A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors
A novel PUS7 mutation causes intellectual disability with autistic and aggressive behaviors
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DOI：
10.1212/nxg.0000000000000356
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发表时间：
2019-10-01
影响因子：
3.1
通讯作者：
Paisan-Ruiz, Coro
中科院分区：
文献类型：
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作者：
Darvish, Hossein;Azcona, Luis J.;Paisan-Ruiz, Coro
最近，纯合子PUS 7突变导致过早停止和截断的基因产物被确定在3个独立的近亲家庭，表现为智力残疾（ID），言语迟缓，身材矮小，小头畸形，和攻击行为。(1)PUS 7编码假尿苷合酶7，其催化RNA尿苷异构化为RNA假尿苷（Psi），其是在所有细胞RNA中发现的最丰富的经修饰的核苷酸，并且其可以充当RNA伴侣。所编码的蛋白质含有TruD家族的假尿苷合酶结构域，其修饰tRNA中的尿嘧啶-13。两个纯合突变c.89_90del（p.Thr3OLysfs20*）和c.1348C>T（p.Arg450*）导致无义介导的mRNA衰变，这意味着含有提前终止密码子的mRNA转录物通过监视机制被消除，而第三个突变，由包含倒数第二个外显子15的纯合缺失组成，逃脱了无义介导的mRNA衰变，编码缺失C末端的突变蛋白，包括TruD催化结构域。所有鉴定的PUS 7变体导致至少10个胞质tRNA在位置13处的异常假尿苷酸化。（一）
Recently, homozygous PUS7 mutations causing premature stop and truncation of the gene product were identified in 3 independent consanguineous families presenting with intellectual disability (ID), speech delay, short stature, microcephaly, and aggressive behavior.(1) PUS7 encodes for a pseudouridine synthase 7 that catalyzes the isomerization of RNA uridine to RNA pseudouridine (Psi), which is the most abundant modified nucleotide found in all cellular RNAs and which may function as an RNA chaperone. The encoded protein contains a pseudouridine synthase domain of the TruD family that modifies uracil-13 in tRNA. Two homozygous mutations c.89_90del (p.Thr3OLysfs20*) and c.1348C>T (p.Arg450*) resulted in nonsense-mediated mRNA decay, meaning that mRNA transcripts containing the premature stop codons were eliminated through surveillance mechanisms, while the third mutation, consisting of a homozygous deletion encompassing the penultimate exon 15, escaped the nonsense-mediated mRNA decay to encode a mutant protein missing the C terminus including the TruD catalytic domain. All identified PUS7 variants resulted in aberrant pseudouridylation of at least 10 cytosolic tRNAs at position 13.(1)