Ilja Boor P K, de Groot Koen, Mejaski-Bosnjak Vlatka, Brenner Christiana, van der Knaap Marjo S, Scheper Gert C, Pronk Jan C
Department of Pediatrics/Child Neurology, VU University Medical Center, Amsterdam, The Netherlands.
Hum Mutat. 2006 Jun;27(6):505-12. doi: 10.1002/humu.20332.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive cerebral white matter disorder in children. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC is caused by mutations in the gene MLC1, which encodes a novel protein, MLC1. Since the first report, 50 mutations in this gene have been found. Mutations occur throughout the entire coding region and include all different types: 11 splice-site mutations; one nonsense mutation; 24 missense mutations; and 14 deletions and insertions. Until now, six polymorphisms within the coding sequence of MLC1 had been reported. In about 20% of the patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found. Several of the families, in which no mutations are found, also do not show linkage with the MLC1 locus, which suggests a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter, 3' and 5' untranslated regions (UTRs), and intron mutations, which may influence the amino acid composition of the end product. In this work we describe 13 novel mutations, including those found with extended mutation analysis on MLC patients. This study shows that extended mutation analysis is a valuable tool to identify at least some of the missing mutations. Therefore, we suggest extended mutation analysis for the MLC1 gene, if no mutations are found during standard analysis.
巨脑回伴皮质下囊肿性白质脑病（MLC）是一种儿童常染色体隐性遗传性脑白质疾病。该疾病在组织病理学上的特征为髓鞘分离和髓鞘内空泡形成。MLC由MLC1基因突变引起，该基因编码一种新蛋白MLC1。自首次报道以来，已在该基因中发现50种突变。突变遍布整个编码区，包括所有不同类型：11种剪接位点突变；1种无义突变；24种错义突变；以及14种缺失和插入突变。到目前为止，已报道了MLC1编码序列内的6种多态性。在约20%具有典型临床和MRI表现的患者中，未发现MLC1基因突变。在一些未发现突变的家族中，也未显示与MLC1基因座连锁，这提示存在第二个与MLC相关的基因。未发现突变也可能是进行标准突变分析的结果，这种分析可能会遗漏杂合缺失、启动子、3'和5'非翻译区（UTR）的突变以及内含子突变，而这些突变可能会影响终产物的氨基酸组成。在这项工作中，我们描述了13种新突变，包括在对MLC患者进行扩展突变分析时发现的突变。这项研究表明，扩展突变分析是识别至少一些缺失突变的有价值工具。因此，我们建议，如果在标准分析中未发现突变，应对MLC1基因进行扩展突变分析。
