Mutations In Fibrillin-1 Gene Research Articles

Multidisciplinary follow-up in a patient with Morgagni hernia leads to diagnosis of Marfan syndrome

Backgroundcongenital diaphragmatic hernia (CDH) is a birth defect occurring in isolated or syndromic (chromosomal or monogenic) conditions. The diaphragmatic defect can be the most common one: left-sided posterolateral, named Bochdalek hernia; or it can be an anterior-retrosternal defect, named Morgagni hernia. Marfan syndrome (MFS) is a rare autosomal dominant inherited condition that affects connective tissue, caused by mutations in fibrillin-1 gene on chromosome 15. To date various types of diaphragmatic defects (about 30 types) have been reported in association with MFS, but they are heterogeneous, including CDH and paraesophageal hernia.Case presentationWe describe the case of a child incidentally diagnosed with Morgagni hernia through a chest X-ray performed due to recurrent respiratory tract infections. Since the diagnosis of CDH, the patient underwent a clinical multidisciplinary follow-up leading to the diagnosis of MFS in accordance with revised Ghent Criteria: the child had typical clinical features and a novel heterozygous de novo single-base deletion in exon 26 of the FBN1 gene, identified by Whole-Exome Sequencing. MFS diagnosis permitted to look for cardiovascular complications and treat them, though asymptomatic, in order to prevent major cardiovascular life-threatening events.ConclusionOur case shows the importance of a long-term and multidisciplinary follow-up in all children with diagnosis of CDH.

A successful case of deceased-donor liver transplantation from a donor with Marfan syndrome: a case report

BackgroundLiver transplantation is the definitive therapy for patients with decompensated cirrhosis. Marfan syndrome is a systemic inheritable connective tissue disease associated with fibrillin-1 gene mutations, which cause abnormalities in connective tissue. Vascular changes due to Marfan syndrome occur mostly in the main vessels due to the high amount of connective tissue within the vessel wall and the high pressure and blood flow to which they are exposed. The incidence of changes in visceral arteries is about 0.42% and usually presents with cystic medial necrosis. This report is the first deceased-donor liver transplantation with a donor with Marfan syndrome with a history of abdominal surgery.Case presentationA patient in his 50s underwent liver transplantation for decompensated alcoholic cirrhosis. The donor, a 50s male with Marfan syndrome, was diagnosed with brain-death due to a cerebral hemorrhage caused by a cerebral aneurysm. The donor’s clinical presentation as Marfan syndrome was aortic dissection, with multiple surgical procedures performed from the aortic root to the abdominal aorta. An intraoperative biopsy of the hepatic artery showed no abnormality, so this organ was considered appropriate. The surgery was completed without any problems of the arterial anastomosis. The patient’s postoperative course was uneventful, and he was transferred to a hospital for recuperation on the 18th postoperative day. One year after the surgery, the patient is still alive without any complications from the transplantation or arterial problems.ConclusionsEven if the patient had a history of surgery for vascular anomalies extending to the abdominal aorta due to Marfan syndrome, the patient can be a donor for liver transplantation under appropriate judgment, including intraoperative biopsy.

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

A common variant rs2054564 in ADAMTS17 is associated with susceptibility to lumbar spondylosis

The molecular pathophysiology underlying lumbar spondylosis development remains unclear. To identify genetic factors associated with lumbar spondylosis, we conducted a genome-wide association study using 83 severe lumbar spondylosis cases and 182 healthy controls and identified 65 candidate disease-associated single nucleotide polymorphisms (SNPs). Replication analysis in 510 case and 911 control subjects from five independent Japanese cohorts identified rs2054564, located in intron 7 of ADAMTS17, as a disease-associated SNP with a genome-wide significance threshold (P = 1.17 × 10–11, odds ratio = 1.92). This association was significant even after adjustment of age, sex, and body mass index (P = 7.52 × 10–11). A replication study in a Korean cohort, including 123 case and 319 control subjects, also verified the significant association of this SNP with severe lumbar spondylosis. Immunohistochemistry revealed that fibrillin-1 (FBN1) and ADAMTS17 were co-expressed in the annulus fibrosus of intervertebral discs (IVDs). ADAMTS17 overexpression in MG63 cells promoted extracellular microfibrils biogenesis, suggesting the potential role of ADAMTS17 in IVD function through interaction with fibrillin fibers. Finally, we provided evidence of FBN1 involvement in IVD function by showing that lumbar IVDs in patients with Marfan syndrome, caused by heterozygous FBN1 gene mutation, were significantly more degenerated. We identified a common SNP variant, located in ADAMTS17, associated with susceptibility to lumbar spondylosis and demonstrated the potential role of the ADAMTS17-fibrillin network in IVDs in lumbar spondylosis development.

