Genomic organization and lack of transcription of the nicotinic acetylcholine receptor subunit genes in myasthenia gravis-associated thymoma.
To investigate the relationship between anti-acetylcholine receptor (AchR) autoimmunity and the occurrence of thymoma in a particular group of myasthenia gravis (MG) patients we analyzed DNA and RNA from MG-associated thymomas and control tissue by Southern and Northern blotting, respectively, using the AchR alpha, beta, gamma, delta and epsilon-subunit cDNAs or oligonucleotides as probes. Restriction analysis of genomic DNA showed an organization of AchR subunit genes in thymomas identical with that of normal tissues. In particular, in thymomas, there was no deletion of exon 4 of the alpha-subunit which encodes the main immunogenic region of the AchR. Dot and Northern blot analysis did not reveal transcription of any AchR subunit gene in thymomas. Instead, an RNA nucleotide sequence was identified in MG-associated thymomas that hybridized to an AchR oligonucleotide probe coding for amino acids 371-378 of the AchR alpha-subunit. With this sequence as a probe, three DNA restriction fragments in addition to a restriction fragment of the AchR alpha-subunit gene could be identified in the human gene. The findings suggest that proteins with extensive homology to the AchR are not expressed in MG-associated thymomas. However, there are three genomic loci in thymoma genomes with a very restricted homology to the AchR alpha-subunit gene. One of these loci might code for the cross-reacting AchR epitope detected in almost all MG-associated thymomas in contrast to thymomas without MG.
Geuder
K I
KI
Pathologisches Institut, Universität Würzburg, Federal Republic of Germany.
Marx
A
A
Witzemann
V
V
Schalke
B
B
Kirchner
T
T
Müller-Hermelink
H K
HK
D000328:Adult; D000368:Aged; D001483:Base Sequence; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009157:Myasthenia Gravis / Q000150:complications / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011978:Receptors, Nicotinic / Q000235:genetics*; D015183:Restriction Mapping; D013945:Thymoma / Q000150:complications / Q000235:genetics*; D014158:Transcription, Genetic
D010446:Peptide Fragments; D012333:RNA, Messenger; D011978:Receptors, Nicotinic