Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young
Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young
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DOI：
10.1007/s00125-007-0798-6
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发表时间：
2007-11-01
期刊：
影响因子：
8.2
通讯作者：
Hattersley, A. T.
中科院分区：
文献类型：
--
作者：
Ellard, S.;Thomas, K.;Hattersley, A. T.
目的/假设葡萄糖激酶（GCK）和肝细胞核因子-1 α （HNF1A，也称为肝转录因子1 [TCF1]）基因的杂合突变是MODY最常见的原因。最近的研究表明，HNF1B（也称为TCF2）基因的基因组缺失导致了三分之一的肾囊肿和糖尿病综合征突变。我们调查了在符合GCK或HNF-1 α /-4 α MODY临床标准的英国患者中部分和全部基因缺失的发生率，这些患者中没有通过序列分析发现突变。方法采用合成的寡核苷酸探针，建立了GCK、HNF1A和HNF4A基因30个外显子的多重连接依赖探针扩增（MLPA）检测方法。结果GCK MLPA法和HNF1A/-4A MLPA法分别在1/29（3.5%）和4/60（6.7%）的先知者中检测到部分或全部基因缺失。检测到4种不同的缺失：GCK外显子2、HNF1A外显子1、HNF1A外显子2 ~ 10和HNF1A外显子1 ~ 10。另一个与HNF1A有关联的丹麦家系有外显子2至10的缺失。对其他家庭成员的检测证实了谱系中缺失突变与糖尿病的共分离。结论/解释包含整个外显子的大缺失可导致GCK或HNF-1 α MODY，并且不会通过测序检测到。基因剂量测定，如MLPA，是一个有用的辅助序列分析，当诊断MODY强烈怀疑。
Aims/hypothesis Heterozygous mutations of glucokinase (GCK) and hepatocyte nuclear factor-1 alpha (HNF1A; also known as hepatic transcription factor 1 [TCF1]) genes are the most common cause of MODY. Genomic deletions of the HNF1B (also known as TCF2) gene have recently been shown to account for one third of mutations causing renal cysts and diabetes syndrome. We investigated the prevalence of partial and whole gene deletions in UK patients meeting clinical criteria for GCK or HNF-1 alpha/-4 alpha MODY and in whom no mutation had been identified by sequence analysis.Methods A multiplex ligation-dependent probe amplification (MLPA) assay was developed using synthetic oligonucleotide probes for 30 exons of the GCK, HNF1A and HNF4A genes.Results Partial or whole gene deletions were identified in 1/29 (3.5%) probands using the GCK MLPA assay and 4/60 (6.7%) of probands using the HNF1A/-4A MLPA assay. Four different deletions were detected: GCK exon 2, HNF1A exon 1, HNF1A exons 2 to 10 and HNF1A exons 1 to 10. An additional Danish pedigree with evidence of linkage to HNF1A had a deletion of exons 2 to 10. Testing other family members confirmed co-segregation of the deletion mutations with diabetes in the pedigrees.Conclusions/interpretation Large deletions encompassing whole exons can cause GCK or HNF-1 alpha MODY and will not be detected by sequencing. Gene dosage assays, such as MLPA, are a useful adjunct to sequence analysis when a diagnosis of MODY is strongly suspected.