К ВОПРОСУ ПРОИСХОЖДЕНИЯ SCAL

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. Â 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