由于N末端乙酰基转移酶损伤，NAA10突变导致长QT的新型智障综合征。,Scientific Reports

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由于N末端乙酰基转移酶损伤，NAA10突变导致长QT的新型智障综合征。
Scientific Reports ( IF 3.8 ) Pub Date : 2015-Nov-02 , DOI: 10.1038/srep16022
Jillian P. Casey , Svein I. Støve , Catherine McGorrian , Joseph Galvin , Marina Blenski , Aimee Dunne , Sean Ennis , Francesca Brett , Mary D. King , Thomas Arnesen , Sally Ann Lynch

我们报告了来自一个非近亲爱尔兰家庭的两个兄弟，他们患有一种以智力残疾，面部畸形，脊柱侧弯和长时间QT为特征的新型综合征。他们的母亲的表型较温和，包括长QT。怀疑X连锁继承。整个外显子组测序鉴定出NAA10（X染色体）中的一种新型错义变体（c.128 A> C； p.Tyr43Ser）是造成该家族疾病的原因。桑格测序证实携带者母亲中发生了从头突变。NAA10编码人类主要N末端乙酰化复合物NatA的催化亚基。与野生型Naa10蛋白相比，p.Tyr43Ser突变酶的体外测定显示催化活性显着降低，稳定性降低。NAA10以前曾与奥格登症候群有关，Lenz小眼症候群和非综合征性发育延迟。我们的发现扩大了NAA10的临床范围，并表明突变的Naa10酶活性与表型严重性之间的拟议相关性比预期的更为复杂。与致命Ogden综合征相关的p.Ser37Pro突变体相比，p.Tyr43Ser突变体酶具有较低的催化活性，但其表型更为温和。重要的是，由于患者和携带者均可能具有较长的QT，因此我们强调需要对具有NAA10变体的男性和女性进行心脏评估。Ser37Pro突变体与致死性Ogden综合征相关，但导致较轻的表型。重要的是，由于患者和携带者均可能具有较长的QT，因此我们强调需要对具有NAA10变体的男性和女性进行心脏评估。Ser37Pro突变体与致死性Ogden综合征相关，但导致较轻的表型。重要的是，由于患者和携带者均可能具有较长的QT，因此我们强调需要对具有NAA10变体的男性和女性进行心脏评估。

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NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment.

We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family's disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.

更新日期：2015-11-04

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