ÁÞËËÅÒÅÍÜ ÑÎ ÐÀÌÍ, ¹ 1 (111), 2004 ã. ÓÄÊ 575.224.2: 599.9 Â.Ë. Îñàêîâñêèé, Ë.Ã. Ãîëüäôàðá, Ô.À. Ïëàòîíîâ Ê ÂÎÏÐÎÑÓ ÏÐÎÈÑÕÎÆÄÅÍÈß SCA1-ÌÓÒÀÖÈÈ Â ßÊÓÒÑÊÎÉ ÏÎÏÓËßÖÈÈ Èíñòèòóò çäîðîâüÿ ÀÍ ÐÑ, ßêóòèÿ Èíñòèòóò íåâðîëîãèè íàöèîíàëüíûõ èíñòèòóòîâ çäîðîâüÿ ÑØÀ ßêóòñêèé íàó÷íûé öåíòð ÐÀÌÍ è Ïðàâèòåëüñòâà Ðåñïóáëèêè ßêóòèÿ  äàííîé ñòàòüå ðàññìàòðèâàåòñÿ ïðè÷èíà, ïî êîòîðîé ìóòàöèÿ ïîÿâèëàñü â ÿêóòñêîé ïîïóëÿöèè, à òàêæå âîçìîæíûå ìåõàíèçìû, ïîääåðæèâàþùèå åå â ïîïóëÿöèè. Èññëåäîâàíèå ãåíåòè÷åñêîé ñâÿçè ÿêóòñêîé ôîðìû ìóòàöèè SCA1 ñ íîñèòåëÿìè äàííîé ìóòàöèè â äðóãèõ ñòðàíàõ ïðîâîäèëîñü ñ ïîìîùüþ àíàëèçà ãàïëîòèïîâ, ñöåïëåííûõ ñ ìóòàíòíûì ãåíîì SCA1 íà 6-é õðîìîñîìå.  êà÷åñòâå ãåíåòè÷åñêèõ ìàðêåðîâ èñïîëüçîâàëèñü ìèêðîñàòåëëèòû D6S260, D6S1567, D6S285, òåñíî ñöåïëåííûå ñ êîíöàìè ìóòàíòíîãî ãåíà SCA1 íà 6-é õðîìîñîìå. Ñðàâíåíèå ãàïëîòèïîâ ó íîñèòåëåé SCA1 – ïðåäñòàâèòåëåé ìîíãîëüñêîé, êèòàéñêîé è àìåðèêàíñêîé ïîïóëÿöèé ÷åëîâåêà – ïîêàçûâàåò, ÷òî ÿêóòñêàÿ ìóòàöèÿ âîçíèêëà â ãàïëîòèïå, îòëè÷íîì îò ïåðå÷èñëåííûõ ïîïóëÿöèé. Êëþ÷åâûå ñëîâà: àòàêñèÿ, ìèêðîñàòåëëèò, ãàïëîòèï Íà òåððèòîðèè ßêóòèè ñàìîé ðàñïðîñòðàíåííîé íàñëåäñòâåííîé ïàòîëîãèåé â ÿêóòñêîé ïîïóëÿöèè íàñåëåíèÿ ÿâëÿåòñÿ àóòîñîìíî-äîìèíàíòíàÿ íàñëåäñòâåííàÿ ìîçæå÷êîâàÿ àòàêñèÿ – SCA1. Îäíîé èç ïðè÷èí íàêîïëåíèÿ ýòîé ïàòîëîãèè â ïîïóëÿöèè ìîæåò áûòü äëèòåëüíàÿ ãåîãðàôè÷åñêàÿ èçîëÿöèÿ ÿêóòñêîãî íàñåëåíèÿ. ×àñòîòà äàííîãî çàáîëåâàíèÿ ñîñòàâëÿåò 35 ñëó÷àåâ íà 10000 ÿêóòñêîãî íàñåëåíèÿ, êîòîðàÿ äëÿ äàííîé ïàòîëîãèè ÿâëÿåòñÿ îäíîé èç ñàìûõ âûñîêèõ â ìèðå.  äàííîé ñòàòüå ðàññìàòðèâàåòñÿ ïðè÷èíà, ïî êîòîðîé ìóòàöèÿ ïîÿâèëàñü â ÿêóòñêîé ïîïóëÿöèè, à òàêæå âîçìîæíûå ìåõàíèçìû, ïîääåðæèâàþùèå åå â ïîïóëÿöèè. Ìîëåêóëÿðíàÿ îñíîâà ðàçâèòèÿ ýòîé áîëåçíè îáóñëîâëåíà óäëèíåíèåì íåñòàáèëüíîãî òðèíóêëåîòèäíîãî (CAG) ïîâòîðà íàòèâíîãî