Roth D E, Venta P J, Tashian R E, Sly W S
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, MO 63104.
Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1804-8. doi: 10.1073/pnas.89.5.1804.
Deficiency of carbonic anhydrase II (carbonate hydro-lyase, EC 4.2.1.1) is the primary defect in the syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. In this report we describe the molecular basis for carbonic anhydrase II deficiency in the American family in which the association of carbonic anhydrase II deficiency with this syndrome was first recognized. The three affected siblings from this family are compound heterozygotes, each having inherited two different mutations in the structural gene for carbonic anhydrase II. The paternal mutation is a splice acceptor site mutation at the 3' end of intron 5. The maternal mutation is a missense mutation in exon 3 that substitutes a tyrosine for histidine-107. We show that the mutant enzyme expressed in bacteria from the cDNA containing the His-107----Tyr mutation has detectable, though greatly reduced, activity. We suggest that residual activity of the His-107----Tyr mutant enzyme may explain the absence of mental retardation and the relatively mild phenotype of carbonic anhydrase II deficiency in affected members of this family.
碳酸酐酶II（碳酸水解酶，EC 4.2.1.1）缺乏是骨质石化、肾小管酸中毒和脑钙化综合征的主要缺陷。在本报告中，我们描述了美国家庭中碳酸酐酶II缺乏的分子基础，在该家庭中首次认识到碳酸酐酶II缺乏与该综合征的关联。这个家庭中的三名患病兄弟姐妹是复合杂合子，每个人在碳酸酐酶II的结构基因中都继承了两个不同的突变。父系突变是内含子5 3'端的一个剪接受体位点突变。母系突变是外显子3中的一个错义突变，用酪氨酸替代组氨酸-107。我们表明，从含有His-107→Tyr突变的cDNA在细菌中表达的突变酶具有可检测到的活性，尽管活性大大降低。我们认为，His-107→Tyr突变酶的残余活性可能解释了该家族患病成员中智力迟钝的缺失以及碳酸酐酶II缺乏相对较轻的表型。
