In the patients with enzymopenic hereditary methemoglobinemia type I, a disease widely distributed on the territory of Yakutia, a search for the mutations in exons 3 and 4 of the DIA1 gene encoding NADH-cytochrome b5 reductase was carried out. It was shown that Yakut patients have none of three missence mutations, Arg57Gln, Leu72Pro, and Val105Met, described in case of this disease in the neighboring populations, Chinese and Japanese, inhabiting the territories south of Yakutia.

Проведен поиск мутаций в 3 и 4 экзонах гена D1A1, кодирующего NADH-цитохром Ь5 редуктазу, у больных с наследственной энзимопенической метгемоглобинемией I типа - заболевании, широко распространенном на территории Якутии. Показано, что в якутской популяции не встречается ни одна из трех миссенс-мутаций - Arg57Gln, Leu72Pro и Val105Met, описанных при данном заболевании в соседних популяциях, проживающих на территориях южнее Якутии, - у китайцев и японцев.

A maximum parsimony tree of 21 complete mitochondrial DNA (mtDNA) sequences belonging to haplogroup X and the survey of the haplogroup-associated polymorphisms in 13,589 mtDNAs from Eurasia and Africa revealed that haplogroup X is subdivided into two major branches, here defined as ""X1"" and ""X2."" The first is restricted to the populations of North and East Africa and the Near East, whereas X2 encompasses all X mtDNAs from Europe, western and Central Asia, Siberia, and the great majority of the Near East, as well as some North African samples. Subhaplogroup X1 diversity indicates an early coalescence time, whereas X2 has apparently undergone a more recent population expansion in Eurasia, most likely around or after the last glacial maximum. It is notable that X2 includes the two complete Native American X sequences that constitute the distinctive X2a clade, a clade that lacks close relatives in the entire Old World, including Siberia. The position of X2a in the phylogenetic tree suggests an early split from the other X2 clades, likely at the very beginning of their expansion and spread from the Near East.

Mutations causing familial hypertrophic cardiomyopathy (HCM) have been described in at least 11 genes encoding cardiac sarcomeric proteins. In this study, three previously unknown deletions have been identified in the human cardiac genes coding for beta-myosin heavy chain (MYH7 on chromosome 14) and myosin-binding protein-C (MYBPC3 on chromosome 11). In family MM, a 3-bp deletion in MYH7 was detected to be associated with loss of glutamic acid in position 927 (DeltaE927) of the myosin rod. In two other families (HH and NP, related by a common founder) a 2-bp loss in codon 453 (exon 16) of MYBPC3 was identified as the presumable cause of a translation reading frame shift. Taken together 15 living mutation carriers were investigated. Six deceased family members (with five cases of premature sudden cardiac death (SCD) in families MM and NP) were either obligate or suspected mutation carriers. In addition to these mutations a 25-bp deletion in intron 32 of MYBPC3 was identified in family MM (five carriers) and in a fourth family (MiR, one HCM patient, three deletion carriers). In agreement with the loss of the regular splicing branch point in the altered intron 32, a splicing deficiency was observed in an exon trapping experiment using MYBPC3 exon 33 as a test substrate. Varying disease profiles assessed using standard clinical, ECG and echocardiographic procedures in conjunction with mutation analysis led to the following conclusions: (1) In family MM the DeltaE927 deletion in MYH7 was assumed to be associated with complete penetrance. Two cases of reported SCD might have been related to this mutation. (2) The two families, HH and NP, distantly related by a common founder, and both suffering from a 2-bp deletion in exon 16 of MYBPC3 differed in their average phenotypes. In family NP, four cases of cardiac death were documented, whereas no cardiac-related death was reported from family HH. These results support the notion that mutations in HCM genes may directly determine disease penetrance and severity; however, a contribution of additional, unidentified factors (genes) to the HCM phenotype can-at least in some cases-not be excluded. (3) The deletion in intron 32 of MYBPC3 was seen in two families, but in both its relation to disease was not unequivocal. In addition, this deletion was observed in 16 of 229 unrelated healthy individuals of the population of the South Indian states of Kerala and Tamil Nadu. It was not seen in 270 Caucasians from Russia and western Europe. Hence, it is considered to represent a regional genetic polymorphism restricted to southern India. The association of the deletion with altered splicing in transfected cells suggests that this deletion may create a ""modifying gene"", which is per se not or only rarely causing HCM, but which may enhance the phenotype of a mutation responsible for disease.

Two polymorphisms in the IL4 (G/C 3'-UTR) and IL5 (C-703T) genes were studied in a sample of families whose probands had atopic bronchial asthma (BA) (66 families, n = 183) and in a group of non-cognate individuals with the severe form of the disease (n = 34). The samples were collected from the Russian population in the city of Tomsk (Russia). Using the transmission/disequilibrium test (TDT), a significant association of allele C-703 IL5 with BA was established (TDT = 4.923, p = 0.007 +/- 0.0007). The analysis of 40 individuals with mild asthma and 49 patients with the severe form of the disease revealed a negative association of genotype GG IL4 (OR = 0.39, 95% CI = 0.15-0.99, p = 0.035), and also a trend towards a positive association of the GC IL4 genotype (OR = 2.52, 95% CI = 0.98-6.57, p = 0.052) with mild BA. There was a concordance of the clinical classification of BA severity with the 'genotype' (McNemar's chi(2) test with continuity correction constituted 0.03, d.f. = 1, p = 0.859). These results suggest that polymorphisms in the IL4 and IL5 genes contribute to the susceptibility to atopic BA and could determine the clinical course of the disease.

