Werren Elizabeth A, Rodriguez Bey Guillermo, Majethia Purvi, Kaur Parneet, Patil Siddaramappa J, Kekatpure Minal V, Afenjar Alexandra, Qebibo Leila, Burglen Lydie, Tomoum Hoda, Demurger Florence, Duborg Christele, Siddiqui Shahyan, Tsan Yao-Chang, Abdullah Uzma, Ali Zafar, Saadi Saadia Maryam, Baig Shahid Mahmood, Houlden Henry, Maroofian Reza, Padiath Quasar Saleem, Bielas Stephanie L, Shukla Anju
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
Brain. 2024 Dec 3;147(12):4033-4042. doi: 10.1093/brain/awae299.
Erythrocyte membrane protein band 4.1 like 3 (EPB41L3: NM_012307.5), also known as DAL1, encodes the ubiquitously expressed, neuronally enriched 4.1B protein, part of the 4.1 superfamily of membrane-cytoskeleton adaptors. The 4.1B protein plays key roles in cell spreading, migration and cytoskeletal scaffolding that support oligodendrocyte axon adhesions essential for proper myelination. We herein describe six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense [c.466C>T, p.(R156*); c.2776C>T, p.(R926*)] and three frameshift [c.666delT, p.(F222Lfs46); c.2289dupC, p.(V764Rfs19); c.948_949delTG, p.(A317Kfs33)]. Quantitative-real time PCR and western blot analyses of human fibroblasts harbouring EPB41L3:c.666delT, p.(F222Lfs46) indicated ablation of EPB41L3 mRNA and 4.1B protein expression. Inhibition of the nonsense mediated decay (NMD) pathway led to an upregulation of EPB41L3:c.666delT transcripts, supporting NMD as a pathogenic mechanism. Epb41l3-deficient mouse oligodendroglia cells showed significant reduction in mRNA expression of key myelin genes, reduced branching and increased apoptosis. Our report provides the first clinical description of an autosomal recessive disorder associated with variants in EPB41L3, which we refer to as EPB41L3-associated developmental disorder (EADD). Moreover, our functional studies substantiate the pathogenicity of EPB41L3 hypothesized loss-of-function variants.
红细胞膜蛋白带4.1样蛋白3（EPB41L3：NM_012307.5），也称为DAL1，编码广泛表达、在神经元中富集的4.1B蛋白，它是膜细胞骨架衔接蛋白4.1超家族的一部分。4.1B蛋白在细胞铺展、迁移和细胞骨架支架形成中起关键作用，这些过程支持少突胶质细胞轴突黏附，而这对于正常髓鞘形成至关重要。我们在此描述了来自五个不相关家族的六名个体，他们患有全球发育迟缓、智力残疾、癫痫、肌张力减退、神经退行性变和髓鞘形成延迟。外显子组测序在所有受影响个体中鉴定出EPB41L3的双等位基因变异：两个无义变异[c.466C>T，p.(R156*); c.2776C>T，p.(R926*)]和三个移码变异[c.666delT，p.(F222Lfs46); c.2289dupC，p.(V764Rfs19); c.948_949delTG，p.(A317Kfs33)]。对携带EPB41L3:c.666delT，p.(F222Lfs46)的人成纤维细胞进行定量实时PCR和蛋白质印迹分析表明，EPB41L3 mRNA和4.1B蛋白表达缺失。抑制无义介导的衰变（NMD）途径导致EPB41L3:c.666delT转录本上调，支持NMD作为一种致病机制。Epb41l3缺陷的小鼠少突胶质细胞显示关键髓鞘基因的mRNA表达显著降低，分支减少且细胞凋亡增加。我们的报告首次对与EPB41L3变异相关的常染色体隐性疾病进行了临床描述，我们将其称为EPB41L3相关发育障碍（EADD）。此外，我们的功能研究证实了EPB41L3假定的功能丧失变异的致病性。
