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Location on Chromosome 15 of the Gene Defect Causing Marfan Syndrome

Authors:
Katariina Kainulainen at Helsinki University Central Hospital
Katariina Kainulainen
Leena Pulkkinen
Leena Pulkkinen
Leena Pulkkinen
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Aslak Savolainen
Aslak Savolainen
Aslak Savolainen
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Ilkka Kaitila at University of Helsinki
Ilkka Kaitila
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Abstract

Marfan syndrome, "the founding member" of the heritable disorders of connective tissue, is a common autosomal dominant disorder with highly variable clinical manifestations in the skeletal, ocular, and cardiovascular systems. The fundamental defect leading to this disease has escaped definition despite decades of research efforts by several groups of investigators. Using linkage analyses with polymorphic markers of the human genome, we mapped the genetic defect to chromosome 15 in five families with Marfan syndrome. With three polymorphic markers we obtained definitive proof of linkage in these families (lod score = 3.92, theta = 0.0 +/- 0.11). The most probable location of the gene for the disease is currently D15S45 (lod score = 3.32, theta = 0.0 +/- 0.12). The chromosomal localization of the mutation in Marfan syndrome is a first step toward the isolation and characterization of the defective gene and serves as a diagnostic test in families in which cosegregation of these markers with the disease has been confirmed.
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The New England Journal of Medicine
Downloaded from nejm.org on November 24, 2015. For personal use only. No other uses without permission.
Copyright © 1990 Massachusetts Medical Society. All rights reserved.
The New England Journal of Medicine
Downloaded from nejm.org on November 24, 2015. For personal use only. No other uses without permission.
Copyright © 1990 Massachusetts Medical Society. All rights reserved.
The New England Journal of Medicine
Downloaded from nejm.org on November 24, 2015. For personal use only. No other uses without permission.
Copyright © 1990 Massachusetts Medical Society. All rights reserved.
The New England Journal of Medicine
Downloaded from nejm.org on November 24, 2015. For personal use only. No other uses without permission.
Copyright © 1990 Massachusetts Medical Society. All rights reserved.
The New England Journal of Medicine
Downloaded from nejm.org on November 24, 2015. For personal use only. No other uses without permission.
Copyright © 1990 Massachusetts Medical Society. All rights reserved.
... The Marfan syndrome (MFS), which was first reported by the pediatrician Antoine Marfan in 1896, is a rare and multi-system disorder with a prevalence of 1 in 5,000 individuals in the general population [40,41]. In 1931 Henriculus Weve first discovered that the cause is located at chromosome 15, more precisely 15q-21.1, and that it is inherited in an autosomal-dominant manner [42]. Later in 1991 Harry C. Dietz identified mutations on the fibrillin-1 (FBN1) gene [43]. ...
... As we found similar extreme distributions for both samples, this reduces the likelihood of sequencing or library preparation errors. Therefore, we hypothesize that this could be related to the physiological or even pathophysiological condition of the Lynx that has not been diagnosed so far, especially since tRNA overexpression has often been associated with various cancer types in human (41)(42)(43). Interestingly, we found that miRNAs and YRNA levels were positively correlated, suggesting that even though their biogenesis pathways are different (44) they might share, potentially complementary, functions. ...
... LIMK2 regulates dynamic changes of the actin cytoskeleton by phosphorylating cofilin and thereby inactivating its F-actin depolymerizing activity [41]. It was shown in mouse models that an activation of LIMK2 is associated with a disturbed flow in the aortic arch and disturbs endothelial cell (EC) barrier function, which was reversed by inhibition of LIMK2 with m-calpain [42]. An up-regulation of LIMK2 likely linked to a down-regulation of miR-1234 in the blood of MFS patients, which was demonstrated in our study, therefore may be related to elevated levels of vascular wall shear stress in the thoracic aorta of MFS patients [43] and be associated with endothelial dysfunction in MFS. ...
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... This disease is caused by the mutation from the FBN1 gene, which codes for fibrillin-1 on chromosome 15 [1] . In clinic, the symptoms of MFS involve the eyes, skeleton, and cardiovascular system [2] . The major manifestations in the eye are lens dislocation or subluxation, high myopia, and retinal detachment. ...
