AFBN1 gene in patients with Marfan syndrome

30 exons have been analyzed using SSCP in patients with MFS or related phenotypes. We report 2 missense mutations occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains and 9 polymorphisms located both in coding and noncoding regions of FBN1 gene. Three intragenic microsatellite polymorphic markers MTS-1, MTS-2 and MTS-4 have been analyzed in patients with MFS and unrelated unaffected control individuals. We found significant differences in allele frequency distribution of MTS-2 and MTS-4 loci between MFS patients and unaffected individuals. Haplotype frequency distribution on normal and mutant chromosomes were significantly different. The most common haplotype was 2-11-8 which was predominant on normal chromosomes of affected individuals. Haplotype 2-2-8 was observed in 18% of cases on mutant chromosomes and in 4% of cases on normal chromosomes. These data demonstrate possibility and application of haplotype-segregation analysis with use of these intragenic markers for diagnostic purposes in affected families by Marfan's syndrome.     

Vascular progenitor cell senescence in patients with Marfan syndrome

Vascular progenitor cells (VPCs) present in the adventitia of the vessel wall play a critical role in the regulation of vascular repair following injury. This study aimed to assess the function of VPCs isolated from patients with Marfan syndrome (MFS). VPCs were isolated from control and MFS donors and characterized. Compared with control‐VPCs, MFS‐VPCs exhibited cellular senescence as demonstrated by increased cell size, higher SA‐β‐gal activity and elevated levels of p53 and p21. RNA sequencing showed that several cellular process‐related pathways including cell cycle and cellular senescence were significantly enriched in MFP‐VPCs. Notably, the expression level of TGF‐β1 was much higher in MFS‐VPCs than control‐VPCs. Treatment of control‐VPCs with TGF‐β1 significantly enhanced mitochondrial reactive oxidative species (ROS) and induced cellular senescence whereas inhibition of ROS reversed these effects. MFS‐VPCs displayed increased mitochondrial fusion and decreased mitochondrial fission. Treatment of control‐VPCs with TGF‐β1 increased mitochondrial fusion and reduced mitochondrial fission. Nonetheless, treatment of mitofusin2 (Mfn2)‐siRNA inhibited TGF‐β1‐induced mitochondrial fusion and cellular senescence. Furthermore, TGF‐β1‐induced mitochondrial fusion was mediated by the AMPK signalling pathway. Our study shows that TGF‐β1 induces VPC senescence in patients with MFS by mediating mitochondrial dynamics via the AMPK signalling pathway.     

Marfan disease

After reviewing the main features of the Marfan syndrome (musculoskeletal, ocular, cardiovascular, pulmonary abnormalities), its autosomal dominant inheritance with high penetrance but variable phenotype and presence of "soft" conditions preventing an easy diagnosis, the authors report their own data relevant to 73 probands: ratio of each clinical manifestation, state of 34% of familial cases and display of a paternal age effect in the sporadic cases. The pathogenic defect is unknown as like the location of the gene. The difficulties of the genetic counseling are then approached: unpredictability of the severity and of the prognosis in the unborn children of an affected patient, benefit of the echocardiography in the management of people at risk.     

Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome

Cardiovascular manifestations in patients with Marfan syndrome (MFS) are related to aortic and valvular abnormalities. However, dilatation of the left ventricle (LV) can occur, even in the absence of aortic surgery or valvular abnormalities. We evaluated genetic characteristics of patients with MFS with LV dilatation. One hundred eighty-two patients fulfilling the MFS criteria, without valvular abnormalities or previous aortic surgery, with a complete FBN1 analysis, were studied. FBN1 mutations were identified in over 81% of patients. Twenty-nine patients (16%) demonstrated LV dilatation (LV end diastolic diameter corrected for age and body surface area > 112%). FBN1-positive patients carrying a non-missense mutation more often had LV dilatation than missense mutation carriers (14/74 versus 5/75; p < 0.05). Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/33 versus 19/149; p < 0.05). It is concluded that LV dilatation in MFS patients is more often seen in patients with a non-missense mutation and in those patients without an FBN1 mutation. Therefore physicians should be aware of the possibility of LV dilatation in these patients even in the absence of valvular pathology.     

