Marfan Syndrome is a heritable connective tissue disorders, mostly caused by mutations in fibrillin-1 gene. In major cases, this syndrome is inherit in autosomal dominant manner, with~25% cases are caused by de novo mutations. Affected persons showed varying patterns of organ involvement including the ocular, skeletal, cardiovascular, pulmonary, dura and skin, in which aortic dissection become the most common cause of mortality. High variability in phenotypic expressions between and within families were also observed in this syndrome.
Two cases of Marfan Syndrome in whom mutation analysis in FBN1 gene have been performed, showed two novel mutations. The first case was a 7-years old boy with a de novo missense mutation in exon 28 of FBN1 gene, c.3545G>A [p.C1182T]. The patient presented with lens dislocation, aortic dilatation, mitral valve prolapsed, pectus carinatum and dolichostenomelia. The second case was a familial Marfan Syndrome. The proband was a 32-years old man with a nonsense mutation in exon 15 of FBN1 gene, c.1924G>T [p.Gly642X]. He presented with tall stature, increased arm span and height ratio, bilateral high myopia, arachnodactily, positive thumb signs and wrist signs, joint laxity of articulatio genu, history of spontaneous pneumothorax, and finally passed away because of aortic dissection. His mother, two sisters and brother were clinically Marfan Syndrome, and will be further described.
The variability in phenotypes and disorders severity should be better considered. The presence of Marfan Syndrome affected person in a family should be followed by further investigation in other family members to conclude the inheritance manner. DNA analysis is important for diagnostic establishment and knowing the recurrence risk in the next generation. Early recognition in affected status will lead to early prevention to complications that may follow. Comprehensive management including genetic counseling thus needed for Marfan Syndrome patients and their family members.
To identify the gene underlying Fanconi anemia (FA) complementation group I we studied informative FA‐I families by a genome‐wide linkage analysis, which resulted in 4 candidate regions together encompassing 351 genes. Candidates were selected via bioinformatics and data mining on the basis of their resemblance to other FA genes/proteins acting in the FA pathway, such as: degree of evolutionary conservation, presence of nuclear localization signals and pattern of tissue‐dependent expression. We found a candidate, KIAA1794 on chromosome 15q25‐26, to be mutated in 8 affected individuals previously assigned to complementation group I. Western blots of endogenous FANCI indicated that functionally active KIAA1794 protein is lacking in FA‐I individuals. Knock‐down of KIAA1794 expression by siRNA in HeLa cells caused excessive chromosomal breakage induced by mitomycin C, a hallmark of FA cells. Furthermore, phenotypic reversion of a patient‐derived cell line was associated with a secondary genetic alteration at the KIAA1794 locus. These data add up to two conclusions. First, KIAA1794 is a FA gene. Second, this gene is identical to FANCI , since the patient cell lines found mutated in this study included the reference cell line for group I, EUFA592.
To determine whether preeclampsia is either associated with or linked to two polymorphisms in the IL1B gene (IL1B-TaqI and IL1B-511) and one polymorphism in the IL1RN gene (IL1RN-IVS2).Genotyping was performed in 150 affected sib-pair families and 104 healthy Dutch blood donors. Genotype and allele frequencies as well as allelic associations were assessed in three groups of unrelated women from these 150 families; 133 with either eclampsia, preeclampsia or the haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, 101 with preeclampsia only, and 63 with HELLP syndrome only. These frequencies were compared to those in controls. Frequencies of transmitted and nontransmitted haplotypes, inferred from the three polymorphisms, were compared. Allele sharing between affected siblings from all 150 families was assessed by means of multipoint nonparametric affected sib-pair analyses.No significant differences in genotype and allele frequencies were found between the unrelated study groups and controls. No allelic associations were apparent, nor were there differences in frequencies of transmitted and nontransmitted haplotypes within affected families. Excess allele sharing for any of the three polymorphic markers was absent in affected sib-pairs.None of the IL1B and IL1RN polymorphisms provided evidence for either association or linkage with the risk for (pre)eclampsia/HELLP syndrome, preeclampsia only or HELLP syndrome only.
Mild biventricular dysfunction is often present in patients with Marfan syndrome. Losartan has been shown to reduce aortic dilatation in patients with Marfan syndrome. This study assesses the effect of losartan on ventricular volume and function in genetically classified subgroups of asymptomatic Marfan patients without significant valvular regurgitation. In this predefined substudy of the COMPARE study, Marfan patients were classified based on the effect of their FBN1 mutation on fibrillin-1 protein, categorised as haploinsufficient or dominant negative. Patients were randomised to a daily dose of losartan 100 mg or no additional treatment. Ventricular volumes and function were measured by magnetic resonance imaging at baseline and after 3 years of follow-up. Changes in biventricular dimensions were assessed in 163 Marfan patients (48 % female; mean age 38 ± 13 years). In patients with a haploinsufficient FBN1 mutation (n = 43), losartan therapy (n = 19) increased both biventricular end diastolic volume (EDV) and stroke volume (SV) when compared with no additional losartan (n = 24): left ventricular EDV: 9 ± 26 ml vs. −8 ± 24 ml, p = 0.035 and right ventricular EDV 12 ± 23 ml vs. −18 ± 24 ml; p < 0.001 and for left ventricle SV: 6 ± 16 ml vs. −8 ± 17 ml; p = 0.009 and right ventricle SV: 8 ± 16 ml vs. −7 ± 19 ml; p = 0.009, respectively. No effect was observed in patients with a dominant negative FBN1 mutation (n = 92), or without an FBN1 mutation (n = 28). Losartan therapy in haploinsufficient Marfan patients increases biventricular end diastolic volume and stroke volume, furthermore, losartan also appears to ameliorate biventricular filling properties.
Abstract The pathophysiology of aortic aneurysms (AA) is far from being understood. One reason for this lack of understanding is basic research being constrained to fixated cells or isolated cell cultures, by which cell-to-cell and cell-to-matrix communications are missed. We present a new, in vitro method for extended preservation of aortic wall sections to study pathophysiological processes. Intraoperatively harvested, live aortic specimens were cut into 150 μm sections and cultured. Viability was quantified up to 92 days using immunofluorescence. Cell types were characterized using immunostaining. After 14 days, individual cells of enzymatically digested tissues were examined for cell type and viability. Analysis of AA sections (N = 8) showed a viability of 40% at 7 days and smooth muscle cells, leukocytes, and macrophages were observed. Protocol optimization (N = 4) showed higher stable viability at day 62 and proliferation of new cells at day 92. Digested tissues showed different cell types and a viability up to 75% at day 14. Aortic tissue viability can be preserved until at least 62 days after harvesting. Cultured tissues can be digested into viable single cells for additional techniques. Present protocol provides an appropriate ex vivo setting to discover and study pathways and mechanisms in cultured human aneurysmal aortic tissue.