Next-generation sequencing panel analysis in 24 Chinese patients with congenital ectopia lentis.

Congenital ectopia lentis (CEL) is a rare but serious disease. We use next-generation sequencing to detect genes associated with lens abnormalities in 24 patients with bilateral CEL and search for pathogenic genes and mutation sites. A total of 24 patients diagnosed with CEL from January 2019 to November 2019 were enrolled in this study, and their clinical data were collected and genome-wide deoxyribonucleic acid was extracted from peripheral venous blood. Targeted gene capture technology was used to obtain 188 exons of lens abnormality-related genes, which were sequenced using a high-throughput method. The mutation sites were determined through data analysis and verified by the Sanger method. According to the data from previous studies, the association between the genotype and clinical phenotype was analysed. Of the 24 patients, 23 had mutations in the fibrillin-1 (FBN1) gene, and 20 were diagnosed with Marfan syndrome. The 23 cases of FBN1 mutations were all heterozygous mutations, including 17 missense mutations, 3 splicing variants, 2 exon deletion mutations, 1 codon mutation, and 9 new mutations. A total of 17 mutations were located in the calcium-binding epidermal growth factor domain, including 16 mutations that contained missense mutations of cysteine. In addition, a heterozygous mutation of the gap junction protein alpha 8 (GJA8) gene was detected in one patient. In this study, we identified 23 FBN1 gene mutations and 1 GJA8 gene mutation in 24 patients with CEL. Of these, 9 new FBN1 mutations and 14 known mutations were found. The results expanded the mutation spectrum of the FBN1 gene, suggesting that FBN1 mutation may be the main cause of CEL in Chinese patients.

Peri-vascular adipose tissue attenuation on chest computed tomography in patients with Marfan Syndrome: a case series.

Marfan Syndrome is a genetic disorder that determines histopathological alterations of the aortic vascular wall leading to increased inflammatory component. The peri-vascular adipose tissue attenuation is a method able to capture localized vascular inflammation by mapping spatial changes of perivascular tissue attenuation on computed tomography. We measured peri-vascular adipose tissue attenuation around the ascending aorta in three consecutive subjects with confirmed genetic diagnosis of Marfan Syndrome. All subjects received the genetic diagnosis of fibrillin-1 gene mutation as part of the family screening of patients with known Marfan Syndrome. Chest computed tomography was performed in such asymptomatic subjects after genetic confirmation of Marfan Syndrome. None of these subjects showed aortic aneurysms or suffered from chronic inflammatory/infectious disease. In the three subjects identified with Marfan Syndrome the value of aortic peri-vascular adipose tissue attenuation measured at chest computed tomography was higher than normal and the volume of aortic peri-vascular adipose tissue was lower. These preliminary observations suggest that peri-vascular adipose tissue attenuation is unexpectedly high in patients with Marfan Syndrome, notwithstanding the normal aortic diameter at the time of computed tomography. Whether this observation may find a clinical use in suspected Marfan Syndrome or in predicting aortic complications in Marfan Syndrome is worth to be assessed in prospective studies.

Respiratory manifestations of Marfan syndrome: a narrative review.

