Robinson P N, Godfrey M
Laboratory of Paediatric Molecular Biology, Department of General Paediatrics, Charité University Hospital, Humboldt University, D-10098 Berlin, Germany.
J Med Genet. 2000 Jan;37(1):9-25. doi: 10.1136/jmg.37.1.9.
Mutations in the gene for fibrillin-1 (FBN1) have been shown to cause Marfan syndrome, an autosomal dominant disorder of connective tissue characterised by pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems. Fibrillin-1 is a major component of the 10-12 nm microfibrils, which are thought to play a role in tropoelastin deposition and elastic fibre formation in addition to possessing an anchoring function in some tissues. Fibrillin-1 mutations have also been found in patients who do not fulfil clinical criteria for the diagnosis of Marfan syndrome, but have related disorders of connective tissue, such as isolated ectopia lentis, familial aortic aneurysm, and Marfan-like skeletal abnormalities, so that Marfan syndrome may be regarded as one of a range of type 1 fibrillinopathies. There appear to be no particular hot spots since mutations are found throughout the entire fibrillin-1 gene. However, a clustering of mutations associated with the most severe form of Marfan syndrome, neonatal Marfan syndrome, has been noted in a region encompassing exons 24 to 32. The gene for fibrillin-2 (FBN2) is highly homologous to FBN1, and mutations in FBN2 have been shown to cause a phenotypically related disorder termed congenital contractural arachnodactyly. Since mutations in the fibrillin genes are likely to affect the global function of the microfibrils, the term microfibrillopathy may be the most appropriate to designate the spectrum of disease associated with dysfunction of these molecules. The understanding of the global and the molecular functions of the fibrillin containing microfibrils is still incomplete and, correspondingly, no comprehensive theory of the pathogenesis of Marfan syndrome has emerged to date. Many, but not all, fibrillin-1 gene mutations are expected to exert a dominant negative effect, whereby mutant fibrillin monomers impair the global function of the microfibrils. In this paper we review the molecular physiology and pathophysiology of Marfan syndrome and related microfibrillopathies.
原纤维蛋白-1（FBN1）基因的突变已被证明会导致马凡综合征，这是一种常染色体显性结缔组织疾病，其特征为多效性表现，主要累及眼、骨骼和心血管系统。原纤维蛋白-1是10 - 12纳米微原纤维的主要成分，除了在某些组织中具有锚定功能外，微原纤维还被认为在原弹性蛋白沉积和弹性纤维形成中发挥作用。在不符合马凡综合征诊断临床标准，但患有相关结缔组织疾病的患者中也发现了FBN1突变，如单纯晶状体异位、家族性主动脉瘤和马凡样骨骼异常，因此马凡综合征可被视为一系列1型原纤维蛋白病之一。由于在整个原纤维蛋白-1基因中都发现了突变，所以似乎没有特定的热点区域。然而，在包含外显子24至32的区域中，已注意到与最严重形式的马凡综合征（新生儿马凡综合征）相关的突变聚集。原纤维蛋白-2（FBN2）基因与FBN1高度同源，并且已证明FBN2突变会导致一种表型相关的疾病，称为先天性挛缩性蜘蛛指症。由于原纤维蛋白基因突变可能会影响微原纤维的整体功能，“微原纤维病”这一术语可能最适合用来指代与这些分子功能障碍相关的疾病谱。目前对含原纤维蛋白的微原纤维的整体和分子功能的理解仍不完整，相应地，迄今为止尚未出现关于马凡综合征发病机制的全面理论。许多（但不是全部）原纤维蛋白-1基因突变预计会产生显性负效应，即突变的原纤维蛋白单体损害微原纤维的整体功能。在本文中，我们综述了马凡综合征及相关微原纤维病的分子生理学和病理生理学。
