Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation
Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation
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由于新的纯合 ABCC8 突变，先天性高胰岛素血症具有显着的临床异质性
DOI：
10.1111/cen.14443
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发表时间：
2021
影响因子：
3.2
通讯作者：
Morio Tomohiro
中科院分区：
文献类型：
--
作者：
Takasawa Kei;Miyakawa Yuichi;Saito Yoko;Adachi Eriko;Shidei Tsunanori;Sutani Akito;Gau Maki;Nakagawa Ryuichi;Taki Atsuko;Kashimada Kenichi;Morio Tomohiro
研究背景最严重的先天性高胰岛素血症（CHI）是由KATP通道基因KCNJ 11和ABCC 8失活突变引起的。对二氮嗪无反应和需要胰腺次全切除术通常可以通过遗传形式预测，特别是KATP通道基因的双等位基因突变。少数报告表明，在ABCC 8中具有相同双等位基因突变的同胞中存在显著的临床异质性。双等位基因KATP CHI的临床异质性被推测是由表观遗传和环境因素引起的，或者与剪接因子机制的差异有关。患者和方法我们报告了一个病例系列，其中包括两个兄弟姐妹和一个无关个体，他们患有CHI，这是由一个同源的1-bp缺失引起的。ABCC 8基因35号外显子突变的剪接受体位点，表现出明显不同的表型。为了评估剪接的突变的影响，我们进行了数字滴聚合酶链反应（ddPCR）对正常胰腺组织和病人的lymphocyte.ResultsddPCR ofABCC 8 cDNA显示，外显子35及其上游和下游区域的表达没有差异。这些数据表明，临床异质性可能不会造成剪接因子machinery.ConclusionThe纯合子的表型变异的差异剪接异常不能解释。虽然KATP CHI的早期基因诊断有助于选择适当的治疗方案，但由于双等位基因ABCC 8突变，可能需要更谨慎地选择弥漫性CHI的治疗方案。
BackgroundThe most severe forms of congenital hyperinsulinism (CHI) are caused by inactivating mutations of two KATP channel genes,KCNJ11andABCC8. Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly biallelic mutations in KATP channel genes. A few reports indicated marked clinical heterogeneity in siblings with identical biallelic mutations inABCC8. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by epigenetic and environmental factors or related to differences in splicing factor machinery.ObjectiveTo elucidate the clinical pathophysiology, especially heterogeneity, among three cases with CHI caused by a homogenous novel mutation.Patients and MethodsWe report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous 1‐bp deletion around the splice acceptor site at the exon 35 mutation ofABCC8, which exhibited markedly distinct phenotypes. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction (ddPCR) on normal pancreas tissue and a patient’s lymphocytes.ResultsddPCR ofABCC8cDNA revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery.ConclusionThe phenotypic variation in homozygotes could not be explained by splicing abnormalities. Though early genetic diagnosis of KATP CHI could contribute to selecting appropriate therapeutic options, more deliberate selection of therapeutic options in diffuse CHI due to biallelicABCC8mutations may be required.