PKHD1 mutations in families requesting prenatal diagnosis for autosomal recessive polycystic kidney disease (ARPKD)
PKHD1 mutations in families requesting prenatal diagnosis for autosomal recessive polycystic kidney disease (ARPKD)
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DOI：
10.1002/humu.20019
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发表时间：
2004-01-01
期刊：
影响因子：
3.9
通讯作者：
Zerres, K
中科院分区：
文献类型：
--
作者：
Bergmann, C;Senderek, J;Zerres, K
常染色体隐性多囊肾病（ARPKD）是儿童最常见的遗传性肾囊性疾病之一。临床范围从死产和新生儿死亡到存活到成年。然而，在特定的家族中，患者通常表现出相似的表型。许多失去患有严重 ARPKD 孩子的家庭都希望得到早期可靠的产前诊断 (PD)。鉴于产前超声的局限性，这只能通过分子遗传学实现，1994 年，当 ARPKD 基因座 PKHD1 被定位到 6p 号染色体时，分子遗传学成为可能。然而，对于有诊断疑问或没有受影响儿童 DNA 的家庭来说，连锁分析可能很困难甚至不可能。在这种情况下，最近对 PKHD1 基因的鉴定为直接突变测试提供了基础。然而，由于基因尺寸较大、对编码蛋白功能特性缺乏了解以及剪接模式复杂，PKHD1突变分析面临重大挑战。因此，在严重受影响的 ARPKD 患者队列中描绘突变谱和可达到的突变检出率非常重要。在本研究中，我们通过 DHPLC 在一系列 40 个明显不相关的家庭中进行了 PKHD1 突变筛查，这些家庭至少有一个围产期或新生儿死亡的孩子。我们观察到了预期 80 个突变中的 68 个，对应的检出率为 85%。在已发现的突变中，有 23 种以前未曾报道过。我们披露了 29 个家族中的两种潜在突变以及十分之一的病例。因此，在除一个家族（98%）之外的所有家族中，我们能够鉴定出至少一种突变，证实 ARPKD 的诊断。预计大约三分之二的变化会截断蛋白质。检测到的错义突变是非保守性的，除了一个受影响的氨基酸残基外，所有受影响的氨基酸残基都被发现在小鼠直向同源物中是保守的。 PKHD1突变分析已被证明是建立ARPKD诊断的高效且有效的手段。 (C) 2004 Wiley-Liss, Inc.
Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary renal cystic diseases in children. The clinical spectrum ranges from stillbirth and neonatal demise to survival into adulthood. In a given family, however, patients usually display comparable phenotypes. Many families who lost a child with severe ARPKD desire an early and reliable prenatal diagnosis (PD). Given the limitations of antenatal ultrasound, this is only feasible by molecular genetics that became possible in 1994 when PKHD1, the locus for ARPKD, was mapped to chromosome 6p. However, linkage analysis might prove difficult or even impossible in families with diagnostic doubts or in whom no DNA of an affected child is available. In such cases the recent identification of the PKHD1 gene provides the basis for direct mutation testing. However, due to the large size of the gene, lack of knowledge of the encoded protein's functional properties, and the complicated pattern of splicing, significant challenges are posed by PKHD1 mutation analysis. Thus, it is important to delineate the mutational spectrum and the reachable mutation detection rate among the cohort of severely affected ARPKD patients. In the present study, we performed PKHD1 mutation screening by DHPLC in a series of 40 apparently unrelated families with at least one peri, or neonatally deceased child. We observed 68 out of an expected 80 mutations, corresponding to a detection rate of 85%. Among the mutations identified, 23 were not reported previously. We disclosed two underlying mutations in 29 families and one in 10 cases. Thus, in all but one family (98%), we were able to identify at least one mutation substantiating the diagnosis of ARPKD. Approximately two-thirds of the changes were predicted to truncate the protein. Missense mutations detected were nonconservative, with all but one of the affected amino acid residues found to be conserved in the murine ortholog. PKHD1 mutation analysis has proven to be an efficient and effective means to establish the diagnosis of ARPKD. (C) 2004 Wiley-Liss, Inc.