Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8
Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8
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DOI：
10.1007/s00439-011-1006-9
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发表时间：
2011-11-01
期刊：
影响因子：
5.3
通讯作者：
Ohno, Kinji
中科院分区：
文献类型：
--
作者：
Kaneko, Hiroshi;Kitoh, Hiroshi;Ohno, Kinji
常染色体显性遗传性成骨不全(OI)是由COL1A1或COL1A2突变引起的。我们在一个轻度OI的日本家系中发现了COL1A1外显子45中的一个显性错义突变c.3235G和gt；A，预测p.G1079S。由于外显子45的突变表现出轻微到致命的表型，我们测试了外显子剪接顺式元件的中断是否决定了临床表型，但没有检测到这样的突变。在日本家系中，幼年型高尿酸血症与OI共分离，但在先前报道的意大利和加拿大C.3235G>；A家系中没有发现。在确认三个家系中缺乏创建者单倍型后，我们分析了COL1A1所在的CHR 17上的PRPSAP1和PRPSAP2作为高尿酸血症的候选基因，但没有发现突变。接下来，我们对日本家族中两个兄弟姐妹的全部外显子进行了重新测序，并确定了ABCG2和SLC22A12中先前报道的与高尿酸血症相关的SNPs的数量可变。然而，同样的SNPs也在三个家系的正常人群中被检测到。然后，我们在17号染色体上的ZPBP2和GPATCH8中发现了两个错义SNV，它们与日本家庭中的高尿酸血症共分离。ZPBP2 p.T69I位于非保守区，经计算机分析预测为良性，而GPATCH8 p.A979P位于高度保守区，被预测为有害的，这使得p.A979P可能成为青少年起病高尿酸血症的候选对象。GPATCH8与COL1A1的距离仅为5.8Mbp，编码一个含有RNA加工结构域和锌指结构域的蛋白质，但其分子功能尚未阐明。
Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2. We identified a dominant missense mutation, c.3235G > A in COL1A1 exon 45 predicting p.G1079S, in a Japanese family with mild OI. As mutations in exon 45 exhibit mild to lethal phenotypes, we tested if disruption of an exonic splicing cis-element determines the clinical phenotype, but detected no such mutations. In the Japanese family, juvenile-onset hyperuricemia cosegregated with OI, but not in the previously reported Italian and Canadian families with c.3235G > A. After confirming lack of a founder haplotype in three families, we analyzed PRPSAP1 and PRPSAP2 as candidate genes for hyperuricemia on chr 17 where COL1A1 is located, but found no mutation. We next resequenced the whole exomes of two siblings in the Japanese family and identified variable numbers of previously reported hyperuricemia-associated SNPs in ABCG2 and SLC22A12. The same SNPs, however, were also detected in normouricemic individuals in three families. We then identified two missense SNVs in ZPBP2 and GPATCH8 on chromosome 17 that cosegregated with hyperuricemia in the Japanese family. ZPBP2 p.T69I was at the non-conserved region and was predicted to be benign by in silico analysis, whereas GPATCH8 p.A979P was at a highly conserved region and was predicted to be deleterious, which made p.A979P a conceivable candidate for juvenile-onset hyperuricemia. GPATCH8 is only 5.8 Mbp distant from COL1A1 and encodes a protein harboring an RNA-processing domain and a zinc finger domain, but the molecular functions have not been elucidated to date.