Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
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DOI：
10.1007/s10048-010-0269-y
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发表时间：
2011-02-01
期刊：
影响因子：
2.2
通讯作者：
Dahl, Niklas
中科院分区：
文献类型：
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作者：
Schuster, Jens;Sundblom, Jimmy;Dahl, Niklas
成人发病的常染色体显性脑白质营养不良 (ADLD) 伴有自主神经症状，表现为尿急、便秘、勃起功能障碍和直立性低血压，通常伴有锥体征和共济失调。周围神经传导正常。该疾病在初始阶段经常被误认为是多发性硬化症。磁共振成像（MRI）显示大脑和脊髓白质变化具有特征性模式，大脑轻度萎缩，脊髓萎缩更明显。 ADLD 与核纤层蛋白 B1 (LMNB1) 基因的重复有关，但重排传递表型的机制尚未完全确定。我们分析了四个不相关的家族，将 ADLD 与自主神经症状分开，以查找 LMNB1 基因的重复。单核苷酸多态性 (SNP) 阵列分析揭示了四个家族中每个家族先证者的整个 LMNB1 基因的新重复。然后，我们通过蛋白质印迹分析对来自两个可用家族的 5 名患者的外周白细胞中核纤层蛋白 B1 的表达进行了分析。发现核纤层蛋白 B1 的蛋白质水平显着增加。这些结果表明与 LMNB1 重复相关的 ADLD 表型是由核纤层蛋白 B1 蛋白水平增加介导的。此外，我们还发现，通过直接分析外周白细胞中的核纤层蛋白 B1，可以对具有自主神经症状的 ADLD 进行分子诊断。
Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.