ObjectiveThe prevalence of Marfan syndrome (MFS) is estimated to be 1 in 10,000 to 15,000 individuals, but the phenotype of MFS may not be apparent and hence its diagnosis may not be considered by clinicians. Furthermore, the effects of MFS on the lungs and breathing are underrecognized despite the high morbidity that can occur. The objective of this Narrative Review is to delineate the molecular consequences of a defective fibrillin-1 protein and the skeletal and lung abnormalities in MFS that may contribute to respiratory compromise. It is important for clinicians to be cognizant of these MFS-associated respiratory conditions, and a contemporaneous review is needed.BackgroundMFS is an autosomal dominant, connective tissue disorder caused by mutations in the FIBRILLIN-1 (FBN1) gene, resulting in abnormal elastic fibers as well as increased tissue availability of transforming growth factor-beta (TGFβ), both of which lead to the protean clinical abnormalities. While these clinical characteristics are most often recognized in the cardiovascular, skeletal, and ocular systems, MFS may also cause significant impairment on the lungs and breathing.MethodsWe searched PubMed for the key words of “Marfan syndrome,” “pectus excavatum,” and “scoliosis” with that of “lung disease,” “breathing”, or “respiratory disease.” The bibliographies of identified articles were further searched for relevant articles not previously identified. Each relevant article was reviewed by one or more of the authors and a narrative review was composed.ConclusionsThough the classic manifestations of MFS are cardiovascular, skeletal, and ocular, FBN1 gene mutation can induce a variety of effects on the respiratory system, inducing substantial morbidity and potentially increased mortality. These respiratory effects may include chest wall and spinal deformities, emphysema, pneumothorax, sleep apnea, and potentially increased incidence of asthma, bronchiectasis, and interstitial lung disease. Further research into approaches to prevent respiratory complications is needed, but improved recognition of the respiratory complications of MFS is necessary before this research is likely to occur.

Fibrillin-1 gene mutations in a Chinese cohort with congenital ectopia lentis: spectrum and genotype–phenotype analysis

AimsTo identify the mutation spectrum and genotype–phenotype correlations of fibrillin-1 (FBN1) mutations in a Chinese cohort with congenital ectopia lentis (EL).MethodsPatients clinically suspected of congenital zonulopathy were screened using panel-based...

Marfan Syndrome with CRHD

AbstractMarfan syndrome (MFS) is an inheritable disorder caused by mutation of fibrillin-1 gene. It is the most common disorder among disorders of connective tissue. Its mode of inheritance is autosomal dominant. The reported prevalence of this disorder is one in three thousand (3000) to five (5000) thousand individuals. It presents with varied manifestation and different range of severity. The organ systems most commonly affected by this disorder include eyes, cardiovascular system, and musculoskeletal system.The other systems which may be affected include respiratory system, skin, and central nervous system. It is diagnosed with the help of revised Ghent score which includes a set of various diagnostic criteria which need to be fulfilled. MFS in this patient was diagnosed after the fulfillment of the revised Ghent score criteria, which included a positive history of MFS in the family and a systemic score of 8.In this case report, we are reporting a case of MFS which is unusual and remarkable in the sense that it is associated with chronic rheumatic heart disease (CRHD), and not the cardiovascular features which are usually present in cases of MFS. We tried to find a similar case if ever reported previously and, after extensive search, we could find only few cases13 14 15 of MFS which were associated with CRHD.

The differences in surgical long-term outcomes between Marfan syndrome and Loeys-Dietz syndrome.

The aim of this study was to disclose the differences of surgical outcomes between Marfan syndrome with mutations in fibrillin-1 gene and Loeys-Dietz syndrome with mutations in transforming growth factor-beta receptor 1 and 2. We reviewed 368 patients aged less than 50years who underwent surgery for thoracic aortic diseases between 1988 and 2019, and enrolled 99 patients with Marfan syndrome (26.9%; 57 men, 33±7.5years) and 24 patients with Loeys-Dietz syndrome (6.5%; 13 men, 28±11years). Freedom from all causes of mortality was similar between the 2 groups (P=.40, log-rank). The cumulative incidence of reintervention was significantly lower in the Marfan syndrome group than in the Loeys-Dietz syndrome group (P=.016, Gray). The cumulative incidence of first aortic arch reoperation for aortic arch aneurysm was significantly lower in the Marfan syndrome group than in the Loeys-Dietz syndrome group (P<.001, Gray). The cumulative incidence of first aortic root reoperation for aortic root aneurysm (P=.57, Gray) and first descending aorta reoperation for descending aortic aneurysm (P=.76, Gray) was similar between the 2 groups. The cumulative incidence of aortic dissection after initial surgery was significantly lower in Marfan syndrome than in Loeys-Dietz syndrome (P=.0059, Gray). Loeys-Dietz syndrome with mutations in transforming growth factor-beta receptor 1 and 2 revealed higher rates of reoperation, and more specifically the arch reoperation was higher in those with Loeys-Dietz syndrome than those with Marfan syndrome. Aggressive arch surgery in the initial operation on the proximal aorta is recommendable in Loeys-Dietz syndrome to avoid additional aortic events. In Marfan syndrome, this is controversial in patients without dissection because of a low possibility to expand.