Pupillary capture following sutureless scleral-fixated intraocular lens in children with Marfan syndrome
Article
  • Nov 2023
AIM: To compare the clinical outcomes between two approaches for sutureless scleral-fixated intraocular lens (SFIOL) in children with Marfan syndrome (MFS). METHODS: The study included 15 children (26 eyes) with lens subluxation due to MFS. These children underwent lensectomy, anterior vitrectomy, and sutureless SFIOL. According to the position of placement of intraocular lens (IOL) haptics, two study groups were reviewed for best corrected visual acuity (BCVA) and postoperative complications: group A, 14 eyes with haptics fixated at 2.0 mm from the limbus; group B, 12 eyes with the haptics fixated at 2.5 mm from the limbus. RESULTS: The mean axial length for all patients was 25.66±2.35 mm. Postoperative BCVA in logMAR were significant improved in both groups (0.77±0.32 to 0.17±0.12 in group A, 0.66±0.25 to 0.24±0.12 in group B, both P<0.001) while no significant difference between two groups (P>0.05). Pupillary capture was main postoperative complication, occurring between 3d and 18mo. It occurred in 7 eyes in group A and one eye in group B (P=0.02). CONCLUSION: Sutureless SFIOL is an effective treatment approach for lens subluxation in children with MFS. Pupillary capture is the main postoperative complication. Fixated IOL haptics at 2.5 mm from the limbus can reduce the occurrence of pupillary capture.
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... A mutation in FBN1, encoding the extracellular matrix glycoprotein fibrillin 1, was identified as the cause of disease in the majority of MFS patients [6,7]. Fibrillin 1 is a main component of extracellular microfibrils and therefore plays a central role in the structural integrity of connective tissues [8]. ...
Is Marfan Syndrome Associated with Primary Structural Changes in the Left Atrium?
Article
Full-text available
  • Oct 2023
Marfan syndrome (MFS) is an autosomal-dominant multisystem connective tissue disorder that is based on mutations in the FBN1 gene and variably affects different organs, including the heart. In this study, we investigated cardiac function with a focus on the left atrium (LA) in a relatively large cohort of patients with MFS. After screening of 1165 patients that had been examined in our center between 2016 and 2020, 231 adult MFS patients with and without aortic operation were included in our study and compared to a healthy control group (n = 106). Cardiac function was assessed by transthoracic echocardiography and NT-proBNP was used as a secretory marker. Most (94.8%) of the patients received genetic testing. Left ventricular function was within normal ranges and not impaired. Interestingly, we found that LA size and secretory activity were increased in MFS patients, despite normal left ventricular filling pressures. This finding was even more pronounced in MFS patients with prior aortic surgery. A correlation between LA size or NT-proBNP levels and the type of pathogenic FBN1 variant could not be identified. Right ventricular function and right atrial size were increased only in MFS patients that had undergone aortic surgery. In conclusion, these findings suggest that MFS leads to structural changes in the LA that are not solely resulting from left ventricular dysfunction, but probably can be considered a primary pathology of MFS.
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... In fact, the molecular analysis showed a "c.3772C>T, p. Pro1258Ser" de-novo mutation of FBN1 gene in heterozygosis, which can be responsible of Marfan Syndrome (MFS). 6,7 Ghent criteria (ectopia lentis and FBN1 gene mutation associated with aortic root dilatation) were then fulfilled and diagnosis accomplished. 8 in the pediatric population, Mr may often occur in the context of a systemic disease, such as connective tissue diseases, rheumatic disease, and various congenital heart defects. ...
Giant mass obstructing oral cavity in a newborn
Article
Full-text available
  • Apr 2023
With this brief report we want to draw attention to a neonatal tumor of oral cavity, with a frightening presentation but a very simple management. An otherwise healthy newborn girl (birth weight: 3660 g) presented at birth with giant mass occupying and protruding from oral cavity; the patient was referred to our multidisciplinary team due to mechanical obstruction of the oral cavity interfering with respiration and oral feeding. Her mother was 34 years old with no notable familiar and medical history; fetal ultrasound examinations did not demonstrate abnormalities; pregnancy and delivery were uneventful. Clinical examination revealed a pedunculated bilobed mass measuring 7.6 cm in maximum diameter implanted at the right alveolar ridge of the upper maxilla; the lesion had a firm consistency and was covered by smooth red mucosa; there was no ulceration, bleeding or pus discharge
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... An initial linkage study of Marfan syndrome in two Finnish families localized the defect to chromosome 15 (reF. 34 ). A linkage analysis of several large American families was subsequently performed to pinpoint the defect to a more precise chromosomal position (15q15-21.3) ...
