PDF(Pubmed)
Abstract：
UNASSIGNED: To investigate whether the novel mutation of PKHD1 could cause polycystic kidney disease by affecting splicing with a recessive inheritance pattern.
UNASSIGNED: A nonconsanguineous Chinese couple with two recurrent pregnancies showed fetal enlarged echogenic polycystic kidney and oligoamnios were recruited. Pedigree WES, minigene splicing assay experiment and following bioinformatics analysis were performed to verify the effects, and inheritance pattern of diseasing-causing mutations.
UNASSIGNED: WES revealed that both fetuses were identified as carrying the same novel mutation c.3592_3628 + 45del, p.? and c.11207 T>C, p.(Ile3736Thr) in the PKHD1 gene (NM_138694.4), which inherited from the father and mother respectively. Both bioinformatic method prediction and minigene splicing assay experience results supported the mutation c.3592_3628 + 45del, p.? affects the splicing of the PKHD1 transcript, resulting in exon 31 skipping. Another missense mutation c.11207 T>C, p.(Ile3736Thr) has a low frequency in populations and is predicted to be deleterious by bioinformatic methods.
UNASSIGNED: These findings provide a direct clinical and functional evidence that the truncating mutations of the PKHD1 gene could lead to more severe phenotypes, and cause ARPKD as a homozygous or compound heterozygous pattern. Our study broadens the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and diagnosis of ARPKD.
UNASSIGNED: A nonconsanguineous Chinese couple with two recurrent pregnancies showed fetal enlarged echogenic polycystic kidney and oligoamnios were recruited. Pedigree WES, minigene splicing assay experiment and following bioinformatics analysis were performed to verify the effects, and inheritance pattern of diseasing-causing mutations.
UNASSIGNED: WES revealed that both fetuses were identified as carrying the same novel mutation c.3592_3628 + 45del, p.? and c.11207 T>C, p.(Ile3736Thr) in the PKHD1 gene (NM_138694.4), which inherited from the father and mother respectively. Both bioinformatic method prediction and minigene splicing assay experience results supported the mutation c.3592_3628 + 45del, p.? affects the splicing of the PKHD1 transcript, resulting in exon 31 skipping. Another missense mutation c.11207 T>C, p.(Ile3736Thr) has a low frequency in populations and is predicted to be deleterious by bioinformatic methods.
UNASSIGNED: These findings provide a direct clinical and functional evidence that the truncating mutations of the PKHD1 gene could lead to more severe phenotypes, and cause ARPKD as a homozygous or compound heterozygous pattern. Our study broadens the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and diagnosis of ARPKD.
摘要：
■研究PKHD1的新突变是否可以通过以隐性遗传方式影响剪接而引起多囊肾病。
■招募了一对有两次反复妊娠的非血缘中国夫妇，显示胎儿回声增大的多囊肾和羊膜少。谱系WES,小基因剪接实验和随后的生物信息学分析进行验证的效果，和致病突变的遗传模式。
■WES显示两个胎儿被鉴定为携带相同的新突变c.3592_362845del，p.？和c.11207T>C，p。（Ile3736Thr）在PKHD1基因（NM_138694.4）中，分别从父亲和母亲那里继承。生物信息学方法预测和小基因剪接实验的经验结果都支持c.3592_362845del突变，p。？影响PKHD1转录本的剪接，导致外显子31跳跃。另一个错义突变c.11207T>C，p。（Ile3736Thr）在种群中的频率较低，并且通过生物信息学方法预测是有害的。
■这些发现提供了直接的临床和功能证据，表明PKHD1基因的截短突变可能导致更严重的表型，并导致ARPKD为纯合或复合杂合模式。我们的研究拓宽了PKHD1基因的变异谱，为ARPKD的遗传咨询和诊断提供了依据。
■招募了一对有两次反复妊娠的非血缘中国夫妇，显示胎儿回声增大的多囊肾和羊膜少。谱系WES,小基因剪接实验和随后的生物信息学分析进行验证的效果，和致病突变的遗传模式。
■WES显示两个胎儿被鉴定为携带相同的新突变c.3592_362845del，p.？和c.11207T>C，p。（Ile3736Thr）在PKHD1基因（NM_138694.4）中，分别从父亲和母亲那里继承。生物信息学方法预测和小基因剪接实验的经验结果都支持c.3592_362845del突变，p。？影响PKHD1转录本的剪接，导致外显子31跳跃。另一个错义突变c.11207T>C，p。（Ile3736Thr）在种群中的频率较低，并且通过生物信息学方法预测是有害的。
■这些发现提供了直接的临床和功能证据，表明PKHD1基因的截短突变可能导致更严重的表型，并导致ARPKD为纯合或复合杂合模式。我们的研究拓宽了PKHD1基因的变异谱，为ARPKD的遗传咨询和诊断提供了依据。