Analysis of FBN1 gene mutations in two pedigrees affected with Marfan syndrome

To detect mutations of fibrillin-1 (FBN1) gene in two pedigrees affected with Marfan syndrome (MFS). Peripheral blood samples were collected from MFS patients and their healthy family members for extracting genomic DNA. All of the 65 exons of the FBN1 gene were analyzed by next-generation sequencing. PolyPhen-2 and SIFT was used to predict structural and functional changes in FBN1 protein. Patients from both pedigrees presented ocular and skeletal manifestations suggestive of MFS. Two novel heterozygous mutations of the FBN1 gene, including c.1879C>T (p.R627C) in exon 16 and c.2584T>C (p.C862R) in exon 22, were identified. The same mutations were not found among unaffected members. By bioinformatic analysis, the mutations may affect the structure and function of the FBN1 protein. The c.1879C>T and c.2584T>C mutations of the FBN1 gene probably account for the disease in the two pedigrees, respectively. Identification of the c.2584T>C has enriched the spectrum of FBN1 gene mutations.

Effect of beta-blocker therapy on progression of aortic dilatation in the Marfan syndrome patients with subtypes of fibrillin 1 gene mutation

Mutation of the fibrillin 1 (FBN1) gene was common in the Marfan syndrome (MFS) leading to aortic dilatation. This study aimed to evaluate the effect of beta-blocker therapy on aortic dilatation in the MFS patients with subtypes of FBN1 gene mutation. An observational prospective study included 67 MFS patients with predicting-happloinsufficiency (PTC) or dominant-negative (DN) mutation of FBN1 gene who were followed up at 2.8 ± 1.8 years. Aortic diameters and the rate of aortic dilatation were evaluated by echocardiography. At the baseline, dimension of aortic sinus of Valsalva of PTC-MFS patients and DN-MFS patients were in the upper bound of normal-range [Z score: 2.3 ± 1.82 (95% CI: 1.69; 2.91) vs. 2.67 ± 1.58 (95% CI: 2.02; 3.32), respectively, P > 0.05]. While, dimension of ascending aorta of DN-MFS patients were in the upper bound of normal range and was higher than PTC-MFS patients [Z score: 2.8 ± 2.16 (95% CI: 2.05; 3.55) vs. 1.69 ± 2.32 (95% CI: 0.66; 2.72), respectively, P > 0.05]. With the beta-blocker therapy, the rate of aortic dilatation was delayed: at aortic sinus of Valsalva in PTC-MFS patients as 0.27 ± 0.69 mm/m 2 .year (95% CI: −0.19; 0.73) was higher than in DN-MFS patients as 0.05 ± 2.78 mm/m 2 .year (95% CI: −1.43; 1.54), P > 0.05; and at ascending aorta in PTC-MFS patients as 0.37 ± 0.93 mm/m 2 .year (95% CI: −0.35; 1.08) was lower than in DN-MFS patients as 1.65 ± 2.75 mm/m 2 .year (95% CI: −0.1; 3.4), P > 0.05. With beta-blocker therapy, the rate of aortic dilatation for FBN1-MFS patients was delayed and not significantly different between subtypes of FBN1 gene mutation.

