Familial Thoracic Aortic Aneurysms And Dissections Research Articles

Multifocal Intracranial Stenosis and Thunderclap Headache in a Patient with Heterozygous MFAP5 Mutation for Familial Thoracic Aortic Aneurysm and Dissection

Recent investigations on familial thoracic aortic aneurysm and dissection (TAAD) identified several genetic variants. Meanwhile, intracranial vasculopathy in familial TAAD has been scarcely reported. We report a case of a young man with Marfanoid habitus and familial TAAD carrying MFAP5, c.472C>T variant. He presented with recurrent thunderclap headache and multifocal intracranial vasculopathy, which is predominantly suggestive of reversible cerebral vasoconstriction syndrome. While the role of MFAP5 in vasculopathy requires clarification, we propose its haploinsufficiency may contribute to both TAAD and intracranial stenosis, highlighting a potential risk of cerebrovascular disease in familial TAAD.

Multi-Omics of Familial Thoracic Aortic Aneurysm and Dissection: Calcium Transport Impairment Predisposes Aortas to Dissection.

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca2+ concentration-multiple calcium channel expression and ADP-ribose synthesis-were attenuated in Myh11ΔK/ΔK aortas. We suggest that the impairment of the Ca2+ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection.

An Myh11 single lysine deletion causes aortic dissection by reducing aortic structural integrity and contractility

Pathogenic variants in myosin heavy chain (Myh11) cause familial thoracic aortic aneurysms and dissections (FTAAD). However, the underlying pathological mechanisms remain unclear because of a lack of animal models. In this study, we established a mouse model with Myh11 K1256del, the pathogenic variant we found previously in two FTAAD families. The Myh11∆K/∆K aorta showed increased wall thickness and ultrastructural abnormalities, including weakened cell adhesion. Notably, the Myh11∆K/+ mice developed aortic dissections and intramural haematomas when stimulated with angiotensin II. Mechanistically, integrin subunit alpha2 (Itga2) was downregulated in the Myh11∆K/∆K aortas, and the smooth muscle cell lineage cells that differentiated from Myh11∆K/∆K induced pluripotent stem cells. The contractility of the Myh11∆K/∆K aortas in response to phenylephrine was also reduced. These results imply that the suboptimal cell adhesion indicated by Itga2 downregulation causes a defect in the contraction of the aorta. Consequently, the defective contraction may increase the haemodynamic stress underlying the aortic dissections.

Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2019 Update and Clinical Implications

Thoracic aortic aneurysm is a typically silent disease characterized by a lethal natural history. Since the discovery of the familial nature of thoracic aortic aneurysm and dissection (TAAD) almost 2 decades ago, our understanding of the genetics of this disorder has undergone a transformative amplification. To date, at least 37 TAAD-causing genes have been identified and an estimated 30% of the patients with familial nonsyndromic TAAD harbor a pathogenic mutation in one of these genes. In this review, we present our yearly update summarizing the genes associated with TAAD and the ensuing clinical implications for surgical intervention. Molecular genetics will continue to bolster this burgeoning catalog of culprit genes, enabling the provision of personalized aortic care.

Human aortic aneurysm genomic dictionary: is it possible?

Thoracic aortic aneurysm (TAA), a typically silent but frequently lethal disease, is strongly influenced by underlying genetics. Approximately 30 genes have been associated with syndromic and non-syndromic familial thoracic aortic aneurysm and dissection (TAAD) to date. An estimated 30% of patients with non-syndromic familial TAAD, which is typically inherited in an autosomal dominant manner, have a mutation in one of these genes. The underlying genetic mutation helps predict patients' clinical presentation, risk of aortic dissection at small aortic sizes (< 5.0cm), and risk of other cardiovascular disease. As a result, a TAAD genomic dictionary based on these genes is necessary to provide optimal patient care, but is not on its own sufficient as this disease is typically inherited with reduced penetrance and has widely variable expressivity. Next-generation sequencing has been and will continue to be critical for identifying novel genes and variants associated with TAAD as well as genotype-phenotype correlations that will allow for management to be targeted to not only the underlying gene harboring the pathogenic variant but also the specific mutation identified. The aortic dictionary, to which a clinician can turn to obtain information on clinical consequences of a specific genetic variants, is not only possible, but has been substantially written already. As additional entries to the dictionary are made, truly personalized, genetically based, aneurysm care can be delivered.

