Muzyamba Morris, Farzaneh Tabasum, Behe Phillip, Thomas Alison, Christesen Henrik B T, Brusgaard Klaus, Hussain Khalid, Tinker Andrew
BHF Laboratories and Department of Medicine, University College London, London, UK.
Clin Endocrinol (Oxf). 2007 Jul;67(1):115-24. doi: 10.1111/j.1365-2265.2007.02847.x. Epub 2007 Apr 27.
Congenital hyperinsulinism (CHI) is a cause of persistent and severe hypoglycaemia in infancy. Mutations in the genes ABCC8 and KCNJ11 encoding SUR1 and Kir6.2, respectively, are the commonest cause of CHI. We investigated whether the possession of two DNA variants leading to coding changes in a single allele of ABCC8 can affect the potential mechanism of disease pathogenesis.
We studied two patients with complex mutations in the ABCC8 gene with CHI and used in vitro studies to explore the potential disease mechanism and the contribution of the various mutant allelles.
The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1. Channel complexes containing the D1193V mutant were delivered to the plasma membrane and were functional and those containing R1436Q were also present at the plasma membrane but were nonfunctional. Combining the two mutations (SUR1D1193V/R1436Q) led to intracellular retention of the channel complex. In a second family, the patient had histologically focal disease and was heterozygous for two mutations from his father (G228D and D1471N) and one from his mother (V1572I). SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function. By contrast, V1572I is trafficked appropriately and is functional, consistent with a mechanism of reduction to hemizygosity of paternal ABCC8 in focal disease. V1572I is likely to be a benign DNA variant.
In one patient the combination of two coding variants led to intracellular retention of channel complex. In a second patient, functional studies allowed us to unravel the DNA variants likely to be causing the abrogation of ATP-sensitive K(+) channel function.
先天性高胰岛素血症（CHI）是婴儿期持续性严重低血糖的一个病因。分别编码SUR1和Kir6.2的ABCC8和KCNJ11基因发生突变是CHI最常见的病因。我们研究了在ABCC8单等位基因中存在两个导致编码改变的DNA变异体是否会影响疾病发病机制的潜在机制。
我们研究了两名患有CHI且ABCC8基因存在复杂突变的患者，并通过体外研究来探索潜在的疾病机制以及各种突变等位基因的作用。
第一例为弥漫性疾病，SUR1中D1193V和R1436Q突变为纯合子。含有D1193V突变体的通道复合物被转运到质膜且具有功能，而含有R1436Q的通道复合物也存在于质膜但无功能。将这两个突变（SUR1D1193V/R1436Q）组合导致通道复合物在细胞内滞留。在第二个家族中，患者组织学上为局灶性疾病，其父亲的两个突变（G228D和D1471N）以及母亲的一个突变（V1572I）为杂合子。SUR1 G228D和D1471N单独或联合导致通道复合物在细胞内滞留并丧失功能。相比之下，V1572I被正确转运且具有功能，这与局灶性疾病中父本ABCC8半合子减少的机制一致。V1572I可能是一个良性DNA变异体。
在一名患者中，两个编码变异体的组合导致通道复合物在细胞内滞留。在另一名患者中，功能研究使我们能够阐明可能导致ATP敏感性钾（+）通道功能丧失的DNA变异体。
