Department of Pediatrics, Medizinische Hochschule Hannover, Germany.
Neurology. 2013 Aug 13;81(7):681-7. doi: 10.1212/WNL.0b013e3182a08f53. Epub 2013 Jul 19.
To identify the underlying genetic defect in a patient with intellectual disability, seizures, ataxia, macrothrombocytopenia, renal and cardiac involvement, and abnormal protein glycosylation.
Genetic studies involved homozygosity mapping by 250K single nucleotide polymorphism array and SLC35A1 sequencing. Functional studies included biochemical assays for N-glycosylation and mucin-type O-glycosylation and SLC35A1-encoded cytidine 5'-monophosphosialic acid (CMP-sialic acid) transport after heterologous expression in yeast.
We performed biochemical analysis and found combined N- and O-glycosylation abnormalities and specific reduction in sialylation in this patient. Homozygosity mapping revealed homozygosity for the CMP-sialic acid transporter SLC35A1. Mutation analysis identified a homozygous c.303G > C (p.Gln101His) missense mutation that was heterozygous in both parents. Functional analysis of mutant SLC35A1 showed normal Golgi localization but 50% reduction in transport activity of CMP-sialic acid in vitro.
We confirm an autosomal recessive, generalized sialylation defect due to mutations in SLC35A1. The primary neurologic presentation consisting of ataxia, intellectual disability, and seizures, in combination with bleeding diathesis and proteinuria, is discriminative from a previous case described with deficient sialic acid transporter. Our study underlines the importance of sialylation for normal CNS development and regular organ function.
鉴定一名智力残疾、癫痫、共济失调、巨血小板减少症、肾和心脏受累以及异常蛋白糖基化患者的潜在遗传缺陷。
遗传研究包括通过 250K 单核苷酸多态性阵列和 SLC35A1 测序进行纯合子作图。功能研究包括生化分析用于 N-糖基化和粘蛋白型 O-糖基化以及 SLC35A1 编码的胞苷 5'-单磷酸唾液酸（CMP-唾液酸）在酵母中异源表达后的转运。
我们进行了生化分析，发现该患者存在联合的 N-和 O-糖基化异常以及唾液酸化特异性减少。纯合子作图显示 CMP-唾液酸转运蛋白 SLC35A1 纯合。突变分析确定了一个纯合的 c.303G > C（p.Gln101His）错义突变，在父母双方均为杂合子。突变 SLC35A1 的功能分析显示高尔基体定位正常，但体外 CMP-唾液酸转运活性降低 50%。
我们证实了一种常染色体隐性遗传的全身性唾液酸缺陷，原因是 SLC35A1 突变。主要的神经表现为共济失调、智力残疾和癫痫，伴有出血倾向和蛋白尿，与以前描述的缺乏唾液酸转运体的病例不同。我们的研究强调了唾液酸化对正常中枢神经系统发育和正常器官功能的重要性。