Ocular Phenotype of Mice with Impaired Fibrillin-1 Function on Hypercholesterolemic Apolipoprotein E-Deficient Background

Aim: Transgenic mice with an elastic fiber mutation (C1039G+/-) in the fibrillin-1 gene and apolipoprotein E deficiency express vulnerable atherosclerotic plaque formation in the aorta and coronary and carotid arteries. The fibrillin-1 gene mutation alone leads to impaired fibrillin-1 function common to Marfan syndrome. The aim was to study for the first time the potential effects of atherosclerosis and vulnerable plaques in mouse eye and spontaneous retinal vessel occlusions in these mice.Methods: Apolipoprotein E-deficient and fibrillin-1 mutated mice (ApoE-/-/Fbn1C1039G+/-) were used for the study. ApoE-/- littermates served as controls. Optical coherence tomography and fluorescein angiography were used to study the retina and retinal vessels before and after the 12-week high-fat diet. Series of staining were performed to study morphology, apoptosis, glial fibrillary acidic protein activation, collagen formation, inflammatory cell infiltration and drusen formation.Results: No pathological changes were found in hypercholesterolemic ApoE-/-/Fbn1C1039G+/- mice in imaging studies nor in the histological stainings. There was neither abnormality in the retinal morphology nor any detectable biomarkers.Conclusion: ApoE-/-/Fbn1C1039G+/- mice did not present the ocular signs of Marfan syndrome.12-week high-fat diet is not sufficient to induce retinal vessel occlusion on 20 to 23 weeks old mice. This indicates that the mechanistic background of retinal vessel occlusion is more complex.

Abstract 681: Enhanced Notch3 Signaling Contributes to Pulmonary Emphysema in a Murine Model of Marfan Syndrome

Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in fibrillin-1 gene. Pulmonary emphysema is one of the most common manifestations in MFS. However, the pathogenesis and molecular mechanism of pulmonary emphysema in MFS patients is underexplored. Notch signaling is essential for lung development. It has been shown that constitutive Notch3 activation inhibited the differentiation of distal lung progenitors into alveolar cells. Upregulation of Notch3 promoted endothelial cell death. As our objective, we investigated whether Notch3 signaling plays a role in pulmonary emphysema in MFS. By using a murine model of MFS, mgR/mgR mice, we found the pulmonary emphysematous-appearing alveolar patterns in the lung of mgR/mgR mice by Verhoeff-Van Gieson connective tissue staining and H&amp;E staining. Lungs in mgR/mgR mice had decreased septation in terminal alveoli compared to wild type controls. Western blot analysis demonstrated that Notch3 levels were increased in the lung of mgR/mgR mice compared to wild type controls. This is associated with decreased expression of vascular endothelia growth factor (VEGF) and increased matrix metalloproteinase (MMP) -2 and MMP-9 production in the lung of mgR/mgR mice. To confirm that the increased Notch3 signaling in mgR/mgR mice were responsible to structure alternations in the lung of mgR/mgR mice, mice were treated with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglucine t-butyl ester (DAPT), a γ -secretase inhibitor of Notch signaling. DAPT treatment was able to restore the normal lung structure in mice with MFS. This study indicates that Notch3 crosstalk with VEGF signaling pathways in the lung contribute to pulmonary emphysema in mgR/mgR mice. The results may have the potential to lead to novel strategies to prevent and treat pulmonary manifestations in patients with MFS.

Betaglycan (TGFBR3) up-regulation correlates with increased TGF-β signaling in Marfan patient fibroblasts in vitro.

Marfan syndrome (MFS), a congenital connective tissue disorder leading to aortic aneurysm development, is caused by fibrillin-1 (FBN1) gene mutations. Transforming growth factor beta (TGF-β) might play a role in the pathogenesis. It is still a matter of discussion if and how TGF-β up-regulates the intracellular downstream pathway, although TGF-β receptor 3 (TGFBR3 or Betaglycan) is thought to be involved. We aimed to elucidate the role of TGFBR3 protein in TGF-β signaling in Marfan patients. Dermal fibroblasts of MFS patients with haploinsufficient (HI; n=9) or dominant negative (DN; n=4) FBN1 gene mutations, leading to insufficient or malfunctioning fibrillin-1, respectively, were used. Control cells (n=10) were from healthy volunteers. We quantified TGFBR3 protein expression by immunofluorescence microscopy and gene expression of FBN1, TGFB1, its receptors, and downstream transcriptional target genes by quantitative polymerase chain reaction. Betaglycan protein expression in FBN1 mutants pooled was higher than in controls (P=.004) and in DN higher than in HI (P=.015). In DN, significantly higher mRNA expression of FBN1 (P=.014), SMAD7 (P=.019), HSP47 (P=.023), and SERPINE1 (P=.008), but a lower HSPA5 expression (P=.029), was observed than in HI. A pattern of higher expression was noted for TGFB1 (P=.059), FN1 (P=.089), and COL1A1 (P=.089) in DN as compared to HI. TGFBR3 protein expression in cells, both presence in the endoplasmic reticulum and amount of vesicles per cell, correlated positively with TGFB1 mRNA expression (Rs=0.60, P=.017; Rs=0.55, P=.029; respectively). TGFBR3 gene expression did not differ between groups. We demonstrated that activation of TGF-β signaling is higher in patients with a DN than an HI FBN1 gene mutation. Also, TGFBR3 protein expression is increased in the DN group and correlates positively with TGFB1 expression in groups pooled. We suggest that TGFBR3 protein expression is involved in up-regulated TGF-β signaling in MFS patients with a DN FBN1 gene mutation.

