs4912911 A/G G: 44,8 %; N = 1000 Èíòðîí Ðåöåññèâíûé òèï ðåçèñòåíòíîñòè ê êîðòèêîñòåðîèäàì [44]
rs4607376 A/G G: 43,8 %; N = 957 Èíòðîí Äàííûõ î ñâÿçè ñ ãëþêîêîðòèêîèäíîé ðåçèñòåíòíîñòüþ íå
âûÿâëåíî [50]
rs6191 G/T G: 42,3 %; N = 923 Ýêçîí 9�/3'-ôëàí-
êèðóþùàÿ îáëàñòü
Âîçìîæíàÿ ñâÿçü ñ ëèòèåâîé ðåçèñòåíòíîñòüþ ó ïàöèåíòîâ ñ
áèïîëÿðíûìè ðàññòðîéñòâàìè [51]; ñâÿçü ñ äåïðåññèåé [51]
rs33388 A/T A: 41,6 %; N = 908 Èíòðîí Âîçìîæíàÿ ñâÿçü ñ ëèòèåâîé ðåçèñòåíòíîñòüþ ó ïàöèåíòîâ ñ
áèïîëÿðíûìè ðàññòðîéñòâàìè [51]; ñâÿçü ñ äåïðåññèåé [51];
íåò àññîöèàöèè ñ ðåâìàòîèäíûì àðòðèòîì [51]; íå ïîêàçàíî
ñâÿçè ñ äåïðåññèåé ó æåíùèí â ïðå-ìåíîïàóçå [52]
rs6198 A/G G: 9,2 %; N = 201 Ýêçîí 9�/3'-ôëàí-
êèðóþùàÿ îáëàñòü
Ñì. îïèñàíèå â òåêñòå
rs41423247 C/G C: 27,7 %; N = 604 Èíòðîí Ñì. îïèñàíèå â òåêñòå
rs6196 A/G G: 13,8 %; N = 302 Äîáàâëåíèå Asn
â 5-ì ýêçîíå
Ðåçèñòåíòíîñòü ê êîðòèêîñòåðîèäàì ó äåòåé ñ áîëåçíüþ
Êðîíà [44]; ñâÿçü ñ èçáûòî÷íîé ìàññîé òåëà [54]; íåò
âçàèìî- ñâÿçè ñ îòâåòîì íà ïñèõîñîöèàëüíûé ñòðåññ ó
äåòåé; àññî- öèàöèÿ ñ ïîâûøåííûì àðòåðèàëüíûì
äàâëåíèåì [31]
Òàáëèöà 6
Îñíîâíûå êëèíè÷åñêè çíà÷èìûå SNP â íåêîäèðóþùèõ îáëàñòÿõ ãåíà NR3C1
1A 1B 1C 2 3 4 5 6 7 8 9� 9�
1
9
8
2
10 11 12 13 14 15
7
6
5
3
4
*
*
Ðèñ. 5. Êàðòà SNP, âõîäÿùèõ â ñîñòàâ îñíîâíûõ ãàïëîòèïîâ ãåíà NR3C1 (ñîãëàñíî [31]). Äåòàëüíîå îïèñàíèå SNP è ãàïëîòèïîâ äàíî â òàáë. 7
òîì ñíèæåííîãî óðîâíÿ êîðòèêîñòåðîíà, íàáëþäà-
åìîãî èç-çà ïîâûøåííîé ÷óâñòâèòåëüíîñòè ðåöåï-
òîðîâ GR è àêòèâèðîâàííîé ïåòëå îòðèöàòåëüíîé
îáðàòíîé ñâÿçè ðåãóëÿöèè àêòèâíîñòè HPA [37].
Äðóãèå ôîðìû ïîëèìîðôèçìîâ, îïèñàííûå
êëèíè÷åñêè. Ñðåäè âñåõ èçâåñòíûõ ïîëèìîðôèç-
ìîâ ãåíà NR3C1 îñîáîå ìåñòî çàíèìàþò ìóòàöèè,
âûÿâëåííûå â åäèíè÷íûõ ñëó÷àÿõ èëè â ñåìüÿõ è
èìåþùèå ÿðêóþ êëèíè÷åñêóþ êàðòèíó. Òàêèå ìó-
òàöèè ïîçâîëÿþò ãëóáæå ïîíÿòü ôóíêöèîíàëüíîå
çíà÷åíèå ðåöåïòîðà è ìåõàíèçìû êîíòðîëÿ åãî àê-
òèâíîñòè. Íèæå ïðèâåäåíà êðàòêàÿ õàðàêòåðèñòèêà
äâóõ èç òàêèõ ìóòàöèé, èìåþùèõñÿ â ëèòåðàòóðå.
