DIFFERENT MISSENSE MUTATIONS AT THE TISSUE-NONSPECIFIC ALKALINE-PHOSPHATASE GENE LOCUS IN AUTOSOMAL RECESSIVELY INHERITED FORMS OF MILD AND SEVERE HYPOPHOSPHATASIA
DIFFERENT MISSENSE MUTATIONS AT THE TISSUE-NONSPECIFIC ALKALINE-PHOSPHATASE GENE LOCUS IN AUTOSOMAL RECESSIVELY INHERITED FORMS OF MILD AND SEVERE HYPOPHOSPHATASIA
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DOI：
10.1073/pnas.89.20.9924
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发表时间：
1992-10-15
影响因子：
11.1
通讯作者：
WHYTE, MP
中科院分区：
文献类型：
--
作者：
HENTHORN, PS;RADUCHA, M;WHYTE, MP
低磷酸酯酶症是一种可遗传的佝偻病/骨软化症，临床表现差异极大。严重的形式是遗传在一个常染色体隐性的方式，传播方式的轻度形式是不确定的。低磷酸酶症的生化标志是组织非特异性碱性磷酸酶同工酶（TNSALP）活性缺乏。以前，我们在一个近亲繁殖的婴儿中证明了编码TNSALP的基因的两个等位基因中的相同错义突变引起致命疾病。我们现在已经检查了TNSALP cDNA从四个无关的严重围产期或婴儿形式的低磷酸酶症患者。来自这四个个体的八个TNSALP等位基因中的每一个都含有引起氨基酸取代的不同点突变。在至少63名正常人中未检测到这些碱基变化，因此，似乎是4名患者中低磷酸酶症的原因。(Two在来自四个患者的每个患者的一个等位基因中发现的另外的碱基替换是连锁多态性。23例无关患者（50例筛选），反映了低磷酸酶症的整个临床谱，具有上述8种突变中的4种。在另外两名患者中，轻度形式的疾病也以常染色体隐性方式遗传。我们的研究结果表明，低磷酸酯酶症可以引起一些不同的错义突变，不同的TNSALP突变等位基因的特定相互作用可能是重要的，以确定临床表达。严重的形式，围产期和婴儿疾病，主要是不同的低磷酸酶症等位基因的复合杂合性的结果。至少有一些儿童和成人低磷酸酶症病例是以常染色体隐性遗传特征遗传的。
Hypophosphatasia is a heritable form of rickets/osteomalacia with extremely variable clinical expression. Severe forms are inherited in an autosomal recessive fashion; the mode of transmission of mild forms is uncertain. The biochemical hallmark of hypophosphatasia is deficient activity of the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Previously, we demonstrated in one inbred infant that an identical missense mutation in both alleles of the gene encoding TNSALP caused lethal disease. We have now examined TNSALP cDNAs from four unrelated patients with the severe perinatal or infantile forms of hypophosphatasia. Each of the eight TNSALP alleles from these four individuals contains a different point mutation that causes an amino acid substitution. These base changes were not detected in at least 63 normal individuals and, thus, appear to be causes of hypophosphatasia in the four patients. (Two additional base substitutions, found in one allele from each of the four patients, are linked polymorphisms.) Twenty-three unrelated patients (of 50 screened), who reflect the entire clinical spectrum of hypophosphatasia, possess one of four of the above eight mutations. In two of these additional patients, mild forms of the disease are also inherited in an autosomal recessive fashion. Our findings indicate that hypophosphatasia can be caused by a number of different missense mutations and that the specific interactions of different TNSALP mutant alleles are probably important for determining clinical expression. Severe forms, perinatal and infantile disease, are largely the result of compound heterozygosity for different hypophosphatasia alleles. At least some cases of childhood and adult hypophosphatasia are inherited as autosomal recessive traits.