ãåíà (àòàêñèíà-1) 6-é õðîìîñîìû. ×èñëî CAG-ïîâòîðîâ â íàòèâíîì ãåíå ó çäîðîâûõ ëþäåé âàðüèðóåò îò 25 äî 33, ïðè ýòîì ïîâòîð ïðåðûâàåòñÿ âêëþ÷åíèåì äâóõ îäèíî÷íûõ òðèïëåòîâ ÑÀÒ (…..CAG ÑÀÒ CAG ÑÀÒ CAG….). Ó áîëüíûõ äàííîé áîëåçíüþ ïîâòîð CAG ãåíà àòàêñèíà âàðüèðóåò îò 39 äî 60–70. Ïðè ýòîì ïîâòîð èñêëþ÷èòåëüíî ãîìîãåííûé, áåç âêëþ÷åíèÿ òðèïëåòà ÑÀÒ. Ìóòàöèÿ ñâÿçàíà ñ çàìåíîé òèìèíà òðèïëåòà ÑÀÒ íà ãóàíèí, ÷òî ïðèâîäèò ê íåñòàáèëüíîñòè ïîâòîðà ãåíà è åãî óäëèíåíèþ [2, 8].  ßêóòèè íàìè âûÿâëåíî 199 íîñèòåëåé ìóòàöèè, ó êîòîðûõ ÷èñëî àëëåëåé ñîñòàâëÿåò 24, âàðüèðóþùèõ – îò 39 äî 70 ïîâòîðîâ. Âñå íîñèòåëè ìóòàöèè ÿâëÿþòñÿ ëèöàìè ÿêóòñêîé íàöèîíàëüíîñòè è îòíîñÿòñÿ ê 11 áîëüøèì è 49 ìàëåíüêèì ðîäîñëîâíûì [1, 4]. Àíàëèç ýòèõ ðîäîñëîâíûõ íå ïîçâîëèë âûÿâèòü îáùåãî ðîäîíà÷àëüíèêà, ÷òî ìîæåò ñâèäåòåëüñòâîâàòü î äîñòàòî÷íî äðåâíåì ïðîèñõîæäåíèè ýòîé ìóòàöèè è óòåðå ðîäñòâåííûõ ñâÿçåé ââèäó ãëóáîêîé äàâíîñòè. Ðàñïðîñòðàíåíèå ìóòàöèè íà òåððèòîðèè ßêóòèè èìååò íåðàâíîìåðíûé õàðàêòåð. Âûÿâëåíî òðè î÷àãà íàêîïëåíèÿ íîñèòåëåé ìóòàöèè, ðàñïîëîæåí- íûõ â ðàçëè÷íûõ ãåîãðàôè÷åñêèõ ðåãèîíàõ ðåñïóáëèêè. Ýòî áàññåéí íèæíåãî òå÷åíèÿ ð. Èíäèãèðêà, Ëåíà-Àëäàíñêîå ìåæäóðå÷üå è áàññåéí âåðõíåãî òå÷åíèÿ ðåê Âèëþé è Ëåíà. Òàê êàê íàèáîëüøåå ãåíåòè÷åñêîå ðàçíîîáðàçèå ìóòàöèè (àëëåëåé) è èõ íàêîïëåíèå îòìå÷åíû â Ëåíà-Àëäàíñêîì ìåæäóðå÷üå, ìîæíî ïðåäïîëîæèòü, ÷òî èìåííî ýòîò ðåãèîí ÿâëÿåòñÿ èçíà÷àëüíûì ìåñòîì ðàñïðîñòðàíåíèÿ äàííîé ìóòàöèè íà òåððèòîðèè ßêóòèè. Äàëüíåéøàÿ ìèãðàöèÿ ïðåäñòàâèòåëåé äàííîãî ýòíîñà íà Ñåâåð ïðèâåëà ê âîçíèêíîâåíèþ î÷àãà çàáîëåâàíèÿ íà ð. Èíäèãèðêà, à ïîçäíåå – è â âåðõîâüå ðåê Âèëþé è Îëåêìà. Ýòè ìèãðàöèîííûå ñîáûòèÿ õîðîøî îñâåùåíû â èñòîðè÷åñêîé ëèòåðàòóðå. Äàííîå çàáîëåâàíèå ðàñïðîñòðàíåíî è õîðîøî èçâåñòíî â äðóãèõ ñòðàíàõ, â òîì ÷èñëå è äðóãèõ ðåãèîíàõ Ðîññèè. Îïèñàíû ñåìüè ñ áîëüøèìè ðîäîñëîâíûìè, ãäå èìåþòñÿ íîñèòåëè ìóòàöèè SCA1 â Èòàëèè, Ôðàíöèè, Ãåðìàíèè, Íèäåðëàíäàõ è ñòðàíàõ Âîñòî÷íîé Åâðîïû è Ðîññèè [6, 8].  