Boğaziçi University, Department of Molecular Biology and Genetics, KP 301, Bebek, 34342 Istanbul, Turkey.
Parkinsonism Relat Disord. 2013 Mar;19(3):320-4. doi: 10.1016/j.parkreldis.2012.11.006. Epub 2012 Dec 2.
Familial parkinson's disease is both clinically and genetically heterogeneous. By mapping the disease locus with a lod score of 5.13 to a < 3.5 Mbp region at 1p31.3 in a consanguineous family and subsequent exome sequencing analysis, we identified homozygous truncating mutation p.Q734X in DNAJC6. Four members of the family were afflicted with juvenile parkinsonism that presented with mental retardation, pyramidal signs and epilepsy, as well as varying degrees of a progressive neurological disease. Recently a splicing mutation in the same gene was reported in two brothers with juvenile parkinsonism that was not L-Dopa responsive and not accompanied by pyramidal signs or mental retardation. Also, an 80-kb deletion that included DNAJC6 sequences was identified in a boy reported as having obesity, epilepsy and mental retardation but not any signs of parkinsonism. The phenotype of our study family resembles both of those families, which among themselves do not share any clinical features. Our findings further establish DNAJC6 as a juvenile parkinsonism gene, and expand the spectrums of the parkinsonism phenotype and DNAJC6 mutation. DNAJC6 encodes the neuronal co-chaperone auxilin. We found that its transcript is highly significantly more abundant in brain as compared to the non-neural tissues assayed.
家族性帕金森病在临床上和遗传上具有异质性。通过在一个有亲缘关系的家庭中将疾病定位与 1p31.3 上 < 3.5 Mbp 区域的连锁得分 5.13 映射，并进行随后的外显子测序分析，我们在 DNAJC6 中发现了纯合截短突变 p.Q734X。该家族的 4 名成员患有青少年帕金森病，表现为智力迟钝、锥体征和癫痫，以及不同程度的进行性神经疾病。最近，在两名患有青少年帕金森病的兄弟中报道了同一基因的剪接突变，该突变对 L-Dopa 无反应，不伴有锥体征或智力迟钝。此外，在一名被报道患有肥胖症、癫痫和智力迟钝但没有任何帕金森病迹象的男孩中，鉴定出包括 DNAJC6 序列的 80kb 缺失。我们研究的家族表型与这两个家族相似，它们彼此之间没有任何共同的临床特征。我们的发现进一步确立了 DNAJC6 为青少年帕金森病基因，并扩展了帕金森病表型和 DNAJC6 突变的范围。DNAJC6 编码神经元共伴侣 auxilin。我们发现，与检测的非神经组织相比，其转录本在大脑中显著更为丰富。
