Camargos Sarah, Scholz Sonja, Simón-Sánchez Javier, Paisán-Ruiz Coro, Lewis Patrick, Hernandez Dena, Ding Jinhui, Gibbs J Raphael, Cookson Mark R, Bras Jose, Guerreiro Rita, Oliveira Catarina Resende, Lees Andrew, Hardy John, Cardoso Francisco, Singleton Andrew B
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lancet Neurol. 2008 Mar;7(3):207-15. doi: 10.1016/S1474-4422(08)70022-X. Epub 2008 Feb 1.
Dystonia and parkinsonism may present as part of the same genetic disorder. Identification of the genetic mutations that underlie these diseases may help to shed light on the aetiological processes involved.
We identified two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. We did autozygosity mapping and candidate gene sequencing in these families.
High-density genome-wide SNP genotyping revealed a disease-segregating region containing 277 homozygous markers identical by state across all affected members from both families. This novel disease locus, designated DYT16, covers 1.2 Mb at chromosome 2q31.2. The crucial interval contains 11 genes or predicted transcripts. Sequence analysis of every exon of all of these transcripts revealed a single disease-segregating mutation, c.665C>T (P222L), in the stress-response gene PRKRA, which encodes the protein kinase, interferon-inducible double-stranded RNA-dependent activator.
We describe a mutation within the gene PRKRA that segregates with a novel, autosomal recessive, dystonia parkinsonism syndrome. These patients have progressive, generalised, early-onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia and, in some cases, parkinsonian features, and do not respond to levodopa therapy.
肌张力障碍和帕金森症可能是同一种遗传疾病的表现形式。确定这些疾病背后的基因突变可能有助于阐明其中涉及的病因学过程。
我们鉴定了两个无关的家族，其成员患有一种明显的常染色体隐性、新型、早发型、全身性肌张力障碍帕金森症。我们对这些家族进行了纯合性定位和候选基因测序。
高密度全基因组单核苷酸多态性（SNP）基因分型显示，一个疾病分离区域包含277个在两个家族所有受影响成员中状态相同的纯合标记。这个新的疾病位点，命名为DYT16，位于2号染色体q31.2处，覆盖1.2兆碱基对。关键区间包含11个基因或预测转录本。对所有这些转录本的每个外显子进行序列分析，在应激反应基因PRKRA中发现了一个单一的疾病分离突变，c.665C>T（P222L），该基因编码蛋白激酶、干扰素诱导双链RNA依赖性激活剂。
我们描述了PRKRA基因内的一个突变，它与一种新型的常染色体隐性肌张力障碍帕金森症综合征相关。这些患者有进行性、全身性、早发型肌张力障碍，伴有轴性肌肉受累、口下颌（苦笑）、喉肌张力障碍，在某些情况下还有帕金森样特征，且对左旋多巴治疗无反应。
