Houston Merritt Neuromuscular Disease Research Center, Columbia University Medical Center, New York, New York.
The Agnes Ginges Center for Human Neurogenetics, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
JAMA Neurol. 2015 Apr;72(4):441-5. doi: 10.1001/jamaneurol.2014.4496.
We describe a deep intronic mutation in adult polyglucosan body disease. Similar mechanisms can also explain manifesting heterozygous cases in other inborn metabolic diseases.
To explain the genetic change consistently associated with manifesting heterozygous patients with adult polyglucosan body disease.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective study took place from November 8, 2012, to November 7, 2014. We studied 35 typical patients with adult polyglucosan body disease, of whom 16 were heterozygous for the well-known c.986A>C mutation in the glycogen branching enzyme gene (GBE1) but harbored no other known mutation in 16 exons.
All 16 manifesting heterozygous patients had lower glycogen branching activity compared with homozygous patients, which showed inactivation of the apparently normal allele. We studied the messenger ribonucleic acid (mRNA) structure and the genetic change due to the elusive second mutation.
When we reverse transcribed and sequenced the mRNA of GBE1, we found that all manifesting heterozygous patients had the c.986A>C mutant mRNA and complete lack of mRNA encoded by the second allele. We identified a deep intronic mutation in this allele, GBE1-IVS15+5289_5297delGTGTGGTGGinsTGTTTTTTACATGACAGGT, which acts as a gene trap, creating an ectopic last exon. The mRNA transcript from this allele missed the exon 16 and 3'UTR and encoded abnormal GBE causing further decrease of enzyme activity from 18% to 8%.
We identified the deep intronic mutation, which acts as a gene trap. This second-most common adult polyglucosan body disease mutation explains another founder effect in all Ashkenazi-Jewish cases.
我们描述了一种成人多聚糖体病的深内含子突变。类似的机制也可以解释其他先天性代谢疾病中表现为杂合子的病例。
解释与成人多聚糖体病的表现型杂合子患者一致相关的遗传变化。
设计、地点和参与者：这项回顾性研究于 2012 年 11 月 8 日至 2014 年 11 月 7 日进行。我们研究了 35 名典型的成人多聚糖体病患者，其中 16 名患者的糖原分支酶基因（GBE1）的 c.986A>C 突变呈杂合子，但在 16 个外显子中没有其他已知突变。
所有 16 名表现型杂合子患者的糖原分支酶活性均低于纯合子患者，表明正常等位基因失活。我们研究了信使 RNA（mRNA）结构和由于第二个难以捉摸的突变引起的遗传变化。
当我们逆转录并测序 GBE1 的 mRNA 时，我们发现所有表现型杂合子患者均具有 c.986A>C 突变型 mRNA，且第二个等位基因编码的 mRNA 完全缺失。我们在这个等位基因中发现了一个深内含子突变，GBE1-IVS15+5289_5297delGTGTGGTGGinsTGTTTTTTACATGACAGGT，它作为一个基因陷阱，创建了一个异位最后外显子。该等位基因的 mRNA 转录物缺失了外显子 16 和 3'UTR，并编码异常的 GBE，导致酶活性进一步从 18%降至 8%。
我们鉴定了作为基因陷阱的深内含子突变。这种第二常见的成人多聚糖体病突变解释了所有阿什肯纳兹犹太人病例中的另一个创始人效应。