 1976 ãîäó àâòîðàìè [38] îïèñàí êëèíè÷åñêèé
ñëó÷àé, â êîòîðîì ó ïàöèåíòà íàáëþäàëñÿ âûñîêèé
óðîâåíü ïðîäóöèðîâàíèÿ êîðòèçîëà è ÀÊÒÃ íà ôî-
íå ãèïåðòåíçèè è ãèïîêàëèåìèè ïðè îòñóòñòâèè èíûõ
îòêëîíåíèé.  èçó÷åííîé ïîçäíåå ÄÍÊ ïðîáàíäà
îáíàðóæåíà ìóòàöèÿ ïî òèïó SNP, ñîñòîÿùàÿ â çà-
ìåíå àñïàðàãèíà íà âàëèí â 641 ïîçèöèè GR-�, ñî-
îòâåòñòâóþùåé äîìåíó ñâÿçûâàíèÿ ñ ãîðìîíîì
(rs104893908) [39]. Ìóòàöèÿ ÿâèëàñü ïðè÷èíîé ñíè-
æåíèÿ àôôèííîñòè ê êîðòèçîëó, íàðóøåíèÿ òðàíñ-
ïîðòà ðåöåïòîðà â ÿäðî è åãî îáùåé íåñòàáèëüíîñ-
òè [39].
Ïðèìå÷àòåëüíû òðè êëèíè÷åñêèõ ñëó÷àÿ, âûÿâ-
ëåííûå àâòîðàìè ðàáîòû [29] â ñîñòàâå îäíîé äàò-
ñêîé ñåìüè, âûçâàííûå äåëåöèåé ÷åòûðåõ íóêëåî-
òèäîâ â äîíîðíîé ñïëàéñ-çîíå (ïðè ýòîì ïî äâà íóê-
ëåîòèäà îòíîñÿòñÿ ê çîíàì øåñòîãî èíòðîíà è ýê-
çîíà). Íîñèòåëÿìè êëèíè÷åñêîé ïàòîëîãèè îêàçà-
ëèñü îòåö è òðîå èç ïÿòè äåòåé; âñå ýòè ïàöèåíòû
èìåëè âûðàæåííûé ãèïåðêîðòèöèçì, îáóñëîâëåí-
íûé ôóíêöèîíèðîâàíèåì ëèøü ïîëîâèíû ðåöåïòî-
ðîâ GR. Ïðîáàíäîì ñòàëà äî÷ü ñ ãèïåðàíäðîãåíèç-
ìîì, âûçâàííûì êîìïåíñàòîðíîé ãèïåðïðîäóêöè-
åé êîðòèêîñòåðîèäíûõ ãîðìîíîâ [29].
Ãàïëîòèïû ãåíà NR3C1 ó ëþäåé. Â ðàáîòå [31]
ïðîâåäåíî äåòàëüíîå èññëåäîâàíèå ãàïëîòèïîâ ãå-
íà NR3C1, ñîñòîÿùèõ èç ðàçëè÷íûõ êîìáèíàöèé îò-
äåëüíûõ SNP, ðàñïðîñòðàíåííûõ ñðåäè îñíîâíûõ
ðàñîâûõ ïîïóëÿöèé àìåðèêàíöåâ. Â ðåçóëüòàòå âû-
ÿâëåíû âîñåìü îñíîâíûõ ãàïëîòèïîâ, ñîñòîÿùèõ èç
äâóõ è áîëåå SNP, âñòðå÷àþùèõñÿ â àññîöèàöèÿõ
ïðè çíà÷åíèÿõ êîýôôèöèåíòà êîððåëÿöèè 0,8 è âû-
øå (ðèñ. 5, òàáë. 7). Ïîìèìî ýòîãî àâòîðû âûäåëèëè
348
ÎÐËÎÂÑÊÈÉ Ì. À.
