Mullany Sean, Souzeau Emmanuelle, Klebe Sonja, Zhou Tiger, Knight Lachlan S W, Qassim Ayub, Berry Ella C, Marshall Henry, Hussey Matthew, Dubowsky Andrew, Breen James, Hassall Mark M, Mills Richard A, Craig Jamie E, Siggs Owen M
Flinders Department of Ophthalmology, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.
Department of Pathology, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.
Hum Mutat. 2021 Jul;42(7):818-826. doi: 10.1002/humu.24214. Epub 2021 May 11.
Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected individuals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected individual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.
凝溶胶蛋白（GSN）变体与芬兰型淀粉样变性有关。本病例系列报告了一个家庭中一种新的GSN:c.1477T>C,p.(Trp493Arg)变体，该家庭具有与芬兰淀粉样变性一致的眼部和全身特征。对两个表现出皮肤松弛和多形性角膜基质混浊的家庭中的患病个体进行外显子组测序，在一个家庭的单个患病个体中发现了经典的GSN:c.654G>A,p.Asp214Asn变体，在另一个家庭的三个患病一级亲属中发现了一个以前未记录的GSN:c.1477T>C变体。对携带c.1477T>C变体的先证者的角膜组织进行免疫组织化学研究，在组织学确定的角膜淀粉样沉积物中鉴定出凝溶胶蛋白。本研究报告了预测的致病性GSN:c.1477T>C变体与芬兰型淀粉样变性之间的新关联，并且首次提供了在远离关键G2钙结合区域的位点上病理性GSN变体的功能证据，导致了芬兰型淀粉样变性的表型。