Alternative splicing of MAGP2 generates a non‐glycosylated variant still capable of localizing to extracellular microfibrils

Alterations in microfibril‐associated glycoprotein 2 (MAGP2) have been linked to familial thoracic aortic aneurysm and dissection (FTAAD) and ovarian cancer, suggesting that this protein has an interesting role in normal adult homeostasis. Here, a previously unstudied splice variant of MAGP2 noted in a public database search was characterized. Two mRNA isoforms of MAGP2 were expressed in a human ovarian cancer cell line (CAOV3) by RT‐PCR; sequencing revealed that the longer mRNA was the canonical MAGP2 mRNA that encodes a 173‐amino acid protein (MAGP2‐a), and the shorter variant encoded a 163‐amino acid protein (MAGP2‐b), due to the removal of the seventh exon. Interestingly, the seventh exon contains the conserved asparagine residue (Asp79) thought to be the major site of N‐glycosylation on MAGP2. As expected, MAGP2‐b was both poorly glycosylated and poorly secreted when overexpressed in either 293T cells or a mouse ovarian epithelial cell line, T3, as measured by immunoblotting analysis; this result is consistent with the canonical role of glycosylation modifications of secreted proteins. Since a small fraction of MAGP2‐b protein was secreted, studies were performed to understand what functions MAGP2‐b was capable of, if secreted. To determine if MAGP2‐b could bind and localize to extracellular microfibrils as previously reported for MAGP2‐a, immunofluorescence studies were conducted in T3 cells that generate a striking fibrillin‐2‐rich microfibril matrix in cell culture. Surprisingly, MAGP2‐b could easily be found localized to microfibrils, at levels similar to the MAGP2‐a isoform that is glycosylated and more effectively secreted than MAGP2‐b. To more clearly delineate the functional consequences of glycosylation versus the loss of ten amino acids via alternative splicing, an Asp79Gln (N79Q) mutation was generated in MAGP2‐a to block N‐glycosylation. The N79Q MAGP2‐a protein does not appear to be glycosylated, since the molecular weight of the protein on immunoblots is unchanged by PNGase F treatment. The secretion and microfibril binding properties of the N79Q mutant are very similar to MAGP2‐b; they are both poorly secreted but still able to bind to microfibrils at levels equal to or greater than the fully glycosylated MAGP2‐a variant. Together, these data indicate that glycosylation of MAGP2 is not required for microfibril binding; it also suggests that the non‐glycosylated MAGP2‐b may preferentially bind to microfibrils after cellular export. Why might it be useful for such a MAGP2 variant to exist? In this regard, there is some correlative evidence to suggest that MAGP2 binding of active TGF‐β may negatively regulate TGF‐β activity, based on studies on MAGP2 biochemistry and FTAAD‐associated mutations of MAGP2. Although speculative, the existence of a mechanism that tethers MAGP2 to microfibrils at the expense of free, soluble MAGP2 may make MAGP2 a more effective microfibril tether for active TGF‐β.Support or Funding InformationCSUF Department of Biological Science. Student research assistants funded by CIRM Bridges to Stem Cell Research (Andrew Yale, Cherie Petersen) and HHMI Undergraduate Research Program (Ryan Daniels).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

DIFFERENTIATING BETWEEN FAMILIAL AND SPORADIC THORACIC AORTIC ANEURYSMS AND DISSECTIONS

Background: Patients with familial thoracic aortic aneurysms and dissections (F-TAAD) have an elevated risk of dissection or rupture, but are more difficult to identify as being hereditary than syndromic patients. We aimed to identify features differentiating patients with F-TAAD from those with

A novel variant in MYLK causes thoracic aortic dissections: genotypic and phenotypic description.

