IMAMAURA Shin-ichiro Tokyo Women's Medical University School of Medicine, Assistant, 医学部, 助手 (00176497)
MINAMISAWA Susumu Tokyo Women's Medical University, School of Medicine, Assistant, 医学部, 助手 (40257332)
NAKAZAWA Makoto Tokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (10075567)
|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Conotruncal anomaly face syndrome (CAFS), DiGeorge syndrome (DGS), and velo-cardio-facial syndrome have similar but varying phenotypic spectra, I.e., cardiac defects, abnormal facies, thymic hypoplasia, cleft palate and hypocalcemia, and share deletion of 22q11.2 as a common feature. The aim of this study was to elucidate disease gene, phenotype/genotype correlation and deletion mechanism in del 22q11.2 syndrome.
We investigated the genome sequence of a candidate gene for del 22q11.2 syndrome, TBX1, in patients with DGS or CAFS/VCFS without the 22q11.2 deletion. We found three de novo point mutations of TBX1 in three sporadic and familial patients. To our knowledge, this is the first report showing that mutations of TBX1 could be responsible for del 22q11.2 syndrome.
To elucidate whether thrombocytopenia in del 22q11.2 syndrome patients is due to the hemizygosity of glycoprotein Ib-β and clarify the correlation between the phenotype and genotype of this gene in del 22q11.2 syndrome patie
nts with thrombocytopenia, we also measured the protein level of glycoprotein Ib-β in del 22q11.2 syndrome patients and controls, and analyzed phenotypes other than thrombocytopenia in these patients. The results showed that thrombocytopenia in patients with del 22q11.2 syndrome, who had a larger mean platelet volume, lower agglutination to ristocetin than control patients, is due to decreased expression of glycoprotein Ib-β. Since patients with del 22q11.2 syndrome show an increased risk of developing a psychotic disorder, patients with thrombocytopenia require total management, especially for the psychotic disorders.
In this study, we also showed in more detail that the chromosome breakpoints of del 22q11.2 syndrome occurred within two complex repeats, LCR22-2 and LCR22-4, that are 3 Mb apart and that the deletions arose from unequal meiotic recombination events. It is important to determine whether the chromosome breakpoints occur in clustered regions or at random sites of sequence homology, since elucidation of the mechanism in which the deletion generated is necessary. Less