Kirschner L S, Sandrini F, Monbo J, Lin J P, Carney J A, Stratakis C A
Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, Building 10, Room 10N262, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, MSC1862, Bethesda, MD 20892, USA.
Hum Mol Genet. 2000 Dec 12;9(20):3037-46. doi: 10.1093/hmg/9.20.3037.
Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome, which has been linked to loci on 2p16 and 17q22-24. We recently reported that PRKAR1A, which codes for the type 1A regulatory subunit of protein kinase A (PKA), is a tumor suppressor gene on chromosome 17 that is mutated in some CNC families. To evaluate the spectrum of PRKAR1A mutations, we identified its genomic structure and screened for mutations in 54 CNC kindreds (34 families and 20 patients with sporadic disease). Fourteen families were informative for linkage analysis: four of four families that mapped to 17q had PRKAR1A mutations, whereas there were no mutations found in seven families exhibiting at least one recombination with 17q. In six of the latter, CNC mapped to 2p16. PRKAR1A mutations were also found in 12 of 20 non-informative families and 7 of 20 sporadic cases. Altogether, 15 distinct PRKAR1A mutations were identified in 22 of 54 kindreds (40.7%). In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay. Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. We conclude that (i) genetic heterogeneity exists in CNC; and (ii) all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. CNC is the first human disease recognized to be caused by mutations of the PKA holoenzyme, a critical component of cellular signaling.
卡尼复合征（CNC）是一种常染色体显性遗传的多发性肿瘤综合征，与2p16和17q22 - 24位点相关。我们最近报道，编码蛋白激酶A（PKA）1A型调节亚基的PRKAR1A是17号染色体上的一个肿瘤抑制基因，在一些CNC家族中发生了突变。为了评估PRKAR1A突变的范围，我们确定了其基因组结构，并在54个CNC家族（34个家族和20例散发性疾病患者）中筛查突变。14个家族可用于连锁分析：定位到17q的4个家族中有4个存在PRKAR1A突变，而在与17q至少有一次重组的7个家族中未发现突变。在后者中的6个家族中，CNC定位到2p16。在20个非信息性家族中的12个以及20例散发性病例中的7个也发现了PRKAR1A突变。总共，在54个家族中的22个（40.7%）鉴定出了15种不同的PRKAR1A突变。在14种突变中，序列变化预计会导致提前出现终止密码子；一种改变了起始ATG密码子。由于无义介导的mRNA降解，含有提前终止密码子的突变mRNA不稳定。因此，这些细胞中预计的截短PRKAR1A蛋白产物缺失。我们得出结论：（i）CNC中存在遗传异质性；（ii）17q上所有的CNC等位基因都是PRKAR1A的功能无效突变。CNC是首个被认为由细胞信号传导关键成分PKA全酶突变引起的人类疾病。