Genetics and mechanisms of thoracic aortic disease
Article
  • Sep 2022
Aortic disease has many forms including aortic aneurysm and dissection, aortic coarctation or abnormalities in aortic function, such as loss of aortic distensibility. Genetic analysis in humans is one of the most important experimental approaches in uncovering disease mechanisms, but the relative infrequency of thoracic aortic disease compared with other cardiovascular conditions such as coronary artery disease has hindered large-scale identification of genetic associations. In the past decade, advances in machine learning technology coupled with large imaging datasets from biobank repositories have facilitated a rapid expansion in our capacity to measure and genotype aortic traits, resulting in the identification of dozens of genetic associations. In this Review, we describe the history of technological advances in genetic discovery and explain how newer technologies such as deep learning can rapidly define aortic traits at scale. Furthermore, we integrate novel genetic observations provided by these advances into our current biological understanding of thoracic aortic disease and describe how these new findings can contribute to strategies to prevent and treat aortic disease.
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... 1, 2 MFS is a spectrum of connective tissue disorders most often caused by mutations in the fibrillin extracellular matrix protein, encoded by the FBN1 gene on chromosome 15. 3 Genetic testing for FBN1 mutations has a screening detection rate of 97%. 4, 5 While mutations in fibrillin have been identified in 66-91% of cases, 6 mutations in transforming growth factor β receptor-2 (TGFBR2) have been demonstrated to have similar phenotype. 7,8 Normally, fibrillin aggregates to form microfibrils to provide strength and elasticity of connective tissues. ...
Orthopaedic Management in Marfan Syndrome: Current Concept Review
Article
Full-text available
  • Aug 2020
Marfan syndrome (MFS) is a variable autosomal dominant connective tissue disorder affecting multiple organ systems. Causative mutations in the fibrillin-1 protein lead to dysregulation of transforming growth factor-β (TGF-β). A diagnosis of MFS can be made using systemic evaluation combining clinical and genetic features. Because the condition is characterized by a variety of musculoskeletal manifestations, orthopaedic surgeons may be the first provider patients encounter. Common musculoskeletal manifestations of MFS include spine deformity, acetabular protrusion, limb length deformity, joint laxity, and foot pathology. Non-musculoskeletal manifestations include major cardiac and ocular conditions. Early identification is important for referral and prompt treatment of cardiovascular abnormalities, which can prevent premature mortality. As medical and surgical interventions have advanced, life expectancy for MFS patients has increased to late 70s. We must remain vigilant, suspect diagnosis, and engage in multidisciplinary care to promote musculoskeletal function at advanced ages.
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Extra-Thoracic Aneurysms in Marfan Syndrome: A Systematic Review of the Literature
Article
  • Aug 2022
  • ANN VASC SURG
Introduction Marfan syndrome (MS) most often shows as thoracic aortic aneurysm (TAA) or aortic dissection, but it may also involve other vascular territories. Objective To identify those extra-thoracic vascular manifestations most frequently associated with MS. Methodology Systematic review of the literature with PRISMA criteria. The following databases were included: Medline, Embase, Web of Science (WOS), Cumulative Index of Nursing and Health Sciences Literature (CINHAL); Spanish database MEDESY Cochrane Central Register of Controlled Trials (CENTRAL). Results 10,008 articles were identified, leaving 155 for the first stage of data analysis (total incidence of aneurysms) and 83 for the second (descriptive data analysis). Overall, 518 aneurysms were identified: 149 in the head and neck, 94 in the extremities 275 in the aortic, iliac and visceral sectors. Mostly, they were simultaneously discovered during studies of the AAT. In the abdominal aorta, the presentation with rupture in 11 of 32 patients stands out. Resection and bypass was the most frequently used method for repair in the treated cases. Conclusions Although its frequency in the general population is unknown, this systematic review suggests that extra-thoracic aneurysmal arterial involvement in the MS may be more frequent than expected. We believe screening for aneurysms in other vascular sectors may be advisable, especially in patients with MS and AAT.
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Pathology of sudden death, cardiac arrhythmias, and conduction system
Chapter
  • Jan 2022
Pathology of sudden death and clinicopathologic correlations are treated in this chapter. Definition, epidemiology, and pathogenetic mechanisms are first addressed. Sudden death is mostly cardiovascular and arrhythmic in origin, with ventricular fibrillation as the precipitating mechanism of cardiac arrest. The majority of cases present with a pathologic substrate at the level of coronary arteries, myocardium, valves, conduction system, and great arteries. However, there are cases without substrate (ion channel diseases) which require molecular investigations in search of transmissible, genetically determined disease. The chapter is mostly devoted to sudden death in the young, with particular reference to the athletes. Anatomy and pathology of the cardiac conduction system is also dealt with, including ECG correlations. AV block and ventricular preexcitation are taken into detailed consideration. Atrial fibrillation, its causes, substrates, potential complications, and treatment are also extensively treated. Guidelines and useful recommendations for postmortem study of sudden death appear at the end of the chapter.
