Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome
Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome
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DOI：
10.1016/j.ajhg.2011.10.008
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发表时间：
2011-11-11
影响因子：
9.8
通讯作者：
Black, Graeme
中科院分区：
文献类型：
--
作者：
Clayton-Smith, Jill;O'Sullivan, James;Black, Graeme
Say-Barber-Biesecker-Young-Simpson 综合征（SBBYSS 或 Ohdo 综合征）是一种多重异常综合征，其特征为严重智力障碍、眼睑裂和面部外观呈面具状。许多 SBBYSS 患者还患有甲状腺异常和腭裂。这种情况通常偶尔发生，因此在大多数情况下被认为是由于新的显性突变所致。在患有 SBBYSS 的个体中，使用全外显子组测序方法在四分之三的测序个体中证明了高度保守的组蛋白乙酰转移酶基因 KAT6B (MYST4/MORF) 中的从头蛋白质截短突变。 Sanger 测序用于确认 KAT6B 的截短突变，该突变聚集在所有 4 名个体以及另外 9 名典型 SBBYSS 个体的基因最后一个外显子中。在可以获得亲本样本的情况下，突变被证明是从头发生的。在哺乳动物发育过程中，KAT6B 特别在发育中的中枢神经系统、面部结构和肢芽中表达上调。 Qkf 小鼠（一种 Kat6b 亚形突变体）的表型特征包括小眼睛、位于腹侧的耳朵和长长的第一根手指，这些特征与人类表型相似。这是一个进一步的例子，说明参与染色质修饰的蛋白质的扰动可能会导致多系统发育障碍。
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.