Ãàïëîòèï SNP ID Îáëàñòü SNP
1 –1225 Äèñòàëüíûé ïðîìîòîð
rs6868190 Äèñòàëüíûé ïðîìîòîð
2 rs10482616 Èíòðîí 1C
rs10482672 Èíòðîí 3
3 rs852978 Èíòðîí 3
rs6196 Ýêçîí 9� (äîáàâà÷íàÿ Asn)
rs258748 3'-ôëàíêèðóþùàÿ îáëàñòü
4 rs852979 Èíòðîí 3
rs6188 Èíòðîí 4
rs258813 Èíòðîí 7
rs258750 Èíòðîí 8
5 rs6191 Ýêçîí 9�/3'-ôëàíêèðóþùàÿ îáëàñòü
rs258747 3'-ôëàíêèðóþùàÿ îáëàñòü
6 rs10482605 Ïðîêñèìàëüíûé ïðîìîòîð
rs10482605 Èíòðîí 2
rs123324 Èíòðîí 3
rs10482689 Èíòðîí 6
rs6198
Ýêçîí 9�/3'-ôëàíêèðóþùàÿ îáëàñòü
(AUUUA-ïîñëåäîâàòåëüíîñòü)
rs17287758 3'-ôëàíêèðóþùàÿ îáëàñòü
7 rs4986593 Èíòðîí 2
rs17209237 3'-ôëàíêèðóþùàÿ îáëàñòü
8 rs10482604 Ïðîêñèìàëüíûé ïðîìîòîð
rs6192 Ýêçîí 2 (Phe � Val)
rs10043662 Ýêçîí 9�/3'-ôëàíêèðóþùàÿ îáëàñòü
9 –921 Äèñòàëüíûé ïðîìîòîð
10 rs6195 Ýêçîí 2 (Asn � Ser)
11 rs41423247 Èíòðîí 2 (BclI)
12 rs10482669 Èíòðîí 3
13 rs10482682 Èíòðîí 5
14 rs258751 Ýêçîí 8 (äîáàâî÷íûé Asp)
15 rs6193 Ýêçîí 9�/3'-ôëàíêèðóþùàÿ îáëàñòü
Òàáëèöà 7
Îïèñàíèå îñíîâíûõ ãàïëîòèïîâ ãåíà NR3C1, âñòðå÷àþùèõñÿ â
ïîïóëÿöèÿõ àôðîàìåðèêàíöåâ, ìåêñèêàíñêèõ è åâðîïåéñêèõ àìå-
ðèêàíöåâ ([31])
ñåìü äîïîëíèòåëüíûõ ãàïëîòèïîâ, âêëþ÷àùèõ ëèøü
îäíó SNP, êîòîðûå ïðè ýòîì äîñòàòî÷íî ÷àñòû ñðå-
äè àìåðèêàíöåâ èëè èìåþò ñóùåñòâåííîå êëèíè÷åñ-
êîå çíà÷åíèå. Ïðè ýòîì óñòàíîâëåíî, ÷òî ãàïëîòèïû
¹¹ 2 è 3 ñòàòèñòè÷åñêè äîñòîâåðíî ñâÿçàíû ñ ïî-
âûøåííûìè óðîâíÿìè àðòåðèàëüíîãî äàâëåíèÿ [31].
Ê ñîæàëåíèþ, íà ñåãîäíÿøíèé äåíü íàì íå óäà-
ëîñü íàéòè äðóãèõ èññëåäîâàíèé ãàïëîòèïîâ ãåíîâ
NR3C1, îáëàäàþùèõ äîñòàòî÷íîé ðåïðåçåíòàòèâ-
íîñòüþ.
Âûâîäû. Ñîâðåìåííàÿ ìåäèöèíñêàÿ íàóêà íà-
÷èíàåò ïåðåõîäèòü â îáëàñòü, îáúåäèíÿþùóþ ðå-
çóëüòàòû ãåíåòè÷åñêèõ è ìîëåêóëÿðíî-áèîëîãè÷å-
ñêèõ èññëåäîâàíèé ñ êëèíè÷åñêîé ïðàêòèêîé. Âíè-
ìàíèå ó÷åíûõ ïîñòåïåííî ïåðåìåùàåòñÿ îò èçó÷å-
íèÿ ìîíîãåííûõ çàáîëåâàíèé, îáëàäàþùèõ íèçêîé
ðàñïðîñòðàíåííîñòüþ, íî ÿðêîé è ñïåöèôè÷åñêîé
êëèíè÷åñêîé êàðòèíîé, ê àíàëèçó ìîëåêóëÿðíûõ ìå-
õàíèçìîâ ïîëèãåííûõ, ìíîãîôàêòîðûõ áîëåçíåé,
âñòðå÷àþùèõñÿ ïîâñåìåñòíî è èìåþùèõ ìíîæåñòâî
êëèíè÷åñêèõ âàðèàíòîâ è òèïîâ òå÷åíèÿ.  ýòîì îò-
íîøåíèè îñîáûé èíòåðåñ ïðåäñòàâëÿþò ðåöåïòîðû
ãëþêîêîðòèêîèäíûõ ãîðìîíîâ, ÿâëÿþùèåñÿ îäíè-
ìè èç êëþ÷åâûõ ðåãóëÿòîðîâ èììóíîëîãè÷åñêèõ,
ñòðåññîðíûõ è àäàïòàöèîííûõ ïðîöåññîâ.
