Mutations in EOGT Confirm the Genetic Heterogeneity of Autosomal-Recessive Adams-Oliver Syndrome
Mutations in EOGT Confirm the Genetic Heterogeneity of Autosomal-Recessive Adams-Oliver Syndrome
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DOI：
10.1016/j.ajhg.2013.02.012
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发表时间：
2013-04-04
影响因子：
9.8
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
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作者：
Shaheen, Ranad;Aglan, Mona;Alkuraya, Fowzan S.
Adams-Oliver 综合征 (AOS) 是一种罕见的常染色体显性或隐性遗传疾病，主要特征为先天性皮肤发育不全和末端横行肢体缺陷。最近，我们证明 DOCK6 的纯合突变会导致常染色体隐性形式的 AOS。在这项研究中，我们试图确定 DOCK6 突变对几个近亲家庭 AOS 病因的贡献。在研究的五个家族中的两个中，我们鉴定了两个纯合截短突变（剪接位点突变和移码重复）。 DOCK6 测序显示其余三个家族没有突变，这与它们的自合性作图和连锁分析结果一致，显示三个家族中三个不同单倍型背景的 3p14.1 中有一个候选基因座。事实上，一个家族的外显子组测序揭示了 EOGT (C3orf64) 中的一个错义突变，随后对该基因的靶向测序揭示了其他两个家族中的纯合错义突变和纯合移码缺失突变。 EOGT 编码 EGF 结构域特异性 O 连接 N-乙酰氨基葡萄糖 (O-GlcNAc) 转移酶，该酶参与细胞外含有 EGF 结构域的蛋白质子集的 O-GlcNAc 酰化（O-GlcNAc 与丝氨酸和苏氨酸残基的连接）。它在果蝇的上皮-细胞-基质相互作用中具有已记录的作用，其中其直系同源物的缺乏会导致翅膀起泡。我们的研究结果强调了 O-GlcNAc 酰化在人类中的发育作用，并扩大了常染色体隐性 AOS 的遗传异质性。
Adams-Oliver syndrome (AOS) is a rare, autosomal-dominant or -recessive disorder characterized primarily by aplasia cutis congenita and terminal transverse limb defects. Recently, we demonstrated that homozygous mutations in DOCK6 cause an autosomal-recessive form of AOS. In this study, we sought to determine the contribution of DOCK6 mutations to the etiology of AOS in several consanguineous families. In two of the five families studied, we identified two homozygous truncating mutations (a splice-site mutation and a frameshift duplication). DOCK6 sequencing revealed no mutation in the remaining three families, consistent with their autozygosity mapping and linkage-analysis results, which revealed a single candidate locus in 3p14.1 on three different haplotype backgrounds in the three families. Indeed, exome sequencing in one family revealed one missense mutation in EOGT (C3orf64), and subsequent targeted sequencing of this gene revealed a homozygous missense mutation and a homozygous frameshift deletion mutation in the other two families. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine (O-GlcNAc) transferase, which is involved in the O-GlcNAcylation (attachment of O-GlcNAc to serine and threonine residues) of a subset of extracellular EGF-domain-containing proteins. It has a documented role in epithelial-cell-matrix interactions in Drosophila, in which deficiency of its ortholog causes wing blistering. Our findings highlight a developmental role of O-GlcNAcylation in humans and expand the genetic heterogeneity of autosomal-recessive AOS.