Zühlke C H, Spranger M, Spranger S, Voigt R, Lanz M, Gehlken U, Hinrichs F, Schwinger E
Institut für Humangenetik, Universität Lübeck, 23538 Lübeck, Germany.
Eur J Hum Genet. 2003 Aug;11(8):629-32. doi: 10.1038/sj.ejhg.5201018.
An expanded polyglutamine domain in the TATA-binding protein (TBP) has been described in patients with spinocerebellar ataxia type 17 (SCA17) characterized by cerebellar ataxia associated with dementia. TBP is a general transcription initiation factor that regulates the expression of most eukaryotic genes transcribed by RNA polymerase II. SCA17, as an autosomal dominantly inherited progressive neurodegenerative disorder, is caused by heterozygous expansion of a CAG repeat coding for glutamine. Alleles with 27 to a maximum of 44 glutamine residues were found as the normal range, whereas expansions above 45 repeat units were considered pathological. Here, we present a patient with a very severe phenotype with a late onset but rapidly progressing ataxia associated with dementia and homozygous 47 glutamine residues caused by an apparent partial isodisomy 6. This extraordinary case has important implications for the insights of TBP and SCA17. The expanded polyglutamine domain in both TBP copies is not correlated with embryonic death indicating that the normal function of the protein is not disrupted by this kind of mutation but may account for the dementia seen in this patient.
在患有17型脊髓小脑共济失调（SCA17）的患者中，已发现TATA结合蛋白（TBP）中的聚谷氨酰胺结构域有所扩展，这些患者的特征是小脑共济失调并伴有痴呆。TBP是一种通用转录起始因子，可调节大多数由RNA聚合酶II转录的真核基因的表达。SCA17是一种常染色体显性遗传的进行性神经退行性疾病，由编码谷氨酰胺的CAG重复序列的杂合性扩展引起。发现含有27至最多44个谷氨酰胺残基的等位基因为正常范围，而重复单元超过45个则被认为是病理性的。在此，我们报告了一名具有非常严重表型的患者，其发病较晚，但共济失调进展迅速，并伴有痴呆，且由明显的6号染色体部分等二体性导致纯合的47个谷氨酰胺残基。这一特殊病例对深入了解TBP和SCA17具有重要意义。两个TBP拷贝中的聚谷氨酰胺结构域扩展与胚胎死亡无关，这表明这种突变不会破坏该蛋白的正常功能，但可能是该患者出现痴呆的原因。
