Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex
Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex
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DOI：
10.1093/hmg/9.20.3037
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发表时间：
2000-12-12
影响因子：
3.5
通讯作者：
Stratakis, CA
中科院分区：
文献类型：
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作者：
Kirschner, LS;Sandrini, F;Stratakis, CA
Carney综合征（CNC）是一种常染色体显性遗传的多发性肿瘤综合征，与2 p16和17 q22 -24位点连锁。我们最近报道，PRKAR 1A，编码蛋白激酶A（PKA）的1A型调节亚基，是一个位于17号染色体上的肿瘤抑制基因，在一些CNC家族中发生突变。为了评估PRKAR 1A突变谱，我们鉴定了其基因组结构，并在54个CNC激酶（34个家族和20名散发性疾病患者）中筛选突变。14个家庭的信息连锁分析：4个家庭，映射到17 q的PRKAR 1A突变，而没有发现在7个家庭表现出至少一个与17 q的重组突变。在后者中的6个中，CNC定位于2 p16，PRKAR 1A突变也在20个无信息家族中的12个和20个散发病例中的7个中发现。总的来说，在54个激酶中的22个（40.7%）中鉴定出15个不同的PRKAR 1A突变。在14个突变中，预计序列变化会导致提前终止密码子;其中一个改变了起始密码子ATG。含有提前终止密码子的突变体mRNA是不稳定的，这是无义介导的mRNA衰变的结果。因此，在这些细胞中不存在预测的截短的PRKAR 1A蛋白产物。我们得出结论：（i）CNC中存在遗传异质性;（ii）17 q上的所有CNC等位基因都是PRKAR 1A的功能无效突变。CNC是第一种被认为是由PKA全酶突变引起的人类疾病，PKA全酶是细胞信号传导的关键组成部分。
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.