DataSheet1_Mutant B3GALT6 in a Multiplex Family: A Dominant Variant Co-Segregated With Moderate Malformations.PDF

B3GALT6 is a well-documented disease-related gene. Several B3GALT6-recessive variants have been reported to cause Ehlers–Danlos syndrome (EDS). To the best of our knowledge, no dominant B3GALT6 variant that causes human disease has been reported. In 2012, we reported on a three-generation, autosomal-dominant family with multiple members who suffered from radioulnar joint rotation limitation, scoliosis, thick vermilion of both lips, and others, but the genetic cause was unknown. Here, exome sequencing of the family identified mutant B3GALT6 as the cause of the multiplex affected family. We observed that, in the compound heterozygous pattern (i.e., c.883C>T:p.R295C and c.510_517del:p.L170fs*268), mutant B3GALT6 led to severe consequences, and in the dominant pattern, an elongated B3GALT6 variant co-segregated with moderate phenotypes. The functional experiments were performed in vitro. The R295C variant led to subcellular mislocalization, whereas the L170fs*268 showed normal subcellular localization, but it led to an elongated protein. Given that most of the catalytic galactosyltransferase domain was disrupted for the L170fs*268 (it is unlikely that such a protein has activity), we propose that the L170fs*268 occupies the normal B3GALT6 protein position in the Golgi and exerts a dominant-negative effect.

B3GALT6是一种文献记载丰富的疾病相关基因。已有多篇报道指出，B3GALT6的隐性变异可导致埃勒斯-当洛斯综合征（EDS）。据我们所知，尚未有关于导致人类疾病的显性B3GALT6变异的报道。2012年，我们报道了一个三代同堂、常染色体显性家族，家族中有多位成员患有桡尺关节旋转受限、脊柱侧弯、双唇唇红增厚等症状，但其遗传原因不明。在本研究中，对该家族成员进行了外显子测序，鉴定出突变型B3GALT6是该家族多发性受影响的基因。我们观察到，在复合杂合子模式（即c.883C>T:p.R295C和c.510_517del:p.L170fs*268）下，突变型B3GALT6导致了严重的后果；在显性模式下，一个延长的B3GALT6变异与中等程度的表型共分离。功能实验在体外进行。R295C变异导致亚细胞定位异常，而L170fs*268则显示出正常的亚细胞定位，但它导致蛋白质延长。鉴于L170fs*268（这种蛋白质活性极低）破坏了大部分催化半乳糖基转移酶结构域，我们提出L170fs*268占据了正常的B3GALT6蛋白在高尔基体的位置，并表现出显性负效应。