Genetic analysis and preimplantation genetic diagnosis of Chinese Marfan syndrome patients

<正>Marfan syndrome(MFS)(OMIM 154700) is a relatively common autosomal dominant genetic disease that causes skeletal, ocular,and cardiovascular defects and was first described by a French pediatrician in 1896(Bitterman and Sponseller, 2017). Its prevalence rate is 1/3000 e1/5000, and more than 25% of cases are sporadic(Chiu et al., 2014). Studies have shown that about 90% of MFS is caused by variants in the fibrillin-1 gene(FBN1, OMIM 134797).     

Snoring and aortic dimension in Marfan syndrome

Recent reports suggest that self-reported snoring, which is a feature of obstructive sleep apnea, is associated with aortic enlargement in Marfan syndrome (MFS). Objective assessment of snoring although lacking, could provide a rational for OSA screening in MFS patients. Our goal in this study was to examine the association between objective measurements of snoring with OSA and aortic size in persons with MFS. Consecutive persons with MFS who reported snoring were recruited at Johns Hopkins, completed the Epworth Sleepiness Scale (ESS) and underwent overnight polysomnography during which inspiratory sound was captured. We measured breath-by-breath peak decibel levels and snoring was defined as flow limitation with sound?≥?40 dB(A). OSA was defined as an apnea–hypopnea-index (AHI)?≥?15 or AHI: 5–15 and ESS?>?10. Participants’ aortic data were collated to ascertain aortic root diameter. Regression models were used to determine the relationship of snoring breath% with OSA and aortic root diameter. In our cohort (M|F:13|16, Age: 37.0?±?15.5 years, Aortic diameter; 38.9?±?4.8 mm), a 1-unit increase in snoring breath percentage increased the odds of having OSA by 5% in both the unadjusted (OR?=?1.05, p?=?0.040) model, and a model adjusted for age and sex (OR?=?1.05, p?=?0.048). Similarly, a 10-unit increase in snoring breath percentage was associated with a 1 mm increase in contemporaneous aortic-root-diameter in both unadjusted (β?=?0.09, p?=?0.007), and adjusted (β?=?0.08, p?=?0.023) models. Objective snoring assessment could provide a means for identifying persons with MFS who need sleep studies, who may also be at risk for more severe aortic disease.

     

Fatal Marfan syndrome in the neonatal period

Case-report of neonatal Marfan Syndrome with at birth the following observations: arachnodactyly, excessive length of arm, cardiac anomalies with hemodynamic troubles leading to death within 4 days. Anatomical data of the postmortem examination and histologic anomalies of the aorta confirm the diagnosis. No case of Marfan syndrome are to be found among forebearers. These characteristics underline the rarity, the gravity of the pronostic and the often sporadic appearance of the Marfan syndrome when revelated in the neonatal period.     

The distal aorta in the Marfan syndrome

Prolonged survival of patients with Marfan syndrome after aortic root replacement has led to an increased number of patients with aortic complications beyond the root. Elective replacement of the aortic root removes the most important predilection site for aneurysms, but the distal aorta remains at risk. Predictors for aortic growth and adverse events in the distal aorta include aortic diameter, aortic distensiblity, previous aortic root replacement, hypertension and aortic regurgitation. After aortic dissection, the initial false lumen diameter is an independent predictor for late aneurysm formation. Although there are a few reports of short-term success after endovascular stent grafting of the descending thoracic aorta, stent grafting in patients with Marfan syndrome is not recommended unless intervention is clearly indicated and the risk of conventional open surgical repair is deemed prohibitive. Optimal long-term outcome demands lifelong radiographic follow-up and medical treatment with β-blocker therapy. After aortic dissection rigorous antihypertensive medication is of utmost importance. Losartan, an angiotensin II type I receptor antagonist, might offer the first potential for primary prevention of clinical manifestations in Marfan syndrome, but the results of clinical trials have to be awaited. (Neth Heart J 2008;16:382-6.)     