Àçèè îíè îòìå÷åíû â Êèòàå, Ìîíãîëèè è ßïîíèè [3, 5, 7]. Èíòåðåñíî âûÿñíèòü ãåíåòè÷åñêèå ñâÿçè ÿêóòñêîé ôîðìû ìóòàöèè SCA1 ñ íîñèòåëÿìè äàííîé ìóòàöèè â äðóãèõ ñòðàíàõ. Åäèíñòâåííûì òåñòîì ñðàâíåíèÿ ìóòàöèè ó íîñèòåëåé ðàçíûõ ãåîãðàôè÷åñêèõ ðåãèîíîâ ÿâëÿåòñÿ àíàëèç ãàïëîòèïîâ, ñöåïëåííûõ ñ äàííîé ìóòàöèåé íà õðîìîñîìå. Ê ñîæàëåíèþ, àíàëèçû ãàïëîòèïîâ íîñèòåëåé ìóòàöèè ðàçíûõ ðåãèîíîâ ïðîâåäåíû íå ó âñåõ.  òàáë. ïðèâåäåíû ðåçóëüòàòû àíàëèçà ãàïëîòèïà ìèêðîñàòåëëèòîâ D6S260, D6S1567, D6S285, ñöåïëåííûõ ñ ìóòàíòíûì ãåíîì SCA1 ÿêóòñêèõ íîñèòåëåé. Äëÿ ñðàâíåíèÿ ïðèâåäåíû äàííûå êèòàéñêîé, ìîíãîëüñêîé è àìåðèêàíñêîé ïîïóëÿöèé. Èç òàáë. âèäíî, ÷òî íîñèòåëè ìóòàöèè SCA1 â òðåõ îïèñàííûõ âûøå î÷àãàõ íà òåððèòîðèè ßêóòèè èìåþò îäèíàêîâûé ãàïëîòèï, ÷òî óêàçûâàåò íà åäèíîãî ðîäîíà÷àëüíèêà äëÿ âñåõ íîñèòåëåé ìóòàöèè. Ñëåäî103 ÁÞËËÅÒÅÍÜ ÑÎ ÐÀÌÍ, ¹ 1 (111), 2004 ã. Òàáëèöà Ãàïëîòèïû ìèêðîñàòåëëèòîâ D6S260, D6S1567, D6S285, ñöåïëåííûõ ñ ìóòàíòíûì ãåíîì SCA1 â ðàçëè÷íûõ ïîïóëÿöèÿõ Ãåîãðàôè÷åñêèå ðåãèîíû ßêóòèÿ ×èñëî àíàëèçèðîâàííûõ õðîìîñîì Àëëåëè ìàðêåðíîãî ìèêðîñàòåëëèòà D6S260 D6S1567 D6S285 15 1 3 Ãàïëîòèïû Âèëþéñê 2 Àëäàí 8 15 1 3 15–1–3 15–1–3 Èíäèãèðêà 9 15 1 3 15–1–3 Ìîíãîëèÿ 2 7 1 3 7–1–3 Êèòàé 4 7 1 3 7–1–3 ÑØÀ 2 7 1 4 7–1–4 Ïðèìå÷àíèå. Ãåíåòè÷åñêîå ðàññòîÿíèå ìåæäó ìàðêåðàìè D6S260 è D6S1567 ñîñòàâëÿåò 3,50 ñÌ; D6S1567 è D6S285 – 0,80 ñÌ. âàòåëüíî, â èñòîðè÷åñêîì ïðîøëîì ÿêóòîâ èìåëè ìåñòî áûòü ìèãðàöèîííûå ñîáûòèÿ. Ôàêò åäèíîãî ïðåäêà ó ÿêóòîâ – íîñèòåëåé ìóòàöèè SCA1 – è íåâîçìîæíîñòü ïðîñëåäèòü ðîäîâûå ñâÿçè ó 60 ðîäîñëîâíûõ äðåâ ñâèäåòåëüñòâóþò î ïðîäîëæèòåëüíîì âðåìåííîì èíòåðâàëå, ïðîøåäøåì ñ ìîìåíòà