Gasser T, Wszolek Z K, Trofatter J, Ozelius L, Uitti R J, Lee C S, Gusella J, Pfeiffer R F, Calne D B, Breakefield X O
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown.
Ann Neurol. 1994 Sep;36(3):387-96. doi: 10.1002/ana.410360310.
Linkage studies were performed in three families (A, B, and C) with autosomal dominantly inherited parkinsonism affecting multiple members in three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian symptoms responded to L-dopa treatment, and an [18F]6-fluoro-L-dopa positron emission tomography scan in 1 affected member of Family B showed decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern Germany and southern Denmark, suggesting the possibility of a common mutation. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxidase (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precursor protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, and CYP2D6, as well as to the chromosomal region containing the genes CAT and BDNF. If families were analyzed individually, exclusion was possible for two (Family A), six (Family B), and five (Family C) of the seven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave slightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.
对三个家族（A、B和C）进行了连锁研究，这三个家族患有常染色体显性遗传性帕金森病，三代中有多名成员患病。受影响个体表现出帕金森病的主要体征和症状，家族A、B和C中患者的平均发病年龄分别为51岁、62岁和61岁。帕金森症状对左旋多巴治疗有反应，家族B的1名受影响成员进行的[18F]6-氟左旋多巴正电子发射断层扫描显示纹状体摄取减少，这是帕金森病的典型表现。所有三个家族的祖先都追溯到德国北部和丹麦南部的一个小区域，提示存在共同突变的可能性。使用与以下候选基因相关的多态性标记进行了连锁研究：谷胱甘肽过氧化物酶基因（GPX1，3q11）、酪氨酸羟化酶基因（TH，11p15.5）、脑源性神经营养因子基因（BDNF，11p14）、过氧化氢酶基因（CAT，11p13）、淀粉样前体蛋白基因（APP，21q21）、铜锌超氧化物歧化酶基因（SOD1，21q21）和异喹胍4-羟化酶基因（CYP2D6，22q13.1）。所有家族的累积连锁分数排除了与基因GPX1、TH、APP、SOD1和CYP2D6以及包含基因CAT和BDNF的染色体区域的连锁。如果单独分析家族，七个候选基因中的两个（家族A）、六个（家族B）和五个（家族C）可以排除。除了TH（在家族A和B中无信息）和CYP2D6（在家族A中给出轻微阳性的成对连锁分数）外，在单独分析的所有家族中，有强有力的证据反对其余位点的连锁。我们的结果表明，所研究的候选基因不参与这些家族中帕金森病的病因。
