NEW YORK – With the help of long-read sequencing, an international team led by investigators at the University of Utah and the University of Tübingen has narrowed in on a repeat expansion linked to a serious, rare late-onset neurological condition called spinocerebellar ataxia 4 (SCA4).

纽约——在长读测序的帮助下，由犹他大学和图宾根大学的研究人员领导的一个国际团队缩小了与一种严重，罕见的迟发性神经系统疾病称为脊髓小脑共济失调4（SCA4）相关的重复扩增的范围。

The team published its findings in Nature Genetics on Monday.

该团队于周一在《自然遗传学》杂志上发表了他们的发现。

'The only step to really improve the life of patients with inherited disease is to find out what the primary cause is,' senior and corresponding author Stefan Pulst, chair of neurology at the University of Utah's Spencer Fox Eccles School of Medicine, said in a statement.

犹他大学斯宾塞·福克斯·埃克尔斯医学院神经病学系主任、资深通讯作者斯特凡·普尔斯特在一份声明中说，真正改善遗传病患者生活的唯一步骤是找出主要原因。

In their search for the genetic culprit, researchers from the University of Utah, the University of Tübingen, and other centers used targeted long-read sequencing and bioinformatics on an extended pedigree spanning more than 15 nuclear families from Utah to assess a chromosome 16 region implicated in SCA4 through linkage analyses in the mid-1990s..

犹他大学、图宾根大学和其他中心的研究人员在寻找遗传罪魁祸首时，对犹他州超过15个核心家庭的扩展谱系进行了有针对性的长读测序和生物信息学研究，以评估20世纪90年代中期通过连锁分析与SCA4有关的16号染色体区域。。

'We were able to trace 15 nuclear families back to a likely common ancestor born in southern Sweden around the start of the 19th century using patient-provided information from census and ancestry records of the Church of Jesus Christ of Latter-day Saints,' the authors explained.

作者解释说：“我们利用患者提供的人口普查信息和耶稣基督后期圣徒教会的祖先记录，可以追溯到19世纪初左右出生在瑞典南部的15个核心家庭的共同祖先。”。

Along with available records from Utah, the team's Pacific Biosciences HiFi and Oxford Nanopore Technologies-based sequencing analyses led to an SCA4-associated GGC repeat expansion in the transcription factor-coding polyglycine (polyG) gene ZFHX3. In contrast to the 21 repeats present in unaffected individuals, SCA4 patients had more than 40 copies of the repeat..

根据犹他州的现有记录，该团队基于太平洋生物科学公司（Pacific Biosciences）HiFi和牛津纳米孔技术公司（Oxford Nanopore Technologies）的测序分析导致转录因子编码聚甘氨酸（polyG）基因ZFHX3中与SCA4相关的GGC重复扩增。与未受影响的个体中存在的21个重复序列相反，SCA4患者有40多个重复序列。。

When they screened nearly 6,500 genome sequence datasets, the researchers identified seven additional affected individuals from families in Lübeck, Munich, and Tübingen, Germany, who carried the same repeat expansion.

当他们筛选近6500个基因组序列数据集时，研究人员从慕尼黑吕贝克和德国蒂宾根的家庭中鉴定出另外7个受影响的个体，他们携带相同的重复扩增。

With more detailed haplotype and rare variant analyses, meanwhile, the team determined that the repeat expansion represents a founder mutation shared between the SCA4 cases in Utah and Germany, though the Tübingen cases were missing one of the six ultrarare variants found in the other families.

同时，通过更详细的单倍型和稀有变异分析，该团队确定重复扩增代表了犹他州和德国SCA4病例之间共有的创始人突变，尽管蒂宾根病例缺少其他家族中发现的六个超稀有变异之一。

Together, the authors explained, the results suggested that 'the repeat expansion haplotypes can be traced to a single, very distant founder with a single de novo [single nucleotide variant] occurring after the repeat expansion event, resulting in two distinguishable alleles.'

作者解释说，这些结果共同表明，“重复扩增单倍型可以追溯到一个非常遥远的创始人，在重复扩增事件之后发生了一个新的[单核苷酸变异]，从而产生了两个可区分的等位基因。”

In fibroblast cell models of SCA4 and induced pluripotent stem cells from individuals with SCA4 — which both contained the ZFHX3 repeat expansion — the researchers saw a significant uptick in ZFHX3 protein levels and polyG aggregates relative to control cells, along with a decline in autophagic processes typically used to recycle proteins..

在SCA4的成纤维细胞模型和来自SCA4个体的诱导多能干细胞中（两者都含有ZFHX3重复扩增），研究人员发现ZFHX3蛋白水平和polyG聚集体相对于对照细胞显着上升，同时通常用于回收蛋白质的自噬过程下降。。

Those findings were backed up by antibody staining analyses showing neuronal intranuclear inclusions involving aggregates of ZFHX3, p62, and ubiquitin proteins in SCA4 brain sections, the team explained, noting that MRI data highlighted further ties between the ZFHX3 expansion length and SCA4 age of onset..

该团队解释说，这些发现得到了抗体染色分析的支持，该分析显示神经元核内包涵体涉及SCA4脑切片中ZFHX3，p62和泛素蛋白的聚集体，并指出MRI数据突出了ZFHX3扩展长度与SCA4发病年龄之间的进一步联系。。

'This mutation is a toxic expanded repeat, and we think that it actually jams up how a cell deals with unfolded or misfolded proteins,' Pulst explained, adding that '[w]e now can attack the effects of this mutation potentially at multiple levels.'

“这种突变是一种有毒的扩展重复序列，我们认为它实际上阻塞了细胞处理未折叠或错误折叠蛋白质的方式，”普尔斯特解释道，并补充说，“我们现在可以在多个层面上潜在地攻击这种突变的影响。”

Because the apparent disease mechanism resembled protein recycling problems previously described in a type of ataxia dubbed SCA2, for example, the authors pointed to the potential benefits of pursuing treatment options similar to those being tested in clinical trials for that condition.

例如，由于这种明显的疾病机制类似于先前在一种称为SCA2的共济失调中描述的蛋白质回收问题，因此作者指出，寻求类似于该疾病临床试验中测试的治疗方案的潜在益处。

The new findings also raise the possibility of offering genetic testing to individuals from affected families to understand their own risk of SCA4 and for making family planning decisions.

新发现还提高了为受影响家庭的个人提供基因检测的可能性，以了解他们自己患SCA4的风险并做出计划生育决策。

'Our study underscores the importance of identifying genetic variation, including novel repeat expansions, in extremely G+C-rich genomic regions, which may account for some of the missing heritability in neurodegenerative disorders,' the authors wrote, adding that the results 'add to the list of neurodegenerative diseases caused by polyG expansions.'.

作者写道：“我们的研究强调了在富含G+C的基因组区域识别遗传变异（包括新的重复扩增）的重要性，这可能是神经退行性疾病遗传力缺失的原因之一。”作者补充说，结果“增加了由polyG扩增引起的神经退行性疾病的清单。”。