BackgroundMutations in MYLK cause non-syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characterize the aortic disease and the presence of other vascular abnormalities in FTAAD caused by a deletion in MYLK and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.MethodsWe studied FTAAD in a 5-generation family that included 19 living members. Exome sequencing was performed to identify the underlying gene defect. Aortic elastic properties measured by TTE, MRI and pulse wave velocity were then compared between mutation carriers and non-carriers.ResultsExome sequencing led to the identification of a 2-bp deletion in MYLK (c3272_3273del, p.Ser1091*) that led to a premature stop codon and nonsense-mediated decay. Eleven people were mutation carriers and eight people were non-carriers. Five aortic ruptures or dissections occurred in this family, with two survivors. There were no differences in aortic diameter or stiffness between carriers and non-carriers of the mutation.ConclusionsIndividuals carrying this deletion in MYLK have a high risk of presenting with an acute aortic dissection or rupture. Aortic events occur over a wide range of ages and are not always preceded by obvious aortic dilatation. Aortic elastic properties do not differ between carriers and non-carriers of this mutation, rendering it uncertain whether and when carriers should undergo elective prophylactic surgery.

Identification and Surgical Repair of Familial Thoracic Aortic Aneurysm and Dissection Caused by TGFBR1 Mutation

This study aimed at exploring the causative gene and summarizing the clinical characteristics in a Chinese thoracic aortic aneurysm and dissection (TAAD) family. Family members were examined for features of syndromic genetic diseases by clinician and geneticist. Genomic DNA was extracted from 2 distantly related members with definite TAAD for exome sequencing. A pathogenic mutation (rs111426349, c.1459C >T) of transforming growth factor β receptor 1 (TGFBR1) was confirmed, which result in the amino acid substitution p.R487W. Fourteen TGFBR1 mutation carriers were detected among 39 tested members in this family. The average age at diagnosis of aortic root dilatation or aneurysm was 23.2 ± 12.6 years (range 3-37 years). Early onset of aortic root dilatation was significant in this family without reported phenotypes. The David procedure was performed prophylactically in 3 carriers of this family. Familial TAAD caused by TGFBR1 mutation (c.1459C >T) was confirmed in a large Chinese Han ethnic family using exome sequencing. Aggressively prophylactic David procedure may be not necessary at a smaller aortic size in familial TAAD patients with TGFBR1 mutation and further observation is warranted.

Single Amino Acid Deletion in MYH11 Segregating in a Family with TAAD

Single Amino Acid Deletion in MYH11 Segregating in a Family with TAAD Background Seven genes have been identified as causative in the development of thoracic aortic aneurysms (TAA) and dissections (TAAD). In this study, we identify a single amino acid deletion in MYH11 gene which segregates with disease in a large TAAD family. Methods We identified five members in one family who had a history of TAA or TAAD. Blood samples from fifteen members of this family were collected for whole exome sequencing (WES) analysis and mutation analysis. Thirteen members of this family underwent echocardiography and cardiac pulse wave velocity (PWV) measurement. Results WES analysis revealed a mutation of myosin heavy chain 11 (MYH11) – a three base-pair deletion of leucine at position 1264 - that segregated with the disease phenotype in this family. PWV was not correlated with mutation or disease status. Conclusion Deletion of leucine at position 1264 in MYH11 appears to play an important role in the development of familial TAA and TAAD.

Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2

The pathophysiology of thoracic aortic aneurysms and dissections(TAAD) is complex and multifactorial. Classic cardiovascular risk fac-tors play an important role in a majority of patients but genetic fac-tors should always be considered, especially in younger subjectsand/or in the presence of a family history of TAAD. To date, severalgenes have been identified in both syndromic and non-syndromicforms of TAAD, including FBN1 (Marfan syndrome, MFS), TGFBR1/2(Loeys-Dietz syndrome, LDS), SMAD3 (Aneurysm-Osteoarthritissyndrome, AOS), ACTA2 (TAA6, TAAD with livedo reticularis and irisflocculi), MYH11 (TAAD with patent ductus arteriosus), and MYLK(TAAD7) [1–7]. Although clinical features show significant overlap,these entities differ in the extent of vascular involvement and clinicalcourse. As a consequence, molecular studies have become pivotal inthe evaluation, counselling and management of the patient withTAAD. Moreover, the identification of new genes has led to new in-sights into the pathogenesis of aneurysm formation.The crucial role of the transforming-growth-factor β (TGFβ)pathwayin TAAD became evident from both studies on mouse models and theanalysis of components of the TGF β pathway on human aortic tissue ofpatients with these disorders [3,8–11].WepreviouslysequencedTGFB2as a candidate gene for TAAD, but did not identify mutations in 40 pa-tients with isolated aortic root dilatation (Callewaert et al., unpublishedresults). The recent findings by Boileau and colleagues identifying thefirst TGFB2 mutations leading to familial TAAD in association with cere-brovascular disease and mild systemic features reminiscent of Marfansyndrome [16] have urged us toscreenthis geneinapatientgroupasso-ciatingTAADwithawiderphenotypicspectrumincludingcerebrovascu-lar disease, arterial tortuosity, ma rfanoid skeletal features and mitralvalve disease. In total, we assessed the prevalence of TGFB2 mutationsin 146 patients.Using direct sequencing after ampli fication of all exons and flankingintronic sequences of the TGFB2 gene on genomic DNA level (TGFB2NM_001135599.2), we identified 4 heterozygous TGFB2 mutations in 6patients: c.475C>T (p.Arg159X), c.979C>T (p.Arg327Trp), c.980G>A(p.Arg327Gln), and c.1125delT (p.Gly376GlufsX17). We found 2 prema-turetruncatingmutationsandalsoidenti fiedthe firstmissensemutationsin TGFB2. All mutations are expected to result in a loss-of-function. Anoverview of the clinical findings is provided in Table 1 and of the muta-tions in Fig. 1 and Supplemental Table 1.Aortic pathology was universally present at middle-age (z-scores >2.5),butaorticdissectionwasthepresentingfeatureinonlyonepatientat the age of 69 years (patient 1). Importantly, type A dissection oc-curredinanotherpatient5 yearsafterinitialevaluationandatanaorticroot diameter below the classical surgical threshold of 50 mm (patient6). Significant mitral valve prolapse occurred in 4 patients and was thereasonforinitialevaluationintwopatients(2and6)thatbothrequiredsurgical replacement. Patient 4 came to medical attention following aroutine echocardiography showing aortic root dilatation and mitralvalve prolapse without other manifestations. One patient (patient 3)was evaluated following transient ischemic attacks at the age of18 yearsoldwithunderlyingtortuosityofthevertebralarteries.Finally,patient 5 was evaluated for skeletal marfanoid features.Fouroutof6 patientshadskeletaland/orskinmanifestationsrem-iniscent of TGFβ-signalopathies which can be mild; 3 patients hadmyopia of which one had cataract. Importantly, family history wasnegative in 3 patients.Our data indicate a prevalence of TGFB2 mutations in the exam-ined TAAD cohort of around 4% (6/146), which is significantly lowerthan the previously reported prevalence of ACTA2 mutations (16%)[11]. The TGFβ superfamily includes 3 isoforms of TGFβ, TGFβ1, −2,and −3 (for a review [12]). The TGFβs are pleiotropic cytokines, con-trolling a broadrange of biologicalprocesses. The3 TGFβ isoforms ex-hibit both overlapping and divergent properties as illustrated by thephenotype of the respective knockout mouse models. Tgfb2 knockoutmice die perinatally and display a wide range of developmental de-fects, including cardiovascular, pulmonary, skeletal, ocular, inner ear

Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections.

Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10−5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.

