Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy
Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy
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DOI：
10.1111/j.1399-0004.2010.01417.x
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发表时间：
2010-11-01
影响因子：
3.5
通讯作者：
Bassi, M. T.
中科院分区：
文献类型：
--
作者：
Tonelli, A.;Romaniello, R.;Bassi, M. T.
婴儿神经轴突营养不良症（INAD）是一种严重的进行性精神运动障碍，在婴儿期发病，其特征是整个中枢和周围神经系统中存在轴突球体。 INAD 患者的一个子集还表现出脑铁积累，这代表了伴有脑铁积累的特发性神经变性（NBIA）的独特特征。这些疾病具有相同的致病基因 PLA2G6，编码 iPLA2-VIA（一种不依赖于钙的磷脂酶）。导致蛋白质完全缺失的突变与严重的 INAD 谱相关，而可能具有残留蛋白质活性的复合杂合突变则与不太严重的 NBIA 表型相关。在这里，我们描述了两名 INAD 患者，两人的疾病进展异常迅速，其中一名患者具有特殊的神经放射学表现。在其中一个中发现了大基因内缺失和无义突变的复合杂合性，而另一个则携带两个新的剪接位点突变。断点序列分析表明非等位基因同源重组（NAHR）事件可能是重排的基础。这些发现在支持已在INAD患者中观察到的基因型-表型相关性的同时，提供了PLA2G6基因基因组重排的第一个序列特征，从而为寻找PLA2G6相关疾病中缺失的突变等位基因指明了方向。
Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase. Mutations that lead to a complete absence of protein are associated with a severe INAD profile, while compound heterozygous mutations with possibly a residual protein activity are instead associated with the less severe NBIA phenotype. Here we describe two INAD patients both with an unusually rapid disease progression and a peculiar neuroradiological presentation in one of them. Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one of them while the other is carrying two novel splice-site mutations. Breakpoint-sequence analysis suggests a non-allelic-homologous-recombination (NAHR) event, probably underlying the rearrangement. These findings, while supporting the genotype-phenotype correlation already observed in INAD patients, provide the first sequence characterization of a genomic rearrangement in PLA2G6 gene, thus orienting the search for missing mutant alleles in PLA2G6 related diseases.