TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

Abstract

A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease, followed by whole exome sequencing of affected relatives, identified causative mutations in TGFB2. These mutations, a frameshift mutation in exon 6 and a nonsense mutation in exon 4, segregated with disease with a combined LOD score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified two additional TGFB2 mutations. TGFB2 encodes the transforming growth factor beta-2 (TGF-β2) and the mutations are predicted to cause haploinsufficiency for TGFB2, but aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency of TGFB2 predisposes to thoracic aortic disease, suggesting the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

A 1-bp duplication in TGFB2 in three family members with a syndromic form of thoracic aortic aneurysm

“…In line with this, normal levels of mutant TGFB2 transcripts but reduced proprotein levels have been detected in smooth muscle cells and fibroblasts from patients with the frameshift mutation c.1106_1110delACAAT (p.Tyr369Cysfs*26) in TGFB2 (RefSeq NM_001135599.2, NP_001129071.1); this alteration was originally described as c.1021_1025delTACAA (p.Tyr341Cysfs*25) (TGFB2 RefSeq NM_003238.3, NP_003229.1). 13 Considering these consequences, our finding of the c.1165dupA mutation in a threegeneration family supports the idea that functional haploinsufficiency of TGF-b2 causes a cellular compensatory overshoot leading to augmented TGF-b signalling in MFS-LDS spectrum disorders. 17 On the other hand, we cannot exclude that, due to structural changes, the p.Tyr341Cysfs*25 mutation enhances TGF-b receptor affinity resulting in increased TGF-b signaling.…”

“…21 Up to date, 12 independent TGFB2 mutations in 34 individuals have been reported (Table 1). 13,14 In our study, the three subjects with the c.1165dupA mutation in TGFB2 share clinical features with other autosomal dominant aortic aneurysm syndromes. Among these features, aortic aneurysm, scoliosis, pectus deformity, joint hyperflexibility, pes planus, retrognathia, high arched palate and hernia occur both in MFS and LDS.…”

“…Similarly, Lindsay et al 14 did not observe ectopia lentis in any of the 15 individuals with TGFB2 mutations (Table 1), 14 and Boileau et al 13 described only a single patient among 13 individuals with TGFB2 mutations who exhibited some sort of 'minor ectopia lentis' , which they stated was 'not recognized as lens dislocation in the USA.' 13 Thus, the clinical presentation of the three affected male relatives described here strengthens the notion that mutations in TGFB2 are associated with an LDS rather than a MFS phenotype. 14 We identified only one mutation carrier in a cohort of 88 individuals (1.1%) with a phenotype within the MFS-LDS spectrum.…”

“…Similarly, TGFB2 mutations were identified in 4 out of 409 probands (1%) including both familial and sporadic cases with thoracic aortic disease. 13 In contrast, Lindsay et al 14 found a relative high frequency of TGFB2 mutations (in 6 out of 86 individuals, 7.0%), which may be the result of testing a cohort of probands with phenotypic features within the LDS spectrum. 14 Notably, only two patients with MFS/LDS-related disorders in combination with developmental delay and heterozygous de novo microdeletions (6.5 Mb and 3.5 Mb) including the TGFB2 gene have been described; 14 however, more detailed copy number analysis may uncover further TGFB2 mutations in patients with thoracic aortic disease.…”

“…2,11,12 Recently, two studies have shown that haploinsufficiency for TGFB2 causes a familial syndrome of TAAD with additional clinical manifestations overlapping MFS and LDS. 13,14 TGFB2 encodes TGF-b2, one of three ligand isoforms that exert their cellular effects, eg, the regulation of organ-specific morphogenesis and adult tissue homeostasis by binding to heterotetrameric complexes of the TGF-b serine/threonine kinase receptors. 15 …”