Relationship between finger length and ridge count in patients with Marfan syndrome]

Palmar dermatoglyphs were studied in 38 patients with lens dislocation. The patients were distributed into three groups: Marfan syndrome, mild Marfan syndrome, isolated lens dislocation. Marked arachnodacytyly was observed in the first group. In these patients increase in finger length was positively correlated with the ridge count. Moderate increase in finger length and ridge count was observed in the second group. The relative finger length was lower in patients with isolated lens dislocation than in unaffected persons, though the ridge count did not differ from the control. The relations noted between the finger length and ridge count in Marfan syndrome are in agreement with the suggestion that these two parameters are determined by common cause, namely, the morphogenetic gradient in digital primordia.     

Abnormal fibrillin assembly by dermal fibroblasts from two patients with Marfan syndrome

The microfibrillar glycoprotein fibrillin is linked to the Marfan syndrome, an autosomal dominant connective tissue disorder. In this study, fibrillin synthesis, deposition and assembly has been investigated in Marfan dermal fibroblast lines from two unrelated patients for whom distinct mutations in the fibrillin gene FBN1 have been identified. In patient NB, a point mutation has occurred which causes an amino acid substitution and the other patient (GK) has a deletion in one allele. The two cell lines were broadly comparable with respect to de novo fibrillin synthesis and its distribution between medium and cell layer compartments. Electrophoresis of fibrillin immunoprecipitates confirmed the presence of fibrillin in medium and cell layers. GK cells secreted an additional higher relative molecular mass fibrillin-immunoreactive component. The time-course of fibrillin secretion was similar for the two lines, but differences in fibrillin aggregation were apparent. Rotary shadowing electron microscopy of extracted cell layers demonstrated the presence of abundant and extensive microfibrils in NB cell layers. These were abnormal in their gross morphology in comparison to microfibrils isolated from control cultures. No periodic microfibrillar structures were isolated from GK cell layers. These studies underline the need to classify fibrillin defects in terms of biochemical and ultrastructural criteria. Examination of the effects of individual mutations on microfibril organization will be particularly informative in elucidating the relationship between microfibril dysfunction and the complex clinical manifestations of Marfan patients.     

Application of next-generation sequencing to screen for pathogenic mutations in 123 unrelated Chinese patients with Marfan syndrome or a related disease

Marfan syndrome(MFS) is a systemic connective tissue disease principally affecting the ocular, skeletal and cardiovascular systems. This autosomal dominant disorder carries a prevalence of 1:3,000 to 1:5,000. This study aims to define the mutational spectrum of MFS related genes in Chinese patients and to establish genotype-phenotype correlations in MFS. Panel-based targeted next-generation sequencing was used to analyze the FBN1, TGFBR1 and TGFBR2 genes in 123 unrelated Chinese individuals with MFS or a related disease. Genotype-phenotype correlation analyses were performed in mutation-positive patients. The results showed that 97 cases/families(78.9%; 97/123) harbor at least one(likely) pathogenic mutation, most of which were in FBN1; four patients had TGFBR1/2 mutations; and one patient harbored a SMAD3 mutation. Three patients had two FBN1 mutations, and all patients showed classical MFS phenotypes. Patients with a dominant negative-FBN1 mutation had a higher prevalence of ectopia lentis(EL). Patients carrying a haploinsufficiency-FBN1 mutation tended to have aortic dissection without EL. This study extends the spectrum of genetic backgrounds of MFS and enriches our knowledge of genotype-phenotype correlations.     

Towards an RNA-based therapy for Marfan syndrome

Dominant genetic disorders, particularly those due to a mutant protein exerting a dominant-negative effect, present a unique challenge for gene therapy. Unlike recessive disorders, where expression of a wild-type gene is likely to be sufficient to ameliorate disease pathology, therapies for dominant disorders are likely to require suppression of the disease allele while maintaining expression of its wild-type counterpart. Marfan syndrome, the most common genetic disorder of the connective tissue, is caused by mutant fibrillin 1 protein exerting a dominant-negative effect. Antisense hammerhead ribozymes—small catalytic RNAs capable of targeting and cleaving specific RNA molecules—appear to offer promise in the development of a therapy for Marfan syndrome.     

