Van Tran-Fadulu

Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Coronary Artery Disease, Stroke, and Moyamoya Disease, Along with Thoracic Aortic Disease

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations

Background: Mutations in the transforming growth factor β receptor type I and II genes (TGFBR1 and TGFBR2) cause Loeys–Dietz syndrome (LDS), characterised by thoracic aortic aneurysms and dissections (TAAD), aneurysms and dissections of other arteries, craniosynostosis, cleft palate/bifid uvula, hypertelorism, congenital heart defects, arterial tortuosity, and mental retardation. TGFBR2 mutations can also cause TAAD in the absence of features of LDS in large multigenerational families, yet only sporadic LDS cases or parent–child pairs with TGFBR1 mutations have been reported to date. Methods: The authors identified TGFBR1 missense mutations in multigenerational families with TAAD by DNA sequencing. Clinical features of affected individuals were assessed and compared with clinical features of previously described TGFBR2 families. Results: Statistical analyses of the clinical features of the TGFBR1 cohort (n = 30) were compared with clinical features of TGFBR2 cohort (n = 77). Significant differences were identified in clinical presentation and survival based on gender in TGFBR1 families but not in TGFBR2 families. In families with TGFBR1 mutations, men died younger than women based on Kaplan–Meier survival curves. In addition, men presented with TAAD and women often presented with dissections and aneurysms of arteries other than the ascending thoracic aorta. The data also suggest that individuals with TGFBR2 mutations are more likely to dissect at aortic diameters <5.0 cm than individuals with TGFBR1 mutations. Conclusion: This study is the first to demonstrate clinical differences between patients with TGFBR1 and TGFBR2 mutations. These differences are important for the clinical management and outcome of vascular diseases in these patients.

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

Background A 24-year-old man presented with previously diagnosed Marfans syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment.Investigations CT scans, arteriogram, genetic mutation screening of transforming growth factor β receptors 1 and 2.Diagnosis Diffuse and rapidly progressing vascular disease in a patient who met the diagnostic criteria for Marfans syndrome, but was later rediagnosed with Loeys–Dietz syndrome. Genetic testing also revealed a de novo mutation in transforming growth factor β receptor 2.Management Regular cardiovascular surveillance for aneurysms and dissections, and aggressive surgical treatment of vascular disease.

Genetic basis of thoracic aortic aneurysms and aortic dissections

Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) can occur in association with a genetic syndrome, such as Marfan syndrome (MFS), or as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified three TAAD loci at 5q13‐14 (TAAD1), 11q23 (FAA1), and 3p24‐25 (TAAD2). The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features. Recently, mutations in the TGFBR2 gene have been identified as the cause of disease linked to the TAAD2 locus, supporting the hypothesis that dysregulation of TGFβ signaling is a mechanism leading to aneurysms and dissections. The recent identification of the TGFβ pathway as a key target in the molecular pathogenesis of TAAD has opened new avenues for future genetic and therapeutic research.

FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly

Congenital contractures involving multiple joints and a crumpled appearance of the helix of the ear are more common in CCA than MFS. Ectopia lentis is a complication present in approximately half of patients with MFS. The most common cardiovascular complication in patients with MFS is pro- gressive dilatation of the ascending aorta, initially involving the sinuses of Valsalva. 6 Although patients affected with CCA were initially felt not to have aortic involvement, three children under 6 years of age with CCA have had dilated aortic roots, further blurring the clinical distinction between the two syndromes. 5 The overlap in the clinical features has a molecular basis; CCA and MFS result from mutations in two homologous genes, FBN2 and FBN1, respectively. 5 7-9

Genetic basis of thoracic aortic aneurysms and dissections: potential relevance to abdominal aortic aneurysms.

Abstract:  Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) have long been known to occur in association with a genetic syndrome such as Marfan syndrome (MFS). More recently, TAAD has also been demonstrated to occur as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified TAAD loci at 5q13‐14 (TAAD1), 11q23 (FAA1), 3p24‐25 (TAAD2), and 16p12.2‐13.13. The genetic heterogeneity of TAAD is reflected by variation in disease in terms of the age of onset, progression, penetrance, and association with additional cardiac and vascular features. The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features. Mutations in the TGFBR2 gene have been identified as the cause of disease linked to the 3p24‐25 locus, implicating dysregulation of TGF‐β signaling in TAAD. Mutations in myosin heavy chain (MYH11), a smooth muscle cell‐specific contractile protein, have been identified in familial TAAD associated with patent ductus arteriosus (PDA) linked to 16p12.2‐12.13. The identification of these novel disease pathways has led to new directions for future research addressing the pathology and treatment of TAAD.

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.

Familial thoracic aortic aneurysms and dissections identification of a novel locus for stable aneurysms with a low risk for progression to aortic dissection

Background—Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease. Methods and Results—A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene. Conclusions—Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.Background— Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease. Methods and Results— A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene. Conclusions— Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.

Familial thoracic aortic aneurysms and dissections: three families with early-onset ascending and descending aortic dissections in women.

Ascending thoracic aortic aneurysms leading to type A dissections can be inherited in an autosomal dominant manner with variable age of onset and decreased penetrance, primarily in women. Three families are described with autosomal dominant inheritance of either ascending aortic aneurysms leading to type A dissections or type B dissections, and a young age of onset of aortic dissections in both men and women. Pedigree analysis suggests that a de novo mutation is responsible for the disease in one family. The discordant age of onset of aortic disease in a monozygotic twin pair in a different family indicates that environmental or stochastic factors may influence the variable expression of disease. Genetic analysis of one family excluded linkage to known loci for TAAD (TAAD1, TAAD2, FAA1, or FBN1) and sequence analysis failed to identify mutations in TGFBR2, the gene encoding transforming growth factor beta receptor type II. Thus, a novel unidentified loci may be responsible for the phenotype in these three families.

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

AbstractMarfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10–30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron–exon boundaries of FBN1 failed to reveal a mutation. Assessment of the FBN1 message in dermal fibroblasts from the patient revealed insertion of a pseudoexon between exons 63 and 64. Sequencing of intron 63 identified a point mutation, IVS63+373, located near the middle of intron 63 of FBN1 that created a donor splice site in intron 63, leading to inclusion of a 93-bp fragment of intronic sequence in the FBN1 message. Identification of a novel pseudoexon mutation in FBN1, in association with a clinical diagnosis of MFS, confirms that cryptic mutations that are missed by the current DNA-based diagnostic methods have a causative role.