Abstract 259: Phenotype Switch and Altered Mechanosignaling in Vascular Smooth Muscle Cells From Marfan Syndrome Mice

Background: Mechanisms whereby fibrillin-1 gene mutations promote aortic aneurysms in Marfan Syndrome (MFS) are complex. Vascular smooth muscle cells (VSMC) are crucial to aneurysm pathophysiology through (1) support of mechanical homeostasis, in which contractile VSMC connect extracellular matrix to shield synthetic VSMC against high mechanical loads and (2) key effects of synthetic VSMC on extracellular matrix organization. However, little is known about VSMC phenotypic adaptation and response to mechanical loading in MFS development. Methods: We investigated phenotypic patterns and response to cyclic stretch in VSMC cultured from aortae of wild-type (WT) mice or MFS mice bearing mgΔ lpn mutation, which develop aortic dilation/thickening from the first month of age, accelerated after 6 months. We studied VSMC from 8-9 week-old mice to focus on early disease stages. VSMC remained either static or underwent 10% cyclic stretching (1Hz, 8h). Protein expression/morphology were evaluated by Western and confocal analyses. We also performed Traction Force Microscopy to assess force distribution profile. Results: There were significant phenotypic changes in MFS-VSMC vs. WT, with loss of fusiform shape and enhanced spreading, promoting ≈7-fold increased in cell area vs. WT (p&lt;0.001, n=5) and &gt;60% decrease in calponin expression vs. WT (p&lt;0.05, n=3). Also, MFS-VSMC had a 10-fold greater expression of endoplasmic reticulum stress marker Grp78 (n=2). Cyclic stretch promoted expected increase in synthetic phenotype markers in WT-VSMC but an opposing contractile phenotype switch in MFS-VSMC, with decreased calponin and pFAK expression and increased stress fiber buildup. Cyclic stretch promoted similar increase in Grp78 expression in WT vs. MFS-VSMC. MFS-VSMC showed ca.60% lower capacity to generate adhesive force and extracellular matrix contractile momentum (p&lt;0.003, n=10), associated with lower deformation energy in vitro (9,16 vs. 1,67 pJ, p&lt;0.004, n=6). Conclusions: MFS associate with important deregulation of VSMC phenotypic adaptations, which may impact on their force development and disrupt force distribution in aorta.

A novel FBN1 gene mutation associated with earlyonset pneumothorax in Marfan syndrome

Marfan syndrome (MFS) is an inherited connective tissue disorder with a mutation in the fibrillin-1 (FBN1) gene. Fibrillin is a major building block...

Fibrillin-1 Gene Mutations in Left Ventricular Non-compaction Cardiomyopathy.

Left ventricular non-compaction cardiomyopathy (LVNC) is a unique cardiomyopathy with a current yield of about 30-40% in identifying a causative gene mutation. A retrospective review of all patients with LVNC at our institution was performed and genetic testing was reviewed. Echocardiographic and cardiac magnetic resonance imaging was reviewed to corroborate the reported phenotype. We present a series of patients with LVNC dilated phenotype associated with fibrillin-1 gene mutations. Fifty-one patients were identified as having LVNC with reduced left ventricular function and/or left ventricular dilation. We retrospectively reviewed gene testing in this cohort when available and identified 5 patients (10%) with an FBN1 gene mutation. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Derangements in fibrillin-1 may impact the compaction process resulting in LVNC. Although causation has not been proven by our report, it certainly raises interest in a possible mechanistic relationship between fibrillin-1 and LVNC given the increased prevalence of Marfan syndrome and fibrillin-1 gene mutations in this cohort.

