Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1

Edwards, Matthew; Challinor, Christopher J; Colley, Peter; Roberts, James M.; Partington, M. W.; Hollway, Georgina E.; Kozman, H.; Mulley, J. C.

doi:10.1002/ajmg.1320530114

Cited by 25 publications

(20 citation statements)

References 19 publications

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“…According to the revised diagnostic criteria of the Genter Nosology (de Paepe et al 1996), an FBN1 mutation can only be used as a diagnostic criterion if it is associated with Marfan syndrome in other patients. Thus, at the present time, it is not possible to determine whether the patient has a classical MFS that is not yet fully manifest or a more mild fibrillinopathy such as isolated dominant ectopia lentis, which has been described as being associated with mild skeletal manifestations such as scoliosis (Edwards et al 1994).…”

Section: Discussionmentioning

confidence: 97%

A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype

et al. 1997

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The Marfan syndrome, an autosomal dominant heritable disorder of connective tissue, is caused by mutations in the gene for fibrillin-1, FBN1. A novel FBN1 mutation was identified using temperature-gradient gel electrophoresis of a reverse-transcribed polymerase chain reaction product spanning exons 14 to 16. The mutation, G1760A, is predicted to result in the amino acid substitution C587Y and thus to disrupt one of the disulfide bonds of the calcium-binding epidermal growth factor-like module encoded by exon 14. C587Y was found to be a de novo mutation in a relatively mildly affected 15-year-old girl whose clinical phenotype was characterized mainly by ectopia lentis and thoracic scoliosis. Metabolic labeling of cultured dermal fibroblasts from the affected patient demonstrated delayed secretion of fibrillin with normal synthesis and no decrease in incorporation into the extracellular matrix compartment. Fibrillin immunostaining of confluent dermal fibroblast cultures revealed no visible difference between the patient's cells and control cells. Characterization of many different FBN1 mutations from different regions of the gene may provide a better understanding of clinical and biochemical genotype-phenotype relationships.

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Section: Discussionmentioning

confidence: 97%

A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype

et al. 1997

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“…Examples of the importance of this recent alteration include a report by Edwards and colleagues, 27 who presented a family with autosomal dominant EL with some mild skeletal features but no cardiological features of MFS, hence diagnosing IEL. However, the mutation they found in FBN1 (R240C) was subsequently described in a family with classical MFS.…”

Section: Autosomal Dominant Elmentioning

confidence: 99%

Molecular pathogenesis and management strategies of ectopia lentis

Chandra

Charteris

2014

Eye

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Ectopia lentis (EL) is a condition that can either herald underlying systemic conditions, or be isolated. The recent expansion in the genetics of these conditions has furthered the understanding of the underlying molecular aetiology. It is becoming apparent that novel genes, and in particular the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, are important in ocular development. The common link in these genes seems to be EL. The clinical management of EL is challenging. In particular, the options for addressing surgically induced aphakia in the context of an ectopic capsule are varied. Little evidence exists to direct management of these issues. This review summarises the molecular pathogenesis of EL and conditions associated with it, using the genetic aetiology as a framework. Furthermore, it summarises some of the issues involved in its clinical management.

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“…Autosomal dominant ectopia lentis refers to bilateral ectopia lentis without the typical skeletal and cardiovascular manifestations of the MFS 129. This disease is linked to the fibrillin-1 gene 130.…”

Section: Fbn1 Mutations In Marfan Syndrome and Related Type 1 Fibrillmentioning

confidence: 99%

The molecular genetics of Marfan syndrome and related microfibrillopathies

Robinson

Godfrey²

2000

Journal of Medical Genetics

257

160

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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 aVect 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 eVect, 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. (J Med Genet 2000;37:9-25)

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Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1

Cited by 25 publications

References 19 publications

A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype

A novel de novo mutation in exon 14 of the fibrillin-1 gene associated with delayed secretion of fibrillin in a patient with a mild Marfan phenotype

Molecular pathogenesis and management strategies of ectopia lentis

The molecular genetics of Marfan syndrome and related microfibrillopathies

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