âîçíèêíîâåíèÿ ìóòàöèè. Ñðàâíåíèå ñî÷åòàíèÿ àëëåëåé òðåõ ìàðêåðîâ (ãàïëîòèïîâ) ó íîñèòåëåé SCA1 – ïðåäñòàâèòåëåé ìîíãîëüñêîé, êèòàéñêîé è àìåðèêàíñêîé ïîïóëÿöèè ÷åëîâåêà – ïîêàçûâàåò, ÷òî ÿêóòñêàÿ ìóòàöèÿ âîçíèêëà â ãàïëîòèïå, îòëè÷íîì îò ïåðå÷èñëåííûõ ïîïóëÿöèé. Ê ñîæàëåíèþ, íåò ñâåäåíèé î ãàïëîòèïàõ åâðîïåéñêèõ ïîïóëÿöèé. Ìîæíî ëèøü ïðåäïîëîæèòü, ÷òî áîëüøèå ìèãðàöèè íàðîäîâ Åâðîïû â Àìåðèêó, ïðîèñõîäèâøèå â òå÷åíèè ïîñëåäíèõ òðåõ–÷åòûðåõ âåêîâ, âïîëíå ìîãëè ïðèâåñòè ê ñõîäñòâó àìåðèêàíñêîãî è åâðîïåéñêîãî ãàïëîòèïîâ ó íîñèòåëåé ìóòàöèè.  òî æå âðåìÿ, ìîæíî îäíîçíà÷íî ñêàçàòü, ÷òî ïðîèñõîæäåíèå ìóòàöèè ãåíà SCA1 íå èìååò ãåíåòè÷åñêèõ êîðíåé ñ ìîíãîëüñêèìè è êèòàéñêèìè íîñèòåëÿìè ìóòàöèè SCA1. Âîïðîñ î âîçìîæíîñòè ïðîèñõîæäåíèÿ äàííîé ìóòàöèè â íåäðàõ ñàìîé ÿêóòñêîé ïîïóëÿöèè ïðåäñòîèò âûÿñíèòü ïðè ñðàâíåíèè ÿêóòñêèõ ãàïëîòèïîâ íîñèòåëåé ìóòàöèè SCA1 ñ åâðîïåéñêèìè, â îñîáåííîñòè ñ ðîññèéñêèìè. leads mutation of a gene SCA1 on 6 chromosome were used. The matching haplotids for the SCA1 bearer of the representatives of the Mongolian, Chinese and American population of the person demonstrates that the Yakutia mutation has arisen in haplotid distinct from listed populations. ËÈÒÅÐÀÒÓÐÀ 1. Áðàõôîãåëü È.Ô. Îñîáåííîñòè âíóòðèïîïóëÿöèîííîé äèíàìèêè ìóòàíòíîãî ãåíà SCA1 â ÿêóòñêîé ïîïóëÿöèè / È.Ô. Áðàõôîãåëü, Ô.À. Ïëàòîíîâ, Â.Ë. Îñàêîâñêèé // Áþë. ÑÎ ÐÀÌÍ. 1999. ¹ 3. Ñ. 117–120. 2. Ìîëåêóëÿðíî-ãåíåòè÷åñêèé ïîäõîä â èçó÷åíèè äîìèíàíòíûõ ñïèíîñåðåáåëëÿðíûõ àòàêñèé / Ñ.Í. Èëëàðèîøêèí, È.Â. Îâ÷èííèêîâ, È.À. Èâàíîâà-Ñìîëåíñêàÿ è äð. // Îáùèå âîïðîñû íåâðîëîãèè è ïñèõèàòðèè. 1996. ¹ 1. Ñ. 37–41. 3. Autosomal dominant spinocerebellar ataxia (SCA1) in a Siberian founder population: assignment to the SCA1 locus / Lunkes A., Goldfarb L.G., Platonov F.A., Alexeev V.P., Duenas-Barajas et al. // Expeximental Neurology. 