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Cell-free synthesis of hyaluronic acid in Marfan Syndrome
Article
Full-text available
  • Jan 1980
The cell-free synthesis of hyaluronic acid has been demonstrated in extracts of cultured human fibroblasts. Preparations from fibroblasts of normal individuals as well as those from patients with Marfan syndrome incorporate glucuronic acid and N-acetylglucosamine from their UDP derivatives into hyaluronic acid. Extracts from Marfan fibroblasts demonstrate 3 to 10 times more total and specific hyaluronic acid synthetase activity than do preparations from normal fibroblasts. All synthetic activity was found in particulate fractions with the bulk of activity localized in material sedimenting as large membrane fragments. Marfan and normal preparations exhibited similar properties with respect to substrate, cofactor, pH requirements, and heat stability. Neither the Marfan nor normal enzyme systems could be stimulated by exogenous acceptors, nor did either preparation contain a soluble factor which stimulated or inhibited the enzymic activity of the other. The genetic defect in Marfan syndrome appears to result in increased activity of hyaluronic acid synthetase without demonstrable changes in properties of the particulate enzymes involved.
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International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986
Article
  • Mar 1988
  • Am J Med Genet
The heritable disorders of connective tissue have proven to be very heterogeneous and problems have arisen concerning syndromic boundaries, nomenclature, and classification. In an attempt to resolve these dilemmas, a group of experts participated in a Workshop held during the 7th International Congress of Human Genetics, Berlin, in September, 1986. At the Workshop, overviews were given of the uses and limitations of nosology (McKusick), diagnostic criteria (Pyeritz), and practical issues in biochemical and molecular diagnosis (Hollister). Invited speakers then gave brief comments on the current status of the nosology of specific categories of inherited connective tissue disorders and made recommendations for possible modification. The Workshop was followed by two closed committee meetings at which the participants attempted to reach agreement on syndromic definition and a standardized nomenclature. The final proposals, with brief comment where relevant, form the subject of this communication.
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Isolation and mapping of a polymorphic DNA sequence (pEFD49.3) on chromosome 15 [DL5S29]
Article
  • Nov 1988
Full textFull text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (55K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References. 10943 Selected References These references are in PubMed. This may not be the complete list of references from this article. Lathrop GM, Lalouel JM, Julier C, Ott J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985 May;37(3):482–498. [PMC free article] [PubMed]
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The Marfan Syndrome: Diagnosis and Management
Article
  • May 1979
Because of the variability in clinical expression of the Marfan syndrome and its variants, the diagnosis may be made in infancy, or those affected may have few if any symptoms to bring them to medical attention even by early adulthood. When problems do develop, a variety of medical specialists, including pediatricians, internist, orthopedists, ophthalmologists, cardiologists and endocrinologists, are consulted. The purposes of this paper are to review the diagnostic criteria, to increase the awareness of this disorder among the various medical specialties and to outline the management of the most common medical problems.
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Clinical variability in Marfan syndrome(s)
Article
  • Feb 1979
The clinical picture of the Marfan syndrome which emerges from medical textbooks is that of a tall, lanky person, with disproportionately long limbs and digits, a pectus excavatum, a narrow palate crowding the teeth, scoliosis, mild laxity of the joints, pes planus, squinting through dislocated lenses, and either dyspneic because of severe aortic regurgitation or dying suddenly from aortic dissection. Those who see a variety of connective tissue disorder have for years recognized that persons may present with only some or even one of the classic features of the Marfan syndrome. No clear consensus has emerged as to the classification, prognosis, management, or counseling of such individuals, as contrasted with the textbook form of the Marfan syndrome where useful information exists on all of these points. The forme fruste concept has not greatly advanced our understanding of the Marfan syndrome any more than most other contexts where it has been used. The manifestations of the classic Marfan syndrome extend from the limits of the normal to the floridly positive case in whom the diagnosis would not be questioned. The underlying biologic mechanism can be ascribed either to variation in the expression of a single gene, from epistasis, environmental challenges, or random events; or to heterogeneity, from allelic and nonallelic genes which in some way specify the characteristics of connective tissue. We have instituted a complete review of our extensive clinical experience with the Marfan syndrome(s) with a view to: 1) documenting the extent of clinical heterogeneity which exists among families, and 2) within families; 3) obtaining evidence on modifier genes (epistasis) as witnessed. by segregation within families; 4) evaluating the natural history of the medical problems which accompany the various clinical presentations; and 5) providing a potentially more rewarding population from which to search for biochemical heterogeneity when appropriate chemical methods become feasible.
