Kelsey G D, Abeliovich D, McMahon C J, Whitehouse D, Corney G, Povey S, Hopkinson D A, Wolfe J, Mieli-Vergani G, Mowat A P
MRC Human Biochemical Genetics Unit, University College London.
J Med Genet. 1988 Jun;25(6):361-8. doi: 10.1136/jmg.25.6.361.
Deficiency of alpha 1 antitrypsin (Pi) is clinically heterogeneous and the unpredictability of the clinical manifestation in a person of phenotype PiZ, which may vary from severe childhood liver disease to normal health, is a problem in genetic counselling. This problem may increase as couples at risk who have not had an affected child are identified in screening programmes. One possibility is that genetic variation of other protease inhibitors may influence the prognosis. With this in mind we report the isolation of the human gene for alpha 1 antichymotrypsin (AACT) on a series of cosmid clones, with restriction mapping of about 70 kb around the gene. A probe pACE3.4 derived from the 5' end of the gene defines sequences which have been assigned to chromosome 14 using somatic cell hybrids and has been used to show a common TaqI polymorphism with allele frequencies of AACT6 = 0.7 and AACT3 = 0.3 in Europeans. pACE3.4 is closely linked to alpha 1 antitrypsin (maximum lod score in males +2.29 at theta = 0; in females Z = +6.11 at theta = 0.032). Analysis of Pi-AACT haplotypes in 31 families ascertained through PiZ or PiSZ subjects did not show any linkage disequilibrium. The distribution of AACT6 and AACT3 alleles in 16 unrelated PiZ patients presenting with childhood liver disease and five unrelated PiZ patients with adult chest disease did not differ significantly from each other. These results suggest that if genetic variation at the AACT locus does influence the outcome of alpha 1 antitrypsin deficiency, such variation is not in linkage disequilibrium with the AACT polymorphism reported here.
α1抗胰蛋白酶（Pi）缺乏在临床上具有异质性，PiZ表型个体临床表现的不可预测性（从严重的儿童肝病到健康正常）是遗传咨询中的一个问题。随着筛查项目中识别出未生育患病子女的高危夫妇，这个问题可能会加剧。一种可能性是其他蛋白酶抑制剂的基因变异可能影响预后。考虑到这一点，我们报告了在一系列黏粒克隆上分离出人类α1抗糜蛋白酶（AACT）基因，并对该基因周围约70kb进行了限制性图谱分析。从该基因5'端衍生的探针pACE3.4确定了一些序列，这些序列利用体细胞杂种被定位到14号染色体上，并已用于显示欧洲人中AACT6 = 0.7和AACT3 = 0.3等位基因频率的常见TaqI多态性。pACE3.4与α1抗胰蛋白酶紧密连锁（男性中最大lod分数在θ = 0时为+2.29；女性中在θ = 0.032时Z = +6.11）。通过PiZ或PiSZ个体确定的31个家庭中Pi - AACT单倍型分析未显示任何连锁不平衡。16例患儿童肝病的不相关PiZ患者和5例患成人胸部疾病的不相关PiZ患者中AACT6和AACT3等位基因的分布彼此之间无显著差异。这些结果表明，如果AACT基因座的基因变异确实影响α1抗胰蛋白酶缺乏的结果，那么这种变异与本文报道的AACT多态性不存在连锁不平衡。
