An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B.
An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B.
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DOI：
10.1002/ajmg.a.36379
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发表时间：
2014-04
影响因子：
2
通讯作者：
Shaikh, Tamim H.
中科院分区：
文献类型：
--
作者：
Yu, Hung-Chun;Geiger, Elizabeth A.;Medne, Livija;Zackai, Elaine H.;Shaikh, Tamim H.
上睑下垂综合征(BPES)是由FOXL2基因突变引起的一种常染色体显性遗传病。我们确定了一名患有BPES和其他表型特征的个体，他没有FOXL2突变。我们使用整个外显子组测序来鉴定该个体中KAT6B(赖氨酸乙酰转移酶6B)的从头突变。该突变是一个2个碱基的插入，导致了一个移码，从而导致了一个过早的终止密码子。由此得到的截短蛋白不具有与其他转录和表观遗传调节因子相互作用所必需的C末端丝氨酸/蛋氨酸转录激活结构域。这种突变可能具有显性负向或功能获得效应，类似于在KAT6B突变引起的其他遗传疾病中观察到的结果，包括Say-Barber-Biesecker-Young-Simpson(SBBYSS)和Genitopatella综合征(GTPTS)。因此，我们的受试者的表型拓宽了与KAT6B突变相关的临床发现的范围。此外，我们的结果建议，没有FOXL2突变的BPES患者应该进行KAT6B突变检测。KAT6B介导的转录和表观遗传调控似乎对早期发育过程至关重要，当受到干扰时，可以导致广泛的表型结果。
Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2 bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and Genitopatellar syndrome (GTPTS). Thus, our subject’s phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes.
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