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Aortic aneurysm in Marfan's Syndrome: changes in the ultrastructure and composition of collagen
Article
  • Nov 1979
Aneurysmal aortic tissue and the mitral valve of a patient with Marfan's syndrome were examined. Biochemical analysis of the tissue showed a qualitative and quantitative defect in alpha 2 chain production of Type I collagen. On polyacrylamide gel electrophoresis of the aortic extract, two separate bands in the alpha 2 region and an increase of the alpha 1 to alpha 2 ratio were found. Examination by electron microscopy revealed elastic fibre degeneration, helical collagen fibres, and metabolically active modified smooth muscle cells. The formation of helical collagen fibres is attributed to a defect in the development of chains and cross-links of collagen precursors produced by the hypertrophic smooth muscle cells. Elastic fibre disintegration is believed to be due to a lack of support by Type I collagen fibres, which have decreased tensile strength. A scheme for the pathogenesis of aortic aneurysm and other connective tissue abnormalities in Marfan's syndrome is proposed as follows. Type I collagen fibres have decreased tensile strength because of a defect in the alpha 2 chain biosynthesis and decreased cross-linking. Over many years the wall of the ascending aorta is subjected to cyclic stresses and it dilates. Elastic fibres disintegrate. The attempt at repair by metabolically activated modified smooth muscle cells is abortive, and rupture is likely to occur.
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Detection of Specific Sequences Among DNA Fragments Separated by Gel Electrophoresis
Article
  • Dec 1975
This paper describes a method of transferring fragments of DNA from agarose gels to cellulose nitrate filters. The fragments can then be hybridized to radioactive RNA and hybrids detected by radioautography or fluorography. The method is illustrated by analyses of restriction fragments complementary to ribosomal RNAs from Escherichia coli and Xenopus laevis, and from several mammals.
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Marfan syndrome: exclusion of genetic linkage to five genes coding for connective tissue components in the long arm of chromosome 2
Article
  • Mar 1990
Marfan syndrome represents a heterogeneous connective tissue disease, the symptoms arising in several tissues and organs. The defective gene(s) behind this autosomal dominant condition has not been found despite considerable research. The main targets of the research have been the genes coding for connective tissue components. Several of the candidate genes suspected to be defective in Marfan syndrome are located on the long arm of chromosome 2. These genes include a cluster of two genes coding for fibrillar collagens COL3A1 and COL5A2, and a third member of the collagen gene family: COL6A3. Furthermore, genes for elastin (ELN) and fibronectin (FN) are also located in this area of chromosome 2. We studied this chromosomal area using restriction fragment length polymorphism (RFLP) linkage analysis in five Finnish Marfan families with affected members in three generations. In two point linkage analyses, Lod scores of -3.192 (theta = 0.1) to COL3A1, -1.683 (theta = 0) to COL6A3 and -2.664 (theta = 0.01) to FN were obtained, whereas the linkage analysis between elastin and the disease was non-informative (Lod score 0.444, theta = 0). With the multipoint linkage analysis that permits simultaneous examination of several loci and more efficient use of family data, we obtained an exclusion of all these loci as the site of the mutation leading to Marfan syndrome in these families.
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Unilateral microfibrillar abnormalities in a case of asymmetric Marfan syndrome
Article
  • May 1990
The Marfan syndrome is a dominantly inherited connective-tissue disorder characterized by ocular, cardiovascular, and musculoskeletal abnormalities. Although the underlying biochemical and molecular defect(s) of this pleiotropic disease is currently unknown, we have consistently observed apparent diminished content of elastin-associated microfibrillar fibers accumulating in skin, or produced by cultured fibroblasts, from patients with the Marfan syndrome and have documented the cosegregation of these immunofluorescent abnormalities of microfibrillar fibers with the Marfan syndrome phenotype in family studies. Recently, an unusual patient has been described with unilateral phenotypic features of the Marfan syndrome, providing an unique opportunity to compare microfibrillar fibers and other connective-tissue components between the affected and nonaffected sides. In the present report, we demonstrate striking differences in apparent content of microfibrillar fibers, as determined by indirect immunofluorescence of skin and fibroblast cultures, that are revealed when multiple homologous samples derived from different sides of the patient's body are compared. In contrast, no differences in apparent content of type III collagen or in the biosynthesis and apparent structure of types I and III (pro)collagens were found. HLA types and chromosome heteromorphisms were identical in fibroblasts from both sides of the body, eliminating the formal possibility of chimerism and suggesting that a postzygotic mutation accounts for the asymmetric manifestation of the Marfan syndrome in this patient. The observation of striking decreases in microfibrillar fibers on the affected side of the body provides further evidence that abnormalities of this component of the elastic fiber system may be central to the pathogenesis and possibly the etiology of the Marfan syndrome.
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