Analysis of the fibrillin-1 gene (FBN1) in patients with Marfan syndrome

Thirty exons of the fibrillin-1 gene (FBN1) were screened in patients with Marfan syndrome (MFS), and eleven point mutations, insertions, and deletions were detected. These included two missense mutations resulting in conformational changes of the calcium-binding EGF-like domains of FBN1 and nine polymorphisms located in both coding and noncoding regions of FBN1. Three intragenic polymorphic microsatellite loci—MTS-1, MTS-2, and MTS-4—were analyzed in MFS patients and unrelated healthy controls, and significant differences between these two groups were found for the MTS-2 and MTS-4 allele frequency distributions. Haplotype frequency distributions on wild-type and mutant chromosomes of MFS patients were also significantly different. The predominant haplotype was 2-11-8 on wild-type chromosomes, and 2-2-8 on mutant chromosomes. These data are a prerequisite to working out DNA diagnosis of MFS.     

Cell-free synthesis of hyaluronic acid in Marfan syndrome.

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.     

Fluid dynamics of aortic root dilation in Marfan syndrome

Aortic root dilation and propensity to dissection are typical manifestations of the Marfan Syndrome (MS), a genetic defect leading to the degeneration of the elastic fibres. Dilation affects the structure of the flow and, in turn, altered flow may play a role in vessel dilation, generation of aneurysms, and dissection. The aim of the present work is the investigation in-vitro of the fluid dynamic modifications occurring as a consequence of the morphological changes typically induced in the aortic root by MS. A mock-loop reproducing the left ventricle outflow tract and the aortic root was used to measure time resolved velocity maps on a longitudinal symmetry plane of the aortic root. Two dilated model aortas, designed to resemble morphological characteristics typically observed in MS patients, have been compared to a reference, healthy geometry. The aortic model was designed to quantitatively reproduce the change of aortic distensibility caused by MS. Results demonstrate that vorticity released from the valve leaflets, and possibly accumulating in the root, plays a fundamental role in redirecting the systolic jet issued from the aortic valve. The altered systolic flow also determines a different residual flow during the diastole.     

Development aggravates the severity of skeletal muscle catabolism induced by endotoxemia in neonatal pigs

Accretion rates of muscle protein are elevated in normal neonates, but this anabolic drive decreases with maturation. As this change occurs, it is not known whether development also influences muscle protein catabolism induced by sepsis. We hypothesize that protein degradation in skeletal muscle induced by endotoxemia becomes more severe as the neonate develops. Fasted 7- and 26-day-old pigs were infused for 8 h with LPS (0 and 10 μg·kg(-1)·h(-1)), while plasma amino acids (AA), 3-methylhistidine (3-MH), and α-actin concentrations and muscle protein degradation signal activation were determined (n = 5-7/group/age). Plasma full-length α-actin was greater in 7- than 26-day-old pigs, suggesting a higher baseline protein turnover in neonatal pigs. LPS increased plasma total AA, 3-MH, and full-length and cleaved α-actin in 26- than in 7-day-old pigs. In muscle of both age groups, LPS increased AMPK and NF-κB phosphorylation, the abundances of activated caspase 3 and E-3 ligases MuRF1 and atrogin1, as well as the abundance of cleaved α-actin, suggesting activation of muscle proteolysis by endotoxin in muscle. LPS decreased Forkhead box 01 (Fox01) and Fox04 phosphorylation and increased procaspase 3 abundance in muscle of 26-day-old pigs despite the lack of effect of LPS on PKB phosphorylation. The results suggest that skeletal muscle in healthy neonatal pigs maintains high baseline degradation signal activation that cannot be enhanced by endotoxin, but as maturation advances, the effect of LPS on muscle protein catabolism manifests its severity.