A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.
A spectrum of mutations in the polycystic kidney disease-2 (PKD2) gene from eight Canadian kindreds.
复制标题
DOI：
--
复制
发表时间：
1998-10
期刊：
影响因子：
--
通讯作者：
Y. Pei;N. He;K. Wang;M. Kasenda;A. Paterson;G. Chan;Y. Liang;J. Roscoe;J. Brissenden;D. Hefferton;P. Parfrey;S. Somlo;P. S. St George-Hyslop
中科院分区：
文献类型：
--
作者：
Y. Pei;N. He;K. Wang;M. Kasenda;A. Paterson;G. Chan;Y. Liang;J. Roscoe;J. Brissenden;D. Hefferton;P. Parfrey;S. Somlo;P. S. St George-Hyslop
常染色体显性遗传性多囊肾病(ADPKD)是一种常见的孟德尔疾病，大约每1000名活产儿中就有一名受到影响。连锁研究表明，大多数病例(约85%)是由染色体16p上的PKD1突变引起的，而其余大多数病例是由染色体4q上的PKD2突变引起的。已知ADPKD的基因座异质性有助于疾病严重程度的差异，与PKD2连锁的家系相比，PKD1连锁的家族比PKD2连锁的家族更早发病终末期肾病(ESRD的平均年龄分别为56岁和70岁)。在这项研究中，对11个患有ADPKD的加拿大家庭进行了PKD2突变筛查。在四个家系中，先前记录了与PKD2相关的基因。在其余七个较小的家庭中，一个或多个受影响的成员在70岁或以上时患有晚发性终末期肾病。应用单链构象多态分析，从每个家系中筛选一个受影响的成员，检测PKD2的全部15个外显子的突变，这些外显子是从基因组模板中扩增出来的。在筛查的家系中，大约73%(8/11)发现了突变谱，PKD2连锁家系和晚发性ESRD家系之间的检测率没有差异。在3个不相关的家系中，在第11外显子上发现了腺苷在多聚腺苷链中的插入或缺失(即，(A)8，在第2152-2159位)，这表明该单核苷酸重复序列容易发生“滑链错配”的突变。所有分散在外显子1和11之间的突变都被预测会导致截短的多囊蛋白2，它既缺乏钙结合的EF-Hand结构域，也缺乏多囊蛋白2与多囊蛋白1及其自身相互作用所需的两个细胞质结构域。此外，未发现PKD2编码序列中突变的位置与疾病严重程度之间的相关性。因此，这些发现与最近发表的其他报告一致，表明大多数PKD2突变是失活的。
Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Linkage studies have shown that the majority (approximately 85%) of cases are due to mutations in PKD1 on chromosome 16p, while mutations in PKD2 on chromosome 4q account for most of the remaining cases. Locus heterogeneity in ADPKD is known to contribute to differences in disease severity, with PKD1-linked families having earlier onset of end-stage renal disease (ESRD) than PKD2-linked families (mean age at ESRD: 56 versus 70, respectively). In this study, 11 Canadian families with ADPKD were screened for PKD2 mutations. In four families, linkage to PKD2 was previously documented. In the remaining seven smaller families, one or more affected members had late-onset ESRD at age 70 or older. Using single-stranded conformational polymorphism analysis, one affected member from each family was screened for mutations in all 15 exons of PKD2, which were PCR-amplified from genomic templates. A spectrum of mutations was found in approximately 73% (8 of 11) of the families screened, with no difference in the detection rate between the PKD2-linked families and the families with late-onset ESRD. In three unrelated families, insertion or deletion of an adenosine in a polyadenosine tract (i.e., (A)8 at nt 2152-2159) was found on exon 11, suggesting that this mononucleotide repeat tract is prone to mutations from "slipped strand mispairing." All mutations, scattered between exons 1 and 11, are predicted to result in a truncated polycystin 2 that lacks both the calcium-binding EF-hand domain and the two cytoplasmic domains required for the interaction of polycystin 2 with polycystin 1 and with itself. Furthermore, no correlation was found between the location of the mutations in the PKD2 coding sequence and disease severity. Thus, these findings are consistent with other recently published reports and suggest that most PKD2 mutations are inactivating.