Copy Number Variation Contributes to Sporadic and Familial Thoracic Aortic Aneurysms and Dissections

1. Prakash SK, LeMaire SA, Guo DC, Russell L, Regalado ES, Golabbakhsh H, Johnson RJ, Safi HJ, Estrera AL, Coselli JS, Bray MS, Leal SM, Milewicz DM, Belmont JW. Rare copy number variants disrupt genes regulating vascular smooth muscle cell adhesion and contractility in sporadic thoracic aortic aneurysms and dissections. Am J Hum Genet. 2010;87(6):743–756. PMID: 21092924. ### Study Hypothesis The genetic origins of thoracic aortic aneurysms and dissections (TAAD) are relatively unknown. Twenty percent of cases have similarly affected family members, but genes previously identified for familial TAAD have exhibited reduced penetrance and variable severity. The genes previously implicated in familial TAAD ( ACTA2 , MYH11 , TGFBR1 , TGFBR2 ) have all been found to be involved in vascular smooth muscle cell (SMC) contractility and adhesion. Copy number variations (CNVs) have been found previously to increase risk of several multifactorial diseases, such as autism and schizophrenia. The authors hypothesized that rare structural variants could contribute to risk of TAAD, and that such …

Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2)

ObjectiveTo evaluate the prevalence and phenotype of smooth muscle alpha-actin (ACTA2) mutations in non-syndromic thoracic aortic aneurysms and dissections (TAAD).DesignObservational study of ACTA2 mutations in TAAD.SettingCentre for Inherited Cardiovascular Diseases.PatientsA...

Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity

Mutations in the gene encoding transforming growth factor-beta receptor type II (TGFBR2) have been described in patients with Loeys-Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). Here, we present a comprehensive and quantitative analysis of TGFBR2 expression, turnover and TGF-β-induced Smad and ERK signaling activity for nine mutations identified in patients with LDS, MFS2 and TAAD. The mutations had different effects on protein stability, internalization and signaling. A dominant-negative effect was demonstrated for mutations associated with LDS and MFS2. No mutation showed evidence of an immediate cell-autonomous paradoxical activation of TGF-β signaling. There were no cell biological differences between mutations described in patients with LDS and MFS2. By contrast, R460C, which has been found in familial TAAD but not in MFS2 or LDS, showed a less-severe dominant-negative effect and retained residual Smad phosphorylation and transcriptional activity. TAAD is characterized primarily by thoracic aortic aneurysms or dissections. By contrast, MFS2 is characterized by numerous skeletal abnormalities, and patients with LDS additionally can display craniofacial and other abnormalities. Therefore, our findings suggest that the balance between defects in Smad and ERK signaling might be an important determinant of phenotypic severity in disorders related to mutations in TGFBR2.

Rare Copy Number Variants Disrupt Genes Regulating Vascular Smooth Muscle Cell Adhesion and Contractility in Sporadic Thoracic Aortic Aneurysms and Dissections

Thoracic aortic aneurysms and dissections (TAAD) cause significant morbidity and mortality, but the genetic origins of TAAD remain largely unknown. In a genome-wide analysis of 418 sporadic TAAD cases, we identified 47 copy number variant (CNV) regions that were enriched in or unique to TAAD patients compared to population controls. Gene ontology, expression profiling, and network analysis showed that genes within TAAD CNVs regulate smooth muscle cell adhesion or contractility and interact with the smooth muscle-specific isoforms of α-actin and β-myosin, which are known to cause familial TAAD when altered. Enrichment of these gene functions in rare CNVs was replicated in independent cohorts with sporadic TAAD (STAAD, n = 387) and inherited TAAD (FTAAD, n = 88). The overall prevalence of rare CNVs (23%) was significantly increased in FTAAD compared with STAAD patients (Fisher's exact test, p = 0.03). Our findings suggest that rare CNVs disrupting smooth muscle adhesion or contraction contribute to both sporadic and familial disease.