Early Impairment of Lung Mechanics in a Murine Model of Marfan Syndrome.

Early morbidity and mortality in patients with Marfan syndrome (MFS) -a connective tissue disease caused by mutations in fibrillin-1 gene- are mainly caused by aorta aneurysm and rupture. However, the increase in the life expectancy of MFS patients recently achieved by reparatory surgery promotes clinical manifestations in other organs. Although some studies have reported respiratory alterations in MFS, our knowledge of how this connective tissue disease modifies lung mechanics is scarce. Hence, we assessed whether the stiffness of the whole lung and of its extracellular matrix (ECM) is affected in a well-characterized MFS mouse model (FBN1C1039G/+). The stiffness of the whole lung and of its ECM were measured by conventional mechanical ventilation and atomic force microscopy, respectively. We studied 5-week and 9-month old mice, whose ages are representative of early and late stages of the disease. At both ages, the lungs of MFS mice were significantly more compliant than in wild type (WT) mice. By contrast, no significant differences were found in local lung ECM stiffness. Moreover, histopathological lung evaluation showed a clear emphysematous-like pattern in MFS mice since alveolar space enlargement was significantly increased compared with WT mice. These data suggest that the mechanism explaining the increased lung compliance in MFS is not a direct consequence of reduced ECM stiffness, but an emphysema-like alteration in the 3D structural organization of the lung. Since lung alterations in MFS are almost fully manifested at an early age, it is suggested that respiratory monitoring could provide early biomarkers for diagnosis and/or follow-up of patients with the Marfan syndrome.

Abstract 14680: Evaluation of the Protective Effects of Long-term Doxycycline Treatment on Progression of Marfan-associated Aortic Aneurysm by High-resolution Ultrasound Imaging

Introduction: Aortic aneurysm is the most life-threatening complication in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in fibrillin-1 gene. We have previously reported that doxycycline, an antibiotic and a general inhibitor of matrix metalloproteinases (MMPs), could improve aortic contractility and elastin fibers structure and organization in a mouse model of MFS. However, the in vivo effects of MMPs inhibition on the progression of aneurysm and pulse wave velocity (PWV) have not been investigated. In this study, we assessed the hypothesis that a long-term treatment with a sub-antibiotic dose of doxycycline would delay the progression of aortic aneurysm and improve the PWV in the Marfan mouse. Methods: In this study, we have used a high-resolution, high-contrast ultrasound imaging technique to conduct a longitudinal study in order to measure aortic diameter (dilatation) and PWV (indication of aortic elasticity/stiffness) in the animals. Marfan (n=12) and control (n=13) mice were given a sub-antibiotic dose of doxycycline in their drinking water at a concentration of 0.24 g/L/day beginning at 6 weeks of age, whereas another group of Marfan (n=12) and control (n=12) mice were given plain drinking water for comparison. At 3, and 6 months of age, aortic diameter and PWV of the experimental animals were measured by ultrasound imaging. Results: At 3 months of age, measurement of aortic root diameter showed significant dilatation in both treated and non-treated Marfan mice as compared to control groups (p &lt; 0.01). However, at 6 months of age, the aortic root diameter in treated Marfan mice was not different from those in controls. The same observation was made for the Sinus of Valsalva region. Especially in this region, treated Marfan aorta showed significantly reduced diameter compared to non-treated Marfan groups (p &lt; 0.05). With respect to the measurement of PWV, a significant increase was observed in 3- and 6-month Marfan mice aorta vs. control (p &lt; 0.01). Interestingly, doxycycline treatment normalized the PWV in 6-month old Marfan mice compared to non-treated Marfan aorta. Conclusions: Our findings show that long-term doxycycline treatment has protective effects in terms of reduction of aortic dilatation and stiffness in Marfan mice.