Ïðîâåäåííîå èçó÷åíèå ñâÿçè ìîëåêóëÿðíîé áèî-
ëîãèè è ãåíåòèêè ðåöåïòîðîâ GR ñ ðàçâèòèåì ðàç-
ëè÷íûõ ôîðì êëèíè÷åñêè âûðàæåííûõ ïàòîëîãè-
÷åñêèõ ñîñòîÿíèé è çàáîëåâàíèé ðàñêðûâàåò íîâûå
âîçìîæíîñòè äëÿ äàëüíåéøèõ èññëåäîâàíèé â îá-
ëàñòè ïàòîôèçèîëîãèè è òåðàïèè «áîëåçíåé öèâè-
ëèçàöèè».
M. A. Orlovsky
Allelic polymorphism of glucocorticoid receptor NR3C1 (GR):
from molecular biology to clinical implications
O. O. Bogomoletz Institute of Physiology, NAS of Ukraine
Akademika Bogomoltsa Str., 4, Kyiv, Ukraine, 01004
Summary
Polymorphism of stress-related genes is a key factor determining diffe-
rence in the stress reactivity and resistance among humans. Glucocorti-
coid receptors are important actors of stress responses. This review is
focused on the molecular biology and clinical implications of gluco-
corticoid receptor gene polymorphism.
Keywords: glucocorticoid receptors, allelic polymorphism, SNP,
NR3C1, GR, stress-induced pathology.
Ì. Î. Îðëîâñüêèé
Àëåëüíèé ïîë³ìîðô³çì ðåöåïòîðà ãëþêîêîðòèêî¿äíèõ ãîðìîí³â
NR3C1 (GR): â³ä ìîëåêóëÿðíî¿ á³îëî㳿 äî êë³í³êè
Ðåçþìå
Ïîë³ìîðô³çì ãåí³â, ÿê³ áåðóòü ó÷àñòü ó ðåàë³çàö³¿ ñòðåñîðíî¿ â³ä-
ïîâ³ä³, º îäíèì ³ç êëþ÷îâèõ ôàêòîð³â, ùî âèçíà÷àþòü ðîçá³æíî-
ñò³ â ñòðåñ-ðåàêòèâíîñò³ ³ ðåçèñòåíòíîñò³ â ëþäñüê³é ïîïóëÿö³¿.
Ñåðåä ãåí³â – ðåãóëÿòîð³â ñòðåñó ó ïåðøó ÷åðãó âàðòî â³äçíà÷èòè
ãåíè ðåöåïòîð³â ãëþêîêîðòèêî¿ä³â.  îãëÿä³ íàäàíî äåòàëüíó õà-
ðàêòåðèñòèêó ìîëåêóëÿðíî¿ á³îëî㳿 äàíèõ ãåí³â, íà ï³äñòàâ³ ÷îãî
çðîáëåíî àíàë³ç ìîæëèâîãî çâ’ÿçêó íàéðîçïîâñþäæåí³øèõ âàð³àí-
ò³â SNP ç àëüòåðàö³ºþ ñòðåñîðíèõ ðåàêö³é òà ðîçâèòêîì êë³í³÷-
íî¿ ïàòîëî㳿.
Êëþ÷îâ³ ñëîâà: ãëþêîêîðòèêî¿äí³ ðåöåïòîðè, àëåëüíèé ïîë³-
ìîðô³çì, SNP, NR3C1, GR, çàõâîðþâàííÿ àäàïòàö³¿.
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Received 09.07.12
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