1994. Vol. 126. P. 310–312 4. Brakhfogel I.F., Platonov F.A., Osakovsky V.L. Distribution of spinocerebellar ataxia type 1 gene mutation in Yakut population of Siberia // Human Genome Meeting, Edinburg, Scotland, 2001. Ð. 46. 5. Spinocerebellar ataxia 1 (SCA1) in the Japanese: analysis of CAG trinucleotide repeats expension and instability of the repeat for paternal transmission / Suzuki Y., Sasaki H., Wakisaka A. et al. // Jpn. J. Hum. Genet. 1995. Vol. 40. Ð. 131–143. 6. Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 family with dominant, recessive, or sporadic ataxia / Ranum L.P.W., Lundgren J.K., Schut L.J. et al. // Am. J. Hum. Genet. 1995. Vol. 57. P. 603–608. 7. The CAG repeats number of spinocerebellar ataxia type 1 gene in normal Taiwanese and in patients with dominant inherited ataxia / Hsieh M.L., Yang C.Y., Tsai H.F. et al. // Proc. Natl. Sci. Counc. Repub. China. 1997. Vol. 21 (3). P. 91–95. 8. Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1 / Goldfarb L.G., Vasconcelos Î., Platonov F.A. et al. // Annals of Neurology. 1996. Vol. 39. ¹ 4. P. 500–506. TO A PROBLEM OF SCA1-MUTATION DERIVATION IN YAKUTIA POPULATION V.L. Osakovsky, L.G. Goldfarb, F.A. Platonov The reason leaded to SCA1-mutation in Yakutia population and probable mechanisms maintaining the mutation in population has been considered in the article. The frequency of this mutation in Yakutia population is one of the highest parameters in a world. Study of genetic connection of the Yakutia form of a mutation SCA1 with the bearers of the given mutation in other countries were conducted with the help of analysis haplotids, linked with a mutation on 6 chromosome. As markets the microsatellites D6S260, D6S1567, D6S285 intimately linked with test 104