LOCALIZATION OF AN ATAXIA-TELANGIECTASIA GENE TO CHROMOSOME 11Q22-23
LOCALIZATION OF AN ATAXIA-TELANGIECTASIA GENE TO CHROMOSOME 11Q22-23
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DOI：
10.1038/336577a0
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发表时间：
1988-12-08
期刊：
影响因子：
64.8
通讯作者：
YODER, F
中科院分区：
文献类型：
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作者：
GATTI, RA;BERKEL, I;YODER, F
共济失调-毛细血管扩张症（AT）是一种人类儿童期常染色体隐性遗传病1,2，其特征为：(1)进行性小脑共济失调伴浦肯野细胞变性；(2)成纤维细胞和淋巴细胞对电离辐射的超敏反应；(3)白人和黑人患者的癌症发病率分别增加61倍和184倍；(4)淋巴细胞的非随机染色体重排；(5)胸腺发育不全伴细胞和体液（IgA和IgG2）免疫缺陷；(6)血清甲胎蛋白水平升高；(7)过早老化；(8)内分泌紊乱，如胰岛素抵抗型糖尿病。DNA加工或修复蛋白被怀疑是这种病理的共同因素。杂合子通常是健康的；然而，他们培养的细胞对电离辐射的敏感性介于正常个体和受影响的纯合子之间。此外，杂合子女性患乳腺癌的风险更高7,8。这些发现，与估计的0.5-5.0%的携带频率相结合，表明(1)多达五分之一的乳腺癌女性可能携带AT基因7；(2)AT杂合子的辐射敏感性增加，可能导致放射治疗师减少用于治疗所有癌症患者的辐射剂量10。为了确定导致这种多方面疾病的遗传缺陷，并提供有效的携带者检测，我们对31个有at影响成员的家庭进行了遗传连锁分析。这使我们能够将AT基因定位在染色体11q22-23区域。
Ataxia-telangiectasia (AT) is a human autosomal recessive disorder of childhood1,2characterized by: (1) progressive cerebellar ataxia with degeneration of Purkinje cells; (2) hypersensitivity of fibroblasts and lymphocytes to ionizing radiation3; (3) a 61-fold and 184-fold increased cancer incidence in white and black patients, respectively4; (4) non-random chromosomal rearrangements in lymphocytes; (5) thymic hypoplasia with cellular and humoral (IgA and IgG2) immunodeficiencies; (6) elevated serum level of alphafetoprotein; (7) premature ageing; and (8) endocrine disorders, such as insulin-resistant diabetes mellitus. A DNA processing or repair protein is the suspected common denominator in this pathology5. Heterozygotes are generally healthy; however, the sensitivity of their cultured cells to ionizing radiation is intermediate between normal individuals and that of affected homozygotes6. Furthermore, heterozygous females are at an increased risk of breast cancer7,8. These findings, when coupled with an estimated carrier frequency of 0.5–5.0%, suggest that (1) as many as one in five women with breast cancer may carry the AT gene7and that (2) the increased radiation sensitivity of AT heterozygotes may be causing radiation therapists to reduce the doses of radiation used for treating cancer in all patients10. To identify the genetic defect responsible for this multifaceted disorder, and to provide effective carrier detection, we performed a genetic linkage analysis of 31 families with AT-affected members. This has allowed us to localize a gene for AT to chromosomal region 11q22-23.