A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some β3GalT6-pathy mutations
A B3GALT6 variant in patient originally described as Al-Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some β3GalT6-pathy mutations
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DOI：
10.1111/cge.13236
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发表时间：
2018-06-01
影响因子：
3.5
通讯作者：
Al-Gazali, L.
中科院分区：
文献类型：
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作者：
Ben-Mahmoud, A.;Ben-Salem, S.;Al-Gazali, L.
Al-Gazali综合征包括几种临床特征，包括产前生长迟缓、大关节挛缩伴弯曲趾、双侧马蹄内翻足、小口、眼前段异常和早期致死。最近，一名与Al-Gazali综合征特征非常相似的婴儿被发现在B3 GALT 6中存在复合杂合变体。该基因编码β-1，3-半乳糖基转移酶6（β 3GalT 6），这是糖胺聚糖合成途径的重要组成部分。B3 GALT 6中的致病性变体也已显示引起Ehlers-Danlos综合征脊柱发育不良型（spEDS-B3 GALT 6）和脊柱干骺端发育不良伴关节松弛I型（SEMD-JL 1）。2017年，一项新的EDS国际分类包括这两种情况，以及据报告具有与脊柱发育不良EDS（spEDS）下的Al-Gazali综合征相似特征的儿童。我们报告了一个致病变异c.618C > G，p.（Cys 206 Trp）1例患者最初描述为Al-Gazali综合征，并于1999年报道。我们评估了内质网相关蛋白降解的参与，在13个B3 GALT 6变异的发病机制。其中6个细胞内质网滞留明显，而c.618C > G，p.（Cys 206 Trp）和其他6个变异体正常运输。我们的研究结果证实了B3 GALT 6参与Al-Gazali综合征的发病机制，并表明Al-Gazali综合征代表了该基因致病性变体引起的表型谱的严重末端。
Al-Gazali syndrome encompasses several clinical features including prenatal growth retardation, large joints contractures with camptodactyly, bilateral talipes equinovarus, small mouth, anterior segment anomalies of the eyes, and early lethality. Recently, a baby with features very similar to Al-Gazali syndrome was found to have compound heterozygous variants in B3GALT6. This gene encodes Beta-1,3-galactosyltransferase 6 (beta 3GalT6), an essential component of the glycosaminoglycan synthesis pathway. Pathogenic variants in B3GALT6 have also been shown to cause Ehlers-Danlos syndrome spondylodysplastic type (spEDS-B3GALT6) and spondyloepimetaphyseal dysplasia with joint laxity type I (SEMD-JL1). In 2017, a new international classification of EDS included these 2 conditions together with the child reported to have features similar to Al-Gazali syndrome under spondylodysplastic EDS (spEDS). We report a disease-causing variant c.618C > G, p.(Cys206Trp) in 1 patient originally described as Al-Gazali syndrome and reported in 1999. We evaluated the involvement of the endoplasmic reticulum-associated protein degradation, in the pathogenesis of 13 B3GALT6 variants. Retention in endoplasmic reticulum was evident in 6 of them while the c.618C > G, p.(Cys206Trp) and the other 6 variants trafficked normally. Our findings confirm the involvement of B3GALT6 in the pathogenesis of Al-Gazali syndrome and suggest that Al-Gazali syndrome represents the severe end of the spectrum of the phenotypes caused by pathogenic variants in this gene.