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与新型变体 p.Glu580Lys 相关的凝胶蛋白淀粉样变性的临床和组织病理学特征。

Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel Variant p.Glu580Lys.

机构信息

Eye Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.

Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia.

出版信息

Int J Mol Sci. 2021 Jan 22;22(3):1084. doi: 10.3390/ijms22031084.

DOI:10.3390/ijms22031084
PMID:33499149
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7865823/
Abstract

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.

摘要

凝胶蛋白淀粉样变性病通常表现为角膜格子状营养不良，最常与致病性变异 p.Asp214Asn 相关。在此，我们报告与新型变异 p.Glu580Lys 相关的凝胶蛋白淀粉样变性病的临床和组织病理学特征。我们研究了两代家族的七名成员的 DNA 样本。对先证者进行外显子组测序，对其他成员进行靶向 Sanger 测序。在六名患者中发现了杂合变异 p.Glu580Lys。患者表现出角膜营养不良（5/6）、皮肤松弛（5/6）和/或心律失常（3/6），其中一名患者出现双侧视神经病变。通过计算机模拟评估了突变对蛋白质结构的影响。该取代位于凝胶蛋白的第五结构域，与包含最常见致病性变异 p.Asp214Asn 的第二结构域同源。结构研究表明，该突变可能影响蛋白质折叠。组织病理学分析显示皮肤中有淀粉样沉积物。p.Glu580Lys 与角膜营养不良有关，这进一步证实了凝胶蛋白第五结构域与典型淀粉样变性表型的关联。此外，视神经病变可能与该疾病有关，在讨论角膜移植之前，必须明确这一点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4607/7865823/c9125c029f07/ijms-22-01084-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4607/7865823/229462ab5874/ijms-22-01084-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4607/7865823/c3bd5f5c6d0b/ijms-22-01084-g003.jpg
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