Neurology Department, University and Polytechnic Hospital La Fe, Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain.
Neuroimmunology Unit, Health Research Institute La Fe (IISLAFE), Avda. Fernando Abril Martorell, 106, 46026, Valencia, Spain.
Neurol Sci. 2021 Sep;42(9):3647-3654. doi: 10.1007/s10072-020-04961-x. Epub 2021 Jan 13.
Recessive mutations in the SLC4A4 gene cause a syndrome characterised by proximal renal tubular acidosis (pRTA), mental retardation, dental and ocular abnormalities, and hemiplegic migraine. Rare cases involving the development of epilepsy or its severe complication-status epilepticus-have been described.
The clinical and genetic status of four affected members in a Spanish family was studied. The SLC4A4 gene mutation was detected with a next-generation sequencing (NGS) panel in the proband, and Sanger confirmed the putative mutations in affected relatives. In silico analysis was performed to elucidate the putative effect of mutation on the splicing process.
A novel mutation, c.2562+2T>G, was identified in the homozygous state in all diseased members of the family. This mutation affected a canonical splice site and is predicted to abolish the wild-type donor site, which predicts a premature truncated NBCe1 protein with cotransport activity. The resulting protein lacks the 190 amino acids of the carboxyl-terminus, and the effect is likely to be a loss of function. All patients suffered from severe pRTA and ocular abnormalities, and the adults also suffered from neurological complications, such as hemiplegic migraine and/or epilepsy. Two developed life-threatening status epilepticus, although they fully recovered and remained free of seizures with valproate.
These results expand the clinical and mutational spectra of SLC4A4-related disease and have implications for understanding the potential role of NBCe1 in the pathophysiologic processes of hemiplegic migraine and epilepsy/status epilepticus associated with the mutation.
SLC4A4 基因突变会导致一种综合征，其特征为近端肾小管酸中毒（pRTA）、智力障碍、牙齿和眼部异常以及偏瘫性偏头痛。已有罕见病例描述了癫痫或其严重并发症——癫痫持续状态的发展。
研究了一个西班牙家庭中 4 名受影响成员的临床和遗传状况。在先证者中使用下一代测序（NGS）面板检测 SLC4A4 基因突变，并通过 Sanger 测序在受影响的亲属中证实了假定的突变。进行了计算机分析以阐明突变对剪接过程的可能影响。
在该家系的所有患病成员中均发现了一种新的突变，c.2562+2T>G，呈纯合状态。该突变影响了一个典型的剪接位点，预计会破坏野生型供体位点，从而导致 NBCe1 具有共转运活性的截短蛋白。产生的蛋白缺少羧基末端的 190 个氨基酸，其作用可能是功能丧失。所有患者均患有严重的 pRTA 和眼部异常，成年人还患有神经并发症，如偏瘫性偏头痛和/或癫痫。其中 2 人发生危及生命的癫痫持续状态，但他们完全康复，并且用丙戊酸钠后不再发作。
这些结果扩展了 SLC4A4 相关疾病的临床和突变谱，并对理解 NBCe1 在与突变相关的偏瘫性偏头痛和癫痫/癫痫持续状态的病理生理过程中的潜在作用具有重要意义。
