Poređenje broja CAG-ponovaka u genu za androgeni receptor u kontrolnoj jugoslovenskoj populaciji i kod bolesnika sa shizofrenijom

Abstract

INTRODUCTION Dynamic mutations were recently discovered causing hereditary non polyposis colon cancer. Soon almost 15 hereditary neurological diseases were described caused by the expansion of trinucleotide repeats in target genes. These mutations are unstable: the number of trinucleotide repeats is increasing from generation to generation. These mutations do not obey Mendelian low. There is a positive correlation between the number of repeats and the severity of clinical symptoms, as well as with the age of onset. This fact explains the genetical basis of anticipation. Since schizophrenia is showing non-Mendelian way of inheritance and anticipation, it is believed that it might be caused by trinucleotide repeats in some gene(s). We analyzed the number of CAG triplets in the gene for androgen receptor (AR) where expansions are causing spinal and bulbar muscular atrophy in healthy and schizophrenic subjects. The aim of this study was to see if the androgen receptor gene in schizophrenic patients shows instability in the number of trinucleotide repeats. PATIENTS AND METHODS In healthy Yugoslav population we analyzed 85 X chromosomes from 52 non-related individuals (33 females and 19 males) from healthy Yugoslav population and 84 X chromosomes (41 females and 2 males) from patients with schizophrenia. DNA was isolated from peripheral blood leukocytes and used for further PCR amplification of the segment of AR gene containing CAG repeats. The exact number of these repeats was determined by electrophoresis on a 5% denaturing polyacrilamide gel stained by silver. RESULTS In healthy Yugoslav population we detected 16 different AR alleles in which the number of CAG triplets was from 14 to 29. The most common alleles were with 23 repeats (14.1%) and with 22 repeats (12.9%). The average number of CAG triplets per allele was 20.91. In patients with schizophrenia we detected 13 AR different alleles. The number of triplets was from 17 to 30. The most common allele was with 22 repeats (25%). The average number of CAG triplets per allele was 22.1.

Ekspanzija trinukleotida CAG u genu za androgeni receptor dovodi do pojave nasledne neurodegeneracione bolesti: spinalne i bulbarne mišićne atrofije. Osim ove bolesti otkriveno je oko 15 naslednih neurodegeneracionih bolesti izazvanih ekspanzijama trinukleotida u određenim genima. Sve ove bolesti odlikuje fenomen anticipacije koji se objašnjava povećanjem broja tripleta iz generacije u generaciju, a što ima za posledicu raniji početak bolesti i težu kliničku sliku. Činjenica da shizofrenija, bipolarni poremećaji i autizam takođe pokazuju fenomen anticipacije, kao i znatan udeo genetičke komponente u patogenezi ove bolesti, razlog je za preduzimanje sve većih napora u potrazi za ekspanzijama trinukleotida u genomu bolesnika sa shizofrenijom. Kako molekularni mehanizam ovih ekspanzija nije poznat, a postoje indikacije da je reč o defektnom reparacionom sistemu DNK, pretpostavili smo da je možda kod bolesnika sa shizofrenijom povećan broj CAG-tripleta u genima koji sadrže triplete. U ovoj studiji izučavan je broj CAG-tripleta u genu za androgeni receptor u kontrolnoj jugoslovenskoj populaciji i kod bolesnika sa shizofrenijom.