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Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2021-10-14 , DOI: 10.1016/j.ajhg.2021.09.012
Matthew P Wilson 1 , Alejandro Garanto 2 , Filippo Pinto E Vairo 3 , Bobby G Ng 4 , Wasantha K Ranatunga 5 , Marina Ventouratou 1 , Melissa Baerenfaenger 6 , Karin Huijben 7 , Christian Thiel 8 , Angel Ashikov 6 , Liesbeth Keldermans 1 , Erika Souche 1 , Sandrine Vuillaumier-Barrot 9 , Thierry Dupré 9 , Helen Michelakakis 10 , Agata Fiumara 11 , James Pitt 12 , Susan M White 13 , Sze Chern Lim 12 , Lyndon Gallacher 13 , Heidi Peters 14 , Daisy Rymen 15 , Peter Witters 15 , Antonia Ribes 16 , Blai Morales-Romero 16 , Agustí Rodríguez-Palmero 17 , Diana Ballhausen 18 , Pascale de Lonlay 19 , Rita Barone 20 , Mirian C H Janssen 21 , Jaak Jaeken 15 , Hudson H Freeze 4 , Gert Matthijs 1 , Eva Morava 22 , Dirk J Lefeber 23
Affiliation  

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.



中文翻译:

STT3A 中的活性位点变异导致具有神经肌肉骨骼发现的显性 I 型先天性糖基化障碍

先天性糖基化障碍 (CDG) 是一组以低糖基化为特征的罕见疾病。我们在此报告了来自 9 个家族的 16 个个体的鉴定,这些个体在STT3A中具有遗传或从头杂合错义变异,导致常染色体显性 CDG。STT3A编码含有 STT3A 的寡糖基转移酶 (OST) 复合物的催化亚基,对蛋白质 N-糖基化至关重要。受影响的个体呈现出多变的骨骼异常、身材矮小、大头畸形和畸形特征;一半有智力障碍。其他功能包括增加肌肉张力和肌肉痉挛。OST 复合物 3D 结构中的变体建模表明所有变体都位于 STT3A 的催化位点,这表明与寡糖转移到新生糖蛋白上的直接机制联系。事实上,成纤维细胞中STT3A在 mRNA 和稳态蛋白水平上的表达是正常的,而糖基化是异常的。在酿酒酵母中,与受影响个体中的那些同源的含有STT3的变体的表达在野生型酵母菌株中诱导羧肽酶Y的糖基化缺陷,并且在STT3亚型stt3-7酵母菌株中相同突变体的表达恶化了已经观察到的糖基化缺陷。这些数据支持糖基化缺陷的主要病理机制。STT3A中的隐性突变先前已被描述为导致 CDG。我们在这里展示了一种主要形式的 STT3A-CDG,由于存在异常的转铁蛋白糖型,在主要的 I 型 CDG 中是不常见的。

更新日期:2021-11-04
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