Supplementary Material for: A de novo KCNA1 Mutation in a Patient with Tetany and Hypomagnesemia

Mutations in the KCNA1 gene encoding the voltage-gated potassium (K+) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg2+) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg2+ levels, renal Mg2+ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K+ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.编码电压门控钾（K+）通道Kv1.1的KCNA1基因发生突变，与罕见神经系统综合征阵发性共济失调1型（EA1）及肌纤维颤搐（myokymia）密切相关。2009年，研究人员在一个患有常染色体显性遗传性低镁血症的大型家系中首次鉴定出KCNA1基因突变。尽管学界已针对EA1的多样临床症状尝试建立基因型-表型关联，但目前对这类患者的血清镁（Mg2+）水平仍缺乏充分认知。本研究报道了一例波兰籍患者身上发现的全新KCNA1从头突变（de novo mutation），该患者临床表现为手足搐搦与低镁血症。研究通过电生理与生化分析手段，对该突变的致病性进行了系统验证。该女性患者存在血清Mg2+水平降低、肾性失镁、肌肉痉挛及强直发作等症状。全外显子组测序结果显示，编码Kv1.1 K+通道的KCNA1基因存在p.Leu328Val突变位点。电生理检测证实，p.Leu328Val突变可导致其编码的Kv1.1通道产生显性负性功能丧失。细胞膜表面生物素化实验结果表明，突变通道的细胞膜表达水平并无异常。综上，本研究是第二篇将KCNA1基因与低镁血症关联起来的学术报道，这一发现强调了需进一步全面评估携带KCNA1突变患者的临床表型。