Molecular genetics of Huntington's disease: When size does matter

Huntington Hastalığı (HH) geç başlangıçlı ve ilerleyici bir merkezi sinir sistemi hastalığıdır. Hastalığın görülme sıklığı Avrupa kökenli bireylerde yaklaşık olarak 1/100 000'dir. Huntington Hastalığı'nın klinik semptomları motor disfonksiyonu, davranış değişiklikleri ve bilişsel bozukluklardır. Huntington Hastalığı'nın patolojisi beyinle sınırlıdır ve en belirgin nöropatolojik bulgu striyatumda selektif nöron kaybıdır. İnsan HH geni (IT-15) kromozom 4pl6.3'e haritalanmıştır ve 180 kb DNA üzerinde 67 eksondan oluşur. Hastalığa yol açan mutasyon, genin birinci eksonundaki polimorfik CAG tekrarlarının sayısındaki artıştır. Huntington Hastalığı, mutasyonun ilgili genlerdeki CAG tekrarlarının artışı olduğu dokuz hastalıktan biridir. Bu hastalıklar "Poliglutamin Hastalıkları" olarak adlandırılır. Huntington Hastalığı'nda normal kromozomlar 6-35 CAG tekrarı, mutasyona uğramış kromozomlar ise 36-250 CAG tekrarı taşırlar. Hastalık başlangıç yaşı ile CAG tekrar sayısı arasında ters orantı vardır. Hastalığın moleküler tanısı 1993'ten itibaren mümkündür, ancak moleküler test sonucunun doğurabileceği olumsuz sonuçlardan kaçınılması için genetik danışmanlık protokolleri ve etik kurallar gözetilmelidir.

Huntington hastalığının moleküler genetiği

Huntington's Disease (HD) is a late-onset and progressive neurodegenerative disease of the central nervous system with autosomal dominant inheritance. The prevalence of the disease is about 1/100 000 among individuals of European descent. The clinical symptoms of HD involve motor dysfunction, behavioural disturbances and cognitive decline. The pathology of HD is restricted to the brain, and the predominant neuropathological hallmark is selective loss of neurons within the striatum. The human HD gene (IT-15) was localized to chromosome 4pl6.3 and consists of 67 exons spanning 180 kb of DNA. The mutation underlying disease is the expansion of the highly polymorphic CAG repeat tract in the first exon of the HD gene In fact, HD belongs to a group of disorders for which the causative mutation is the expansion of CAG repeats in the respective genes. A total of nine such conditions have been described so far, which are collectively described as "Polyglutamine Diseases". In HD, normal chromosomes possess 6-35 CAG repeats; mutated chromosomes carry 36-250 repeat units. There is a strong inverse correlation between the age of onset and expanded CAG repeat length. The direct molecular diagnosis for the disease is available since 1993, however genetic counseling protocols and ethical rules should be followed in order to avoid possible negative impli- cations of a molecular test result.

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