Report of the National Heart, Lung, and Blood Institute and National Marfan Foundation Working Group on Research in Marfan Syndrome and Related Disorders

Aortic aneurysm and dissection is a common phenotype, accounting for 1% to 2% of all deaths in industrialized countries and ≈50 000 deaths annually in the United States.1 In contrast to abdominal aortic aneurysm, thoracic aortic aneurysm, particularly in the ascending segment, commonly occurs in young individuals in the absence of identifiable environmental risk factors. Marfan syndrome (MFS) is the most common syndromic presentation of ascending aortic aneurysm, but other syndromes such as vascular Ehlers-Danlos syndrome and Loeys-Dietz syndrome (LDS) also have ascending aortic aneurysms and the associated cardiovascular risk of aortic dissection and rupture. Familial segregation of the risk for ascending aortic aneurysm can also occur in the absence of associated systemic findings of a connective tissue abnormality in patients with familial thoracic aortic aneurysm and dissection (FTAAD) or bicuspid aortic valve with ascending aortic aneurysm (BAV/AscAA). The knowledge gained through basic and clinical research focused on MFS has improved and will continue to improve the care of patients with these related conditions. Recent paradigm-shifting discoveries about the molecular pathogenesis of MFS have highlighted the need for a focused research agenda to solidify the gains of the past 30 years and set the stage for future advances in MFS and related conditions. In April 2007, the National Heart, Lung, and Blood Institute (NHLBI) and the National Marfan Foundation convened a working group on research in MFS and related disorders to foster a multidisciplinary discussion. The working group, which included experts in cardiovascular disease, developmental biology, genetics and genomics, and proteomics, was charged with identifying opportunities and barriers to advancing the research agenda and developing recommendations to the NHLBI in the context of the Institute’s strategic plan (http://apps.nhlbi.nih.gov/strategicplan/). MFS is a systemic disorder of connective tissue caused by heterozygous mutations in the gene ( FBN1 ) that encodes the extracellular matrix …

Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.

Abstract 2681: Mutations in Smooth Muscle-Specific Contractile Proteins Cause Familial Thoracic Aortic Aneurysms and Dissections and Lead to Increased IGF-1 Expression

Aortic aneurysms and dissections are the most common disorders affecting the aorta, and are a major cause of morbidity and mortality in the United States. Familial thoracic aortic aneurysms and dissections (FTAAD) are inherited in an autosomal dominant manner with variable expression and decreased penetrance. The disorder is genetically heterogeneous with four loci and three genes identified. Mutations in either TGFBR2 , encoding the transforming growth factor β (TGF-β) type II receptor, or MYH11 , encoding the smooth muscle cell (SMC)-specific β-myosin heavy chain, were previously found to cause FTAAD. Recently, positional cloning identified smooth muscle α-actin ( ACTA2 ) mutations as a novel cause in 10% of FTAAD. Mutations in ACTC and MYH7 cause hypertrophic cardiomyopathy (HCM), characterized by myocyte disarray and upregulation of mitotic and trophic factors. Histologic examination of aortic tissue from patients with ACTA2 (n = 6) and MYH11 (n = 2) mutations revealed SMC disarray in the aortic media similar to that seen in HCM. Furthermore, we hypothesized that mutations in ACTA2 and MYH11 cause a similar increase of mitotic and trophic factors in SMCs. The expression of two factors known to be increased in HCM, TGF-β1 and insulin-like growth factor 1 (IGF-1), were analyzed in patients’ aortic SMCs and dermal myofibroblasts. No changes in TGF-β1 were found; however, both mRNA, as measured by Q-PCR (p&lt;0.05), and protein levels, as assessed by immunostaining, of IGF-1 were markedly increased in MYH11 and two ACTA2 mutant SMCs and aortic tissue compared with control SMCs and tissue. Differentiation of dermal fibroblasts into myofibroblasts was accomplished using TGF-β1 treatment; myofibroblast differentiation was confirmed by assessing α-actin mRNA and protein levels in untreated vs. TGF-β1-treated fibroblasts. Upon differentiation, patients’ myofibroblasts (n = 3) demonstrated increased IGF-1 expression compared with controls (p&lt;0.05), similar to the increased IGF-1 expression by SMCs. In conclusion, IGF-1 secretion is increased in response to defects in SMC contractile proteins in SMCs and myofibroblasts. Future studies will clarify the role of IGF-1 in FTAAD and identify the pathways leading to increased IGF-1 expression.