关键词: ligneous conjunctivitis missense mutations plasminogen plasminogen deficiencies single nucleotide polymorphisms

来  源:   DOI:10.3389/fcvm.2024.1406953   PDF(Pubmed)

Abstract:
Human plasminogen (PLG), the zymogen of the fibrinolytic protease, plasmin, is a polymorphic protein with two widely distributed codominant alleles, PLG/Asp453 and PLG/Asn453. About 15 other missense or non-synonymous single nucleotide polymorphisms (nsSNPs) of PLG show major, yet different, relative abundances in world populations. Although the existence of these relatively abundant allelic variants is generally acknowledged, they are often overlooked or assumed to be non-pathogenic. In fact, at least half of those major variants are classified as having conflicting pathogenicity, and it is unclear if they contribute to different molecular phenotypes. From those, PLG/K19E and PLG/A601T are examples of two relatively abundant PLG variants that have been associated with PLG deficiencies (PD), but their pathogenic mechanisms are unclear. On the other hand, approximately 50 rare and ultra-rare PLG missense variants have been reported to cause PD as homozygous or compound heterozygous variants, often leading to a debilitating disease known as ligneous conjunctivitis. The true abundance of PD-associated nsSNPs is unknown since they can remain undetected in heterozygous carriers. However, PD variants may also contribute to other diseases. Recently, the ultra-rare autosomal dominant PLG/K311E has been found to be causative of hereditary angioedema (HAE) with normal C1 inhibitor. Two other rare pathogenic PLG missense variants, PLG/R153G and PLG/V709E, appear to affect platelet function and lead to HAE, respectively. Herein, PLG missense variants that are abundant and/or clinically relevant due to association with disease are examined along with their world distribution. Proposed molecular mechanisms are discussed when known or can be reasonably assumed.
摘要:
人纤溶酶原(PLG),纤维蛋白溶解蛋白酶的酶原,纤溶酶,是一种具有两个广泛分布的显性等位基因的多态蛋白,PLG/Asp453和PLG/Asn453。约15个其他错义或非同义单核苷酸多态性(nsSNP)的PLG显示主要,但不同,世界人口的相对丰富。虽然这些相对丰富的等位基因变体的存在是公认的,它们经常被忽视或被认为是非致病性的。事实上,这些主要变异中至少有一半被归类为具有相互冲突的致病性,目前尚不清楚它们是否有助于不同的分子表型。从那些,PLG/K19E和PLG/A601T是与PLG缺陷(PD)相关的两种相对丰富的PLG变体的例子。但其致病机制尚不清楚。另一方面,据报道,大约有50种罕见和超罕见的PLG错义变体导致PD为纯合或复合杂合变体,通常导致一种叫做结膜炎的使人衰弱的疾病。PD相关nsSNP的真实丰度是未知的,因为它们在杂合携带者中仍未被检测到。然而,PD变体也可能导致其他疾病。最近,发现超罕见常染色体显性遗传PLG/K311E是C1抑制剂正常的遗传性血管性水肿(HAE)的病因.另外两个罕见的致病性PLG错义变异,PLG/R153G和PLG/V709E,似乎影响血小板功能并导致HAE,分别。在这里,检查由于与疾病相关而丰富和/或临床相关的PLG错义变体及其世界分布。在已知或可以合理假设的情况下,讨论了拟议的分子机制。
公众号