AT LEAST 2 MUTANT ALLELES OF ORNITHINE DELTA-AMINOTRANSFERASE CAUSE GYRATE ATROPHY OF THE CHOROID AND RETINA IN FINNS
AT LEAST 2 MUTANT ALLELES OF ORNITHINE DELTA-AMINOTRANSFERASE CAUSE GYRATE ATROPHY OF THE CHOROID AND RETINA IN FINNS
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DOI：
10.1073/pnas.86.1.197
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发表时间：
1989-01-01
影响因子：
11.1
通讯作者：
VALLE, D
中科院分区：
文献类型：
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作者：
MITCHELL, GA;BRODY, LC;VALLE, D
脉络膜和视网膜（GA）的回旋状萎缩是由鸟氨酸δ缺乏引起的遗传性脉络膜视网膜变性。转氨酶（OAT; L-鸟氨酸：2-氧代酸转氨酶; EC 2.6.1.13）。GA是“芬兰遗传病”之一，这是一组在芬兰人群中发生频率增加的几种罕见的单基因疾病。使用RNase A保护，基因组克隆，和聚合酶链反应扩增基因组DNA的组合，我们发现两个错义突变OAT等位基因之一是存在于每个16芬兰GA家系。第一个突变R180 T，其中精氨酸-180被苏氨酸取代，是目前在纯合子形式的患者从两个家系。第二个突变L402 P，其中亮氨酸-402被脯氨酸取代，在14个家系的患者中以纯合形式存在。在19个芬兰对照组中，两种突变都不存在。L402 P在18例非芬兰GA患者中不存在，但在1例美国GA患者中发现了R180 T。我们构建了全长突变cDNA扩增患者的cDNA与聚合酶链反应和克隆到一个正常的人OAT cDNA的限制性片段含有突变。然后，这些突变cDNA在缺乏内源性OAT的CHO-K1细胞中表达。R180 T和L402 P均为双金属。这些结果表明，即使在芬兰人口GA等位基因的分子异质性。
Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine .delta.-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increased frequency in the Finnish population. Using a combination of RNase A protection, genomic cloning, and polymerase chain reaction amplification of genomic DNA, we found one of two missense mutant OAT alleles to be present in each of 16 Finnish GA pedigress. The first mutation R180T, in which arginine-180 is replaced by threonine, was present in homozygous form in patients from two pedigrees. The second mutation L402P, in which leucine-402 is replaced by proline, was present in homozygous form in patients from 14 pedigress. Neither mutation was present in 19 Finnish controls. L402P was not present in 18 non-Finnish GA patients but R180T was found in an American GA patient. We constructed full-length mutant cDNAs by amplifying patient cDNA with the polymerase chain reaction and cloning a restriction fragment containing the mutation into an otherwise normal human OAT cDNA. These mutant cDNAs were then expressed in CHO-K1 cells, which lack endogenous OAT. Both R180T and L402P inactivate OAT. These results show molecular heterogeneity in GA alleles even in the Finnish population.