Huntington’s disease pathogenesis involves a genetic gain-of-function toxicity mechanism triggered by the expanded HTT CAG repeat. Current therapeutic efforts aim to suppress expression of total or mutant huntingtin, though the relationship of huntingtin’s normal activities to the gain-of-function mechanism and what the effects of huntingtin-lowering might be are unclear. Here, we have re-investigated a rare family segregating two presumed HTT loss-of-function (LoF) variants associated with the developmental disorder, Lopes-Maciel-Rodan syndrome (LOMARS), using whole-genome sequencing of DNA from cell lines, in conjunction with analysis of mRNA and protein expression. Our findings correct the muddled annotation of these HTT variants, reaffirm they are the genetic cause of the LOMARS phenotype and demonstrate that each variant is a huntingtin hypomorphic mutation. The NM_002111.8: c.4469+1G>A splice donor variant results in aberrant (exon 34) splicing and severely reduced mRNA, whereas, surprisingly, the NM_002111.8: c.8157T>A NP_002102.4: Phe2719Leu missense variant results in abnormally rapid turnover of the Leu2719 huntingtin protein. Thus, although rare and subject to an as yet unknown LoF intolerance at the population level, bona fide HTT LoF variants can be transmitted by normal individuals leading to severe consequences in compound heterozygotes due to huntingtin deficiency.

中文翻译：

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导致 Lopes-Maciel-Rodan 综合征的突变是亨廷顿亚型

亨廷顿氏病发病机制涉及由扩展的 HTT CAG 重复触发的遗传功能获得毒性机制。目前的治疗工作旨在抑制总亨廷顿蛋白或突变亨廷顿蛋白的表达，尽管亨廷顿蛋白的正常活动与功能获得机制的关系以及亨廷顿蛋白降低的影响可能尚不清楚。在这里，我们使用来自细胞系的 DNA 的全基因组测序，重新研究了一个罕见的家族，该家族分离了与发育障碍 Lopes-Maciel-Rodan 综合征 (LOMARS) 相关的两种推测的 HTT 功能丧失 (LoF) 变体，结合 mRNA 和蛋白质表达的分析。我们的发现纠正了这些 HTT 变体的混乱注释，重申它们是 LOMARS 表型的遗传原因，并证明每个变体都是亨廷顿亚型突变。NM_002111.8：c.4469+1G>A 剪接供体变体导致异常（外显子 34）剪接并严重减少 mRNA，而令人惊讶的是，NM_002111.8：c.8157T>A NP_002102.4：Phe2719Leu 错义变体结果在 Leu2719 亨廷顿蛋白异常快速的周转中。因此，虽然罕见并且在人群水平上存在未知的 LoF 不耐受，但真正的 HTT LoF 变体可以由正常个体传播，导致由于亨廷顿蛋白缺乏而导致复合杂合子的严重后果。8157T>A NP_002102.4：Phe2719Leu 错义变体导致 Leu2719 亨廷顿蛋白异常快速更新。因此，虽然罕见并且在人群水平上存在未知的 LoF 不耐受，但真正的 HTT LoF 变体可以由正常个体传播，导致由于亨廷顿蛋白缺乏而导致复合杂合子的严重后果。8157T>A NP_002102.4：Phe2719Leu 错义变体导致 Leu2719 亨廷顿蛋白异常快速更新。因此，虽然罕见并且在人群水平上存在未知的 LoF 不耐受，但真正的 HTT LoF 变体可以由正常个体传播，导致由于亨廷顿蛋白缺乏而导致复合杂合子的严重后果。