Arcos-Burgos O M, Restrepo Arango T, Rivera Valencia D, Palacio L G, Castañeda M, Palacio O, Arboleda Velázquez J, Lopera Restrepo F
Grupo Genética Poblaciones y Epidemología Genética; Universidad de Antioquía. Facultad de Ciencias Exactas y Naturales. Depart. Biología, Medellín, Antioquía, Colombia.
Rev Neurol. 2001;32(8):701-4.
To perform linkage analysis between the Short Tandem Repeats (STR) microsatellite markers D19S923, D19S929, D19S22, which are in strong genetic linkage to Notch3 gene in order to contrast the hypothesis that the vascular hereditary dementia phenotype described in a multigenerational extended pedigree from Colombia correspond to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Even we know that using techniques as the Single Strand Conformational Polymorphisms (SSCP) could determine mutations in Notch3, the rationality of this approach is that intronic variations could not be defined and that we are interested in determine if some forms of the clinical presentation and its phenotypic variability make part of CADASIL.
The CADASIL phenotype is caused by mutations in the Notch3 gene. Clinical features of CADASIL are: 1. Recurrent cerebra-vascular episodes; 2. Migraine history; 3. History of transitory ischemic attack and, 4. Behavior changes and dementia.
By using SIMLINK we showed that the extended genealogy had the enough power to detect significant LOD (logarithm of oods) score values when Notch3 was considered the disorder cause. Linkage analysis was carried out by using parametric and non parametrical methods. The Elston-Stewart general method was used as the parametrical analysis and the sib pair method as the non-parametrical one. We perform simulations changing the affection status codification by including as affected or not including those individuals with migraine. Furthermore, in order to detect the stability of the results, we changed the penetrance values, the genetic frequencies on both, the marker loci and the affection locus.
The maximum pair-wise LOD score was 2.04 which was detected at the marker D19S23 with q= 0.11cM. This distance correspond exactly with the Notch3 location. That is 100 times more probable that there is linkage that there is not. In other words this probability could be explained as if the phenotype correspond to CADASIL than to other vascular dementia. The non parametric results were compatibles with the parametric ones. When the migraine symptom was considered as a part of the affected status, the LOD score values showed not linkage.
The results of the linkage analysis to these STR microsatellite markers suggest that the vascular hereditary dementia phenotype described in this family correspond to CADASIL caused by a polymorphism on the Notch3 gene. On the contrary, these same results suggest that the migraine phenotype is not a part of the progressive dementia.
对与Notch3基因存在强遗传连锁关系的短串联重复序列（STR）微卫星标记D19S923、D19S929、D19S22进行连锁分析，以验证来自哥伦比亚的一个多代大家庭中所描述的血管性遗传性痴呆表型是否符合伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）这一假说。即便我们知道使用单链构象多态性（SSCP）等技术能够确定Notch3基因的突变情况，但采用这种方法的合理性在于无法明确内含子变异情况，且我们想要确定某些临床表现形式及其表型变异性是否属于CADASIL的一部分。
CADASIL表型由Notch3基因突变引起。CADASIL的临床特征包括：1. 反复发生脑血管事件；2. 偏头痛病史；3. 短暂性脑缺血发作病史；4. 行为改变和痴呆。
通过使用SIMLINK软件，我们发现当把Notch3基因视为致病因素时，这个大家庭系具有足够的能力来检测到显著的对数优势（LOD）分值。采用参数法和非参数法进行连锁分析。参数分析采用Elston - Stewart通用方法，非参数分析采用同胞对法。我们通过改变患病状态编码进行模拟，包括将偏头痛患者视为患病或不视为患病。此外，为检测结果的稳定性，我们改变了外显率值、标记位点和致病位点的基因频率。
在标记D19S23处检测到最大成对LOD分值为2.04，其与Notch3基因的位置精确对应，该距离为0.11厘摩（cM）。存在连锁的可能性是不存在连锁的100倍。换言之，这种概率可以解释为该表型更符合CADASIL而非其他血管性痴呆。非参数分析结果与参数分析结果一致。当将偏头痛症状视为患病状态的一部分时，LOD分值显示无连锁关系。
对这些STR微卫星标记进行连锁分析的结果表明，这个家族中所描述的血管性遗传性痴呆表型符合由Notch3基因多态性导致的CADASIL。相反，同样的结果表明偏头痛表型并非进行性痴呆的一部分。
