Revising pathogenesis of AP1S1-related MEDNIK syndrome: a missense variant in the AP1S1 gene as a causal genetic lesion

Journal of Molecular Medicine Pub Date : 2024-09-13 DOI:10.1007/s00109-024-02482-0

Marketa Rackova, Rafael Mattera, Michael Svaton, Filip Fencl, Veronika Kanderova, Karolina Spicakova, Sang Yoon Park, Ondrej Fabian, Miroslav Koblizek, Eva Fronkova, Juan S. Bonifacino, Karolina Skvarova Kramarzova

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Abstract

MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome.

Key messages

A missense AP1S1 c.269 T > C (σ1A L90P) variant causes full MEDNIK syndrome.
The σ1A L90P variant is largely unable to assemble into the AP-1 complex.
The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs.
The σ1A L90P variant results in loss-of-function of the protein.

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修正 AP1S1 相关 MEDNIK 综合征的发病机制：AP1S1 基因中的错义变异是致病基因病变

摘要MEDNIK 综合征是一种罕见的常染色体隐性遗传病，以智力低下、肠病、耳聋、周围神经病变、鱼鳞病和角化病为特征，由适配器相关蛋白复合体 1 亚基 sigma 1（AP1S1）基因变异引起。该基因编码σ1A蛋白，它是适配蛋白复合物1（AP-1）的一个亚基，而适配蛋白复合物1是细胞内蛋白质转运机制的一个关键组成部分。之前的研究发现，MEDNIK 患者体内存在三种 AP1S1 无义、框架移位和剪接位点变异，预测这些变异编码截短的σ1A 蛋白，从而导致 AP-1 功能障碍。然而，最近有报告称，在出现严重肠病但没有其他 MEDNIK 症状的患者中，出现了两个 AP1S1 错义变异（c.269 T > C 和 c.346G >A）。这种情况被描述为由 AP1S1 错义变体引起的一种新型非综合征形式的先天性腹泻。在本研究中，我们报告了两名具有相同 c.269 T > C 变异的患者，与之前的病例相反，他们表现为完全的 MEDNIK 综合征。这些数据大大改变了与 AP1S1 基因变异相关的疾病的表现形式，并表明所有已确定的致病 AP1S1 变异都会导致 MEDNIK 综合征。我们还提供了一系列功能分析，阐明了 c.269 T > C 变异对 σ1A 功能的影响，有助于更好地理解 MEDNIK 综合征的分子发病机制。T > C (σ1A L90P)变异体导致完全 MEDNIK 综合征。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Journal of Molecular Medicine

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