Two tribal groups from southern India--the Chenchus and Koyas--were analyzed for variation in mitochondrial DNA (mtDNA), the Y chromosome, and one autosomal locus and were compared with six caste groups from different parts of India, as well as with western and central Asians. In mtDNA phylogenetic analyses, the Chenchus and Koyas coalesce at Indian-specific branches of haplogroups M and N that cover populations of different social rank from all over the subcontinent. Coalescence times suggest early late Pleistocene settlement of southern Asia and suggest that there has not been total replacement of these settlers by later migrations. H, L, and R2 are the major Indian Y-chromosomal haplogroups that occur both in castes and in tribal populations and are rarely found outside the subcontinent. Haplogroup R1a, previously associated with the putative Indo-Aryan invasion, was found at its highest frequency in Punjab but also at a relatively high frequency (26%) in the Chenchu tribe. This finding, together with the higher R1a-associated short tandem repeat diversity in India and Iran compared with Europe and central Asia, suggests that southern and western Asia might be the source of this haplogroup. Haplotype frequencies of the MX1 locus of chromosome 21 distinguish Koyas and Chenchus, along with Indian caste groups, from European and eastern Asian populations. Taken together, these results show that Indian tribal and caste populations derive largely from the same genetic heritage of Pleistocene southern and western Asians and have received limited gene flow from external regions since the Holocene. The phylogeography of the primal mtDNA and Y-chromosome founders suggests that these southern Asian Pleistocene coastal settlers from Africa would have provided the inocula for the subsequent differentiation of the distinctive eastern and western Eurasian gene pools.

Разработанные в настоящее время технологии сделали доступной пренатальную диагностику многих врожденных пороков развития и наследственных заболеваний. Более того, новые диагностические методы создали реальную возможность предупреждать рождение детей с грубой патологией невральной трубки, сердца, почек, скелета и др. Техника оперативного лечения врожденных пороков развития разрабатывается в течение последних 15 лет в эксперименте и клинике.

С целью выявления взаимосвязи между молекулами адгезии сыворотки крови и основными маркерами аллергического воспаления были обследованы 10 семей (n=49), в которых дети болели атопической бронхиальной астмой. Для всех семей собирали генеалогический и семейный анамнез, оценивали уровни IgA, IgM, IgG, общего IgE, ICAM-1, оценивали функцию внешнего дыхания и гиперреактивность бронхов, количество эозинофилов в мазках носовой слизи и клеточных элементах. в индуцированной мокроте подсчитывали. Выявлено участие молекул адгезии в поддержании позднего воспаления при бронхиальной астме, что приводит к повышению гиперчувствительности бронхов и прогрессированию заболевания.

В лекции изложены новые феномены в структурно-функциональной организации генома человека, оказавшиеся неожиданными для постулатов классической генетики (вольности генома), даны современные представления о формах наследственной изменчивости. Отмечено участие новых геномных явлений в патогенетике и выделении новых форм патологии человека (болезни прионные, митохондриальные, экспансии триплетных повторов, геномного импринтинга). Обосновано значение концепции синтропий в исследовании генетики мультифакториальных заболеваний. Высказан тезис о единстве трех разделов медицины - социальной, геномной и индивидуализированной. Актовая лекция, прочитанная 18 декабря 2001 года на заседании Ученого Совета Сибирского государственного медицинского университета.

Молекулярная генетика открыла принципиально новые перспективы в познании природы сахарного диабета (СД). Изучение генетических факторов риска при мультифакториальных заболеваниях, к которым относится и СД, имеет особенности, обусловленные концепцией молекулярной генетики об ассоциации полиморфных генетических маркеров с предрасположенностью или устойчивостью к развитию патологии. Изучение этих маркеров позволяет определить риск развития патологии, сформировать группы повышенного риска, организовать их мониторинг и в случае необходимости назначать превентивную терапию.

Для изучения клинических особенностей тяжелой бронхиальной астмы (БА) у детей в различные возрастные периоды было обследовано 60 пациентов.

В работе использован общепринятый комплекс, включающий сбор анамнеза, клиническое и аллергологическое обследование, функциональные и лабораторные методы.

Настоящей работой показано, что течение тяжелой БА имеет особенности в различных возрастных группах. Для раннего возраста характерны обострения на фоне ОРЗ, предшествующий или сопутствующий атопический дерматит, нередко пищевая сенсибилизация, низкая эффективность b2-агонистов. Для детей старшего возраста отмечается возрастание роли триггерных факторов, наличие психопатологических изменений, значительное влияние заболевания на ежедневное качество жизни, риск развития стероидной резистентности и осложнений БА.

Полученные данные позволяют полагать, что основным предиктором тяжелой БА у детей является высокий индекс атопии.