Shukla Anju, Hebbar Malavika, Srivastava Anshika, Kadavigere Rajagopal, Upadhyai Priyanka, Kanthi Anil, Brandau Oliver, Bielas Stephanie, Girisha Katta M
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
J Hum Genet. 2017 Jul;62(7):723-727. doi: 10.1038/jhg.2017.35. Epub 2017 Mar 30.
The iron-sulfur (Fe-S) cluster (ISC) biogenesis pathway is indispensable for many fundamental biological processes and pathogenic variations in genes encoding several components of the Fe-S biogenesis machinery, such as NFU1, BOLA3, IBA57 and ISCA2 are already implicated in causing four types of multiple mitochondrial dysfunctions syndromes (MMDS). We report on two unrelated families, with two affected children each with early onset neurological deterioration, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise. Exome sequencing of two affected individuals, one from each family, revealed a homozygous c.259G>A [p.(Glu87Lys)] variant in ISCA1 and Mendelian segregation was confirmed in both families. The ISCA1 variant lies in the only shared region of homozygosity between the two families suggesting the possibility of a founder effect. In silico functional analyses and structural modeling of the protein predict the identified ISCA1 variant to be detrimental to protein stability and function. Notably the phenotype observed in all affected subjects with the ISCA1 pathogenic variant is similar to that previously described in all four types of MMDS. Our findings suggest association of a pathogenic variant in ISCA1 with another MMDS.
铁硫（Fe-S）簇生物合成途径对于许多基本生物学过程不可或缺，编码Fe-S生物合成机制几个组分的基因发生致病性变异，例如NFU1、BOLA3、IBA57和ISCA2，已被证实与四种类型的多重线粒体功能障碍综合征（MMDS）相关。我们报告了两个不相关的家庭，每个家庭有两名患病儿童，均有早发性神经功能恶化、癫痫发作、广泛的白质异常、皮质迁移异常、乳酸酸中毒及早夭。对来自每个家庭的一名患病个体进行外显子组测序，发现ISCA1基因存在纯合的c.259G>A [p.(Glu87Lys)]变异，且在两个家庭中均证实符合孟德尔遗传模式。ISCA1变异位于两个家庭唯一共享的纯合区域，提示可能存在奠基者效应。对该蛋白质进行的计算机功能分析和结构建模预测，所鉴定的ISCA1变异对蛋白质稳定性和功能有害。值得注意的是，所有携带ISCA1致病变异的患病个体所观察到的表型与先前在所有四种类型的MMDS中所描述的相似。我们的研究结果提示ISCA1中的致病变异与另一种MMDS有关联。
