TGF-β Pathway Genes in Familial Cases of Intracranial Aneurysm

Field: Medicine (Health Sciences)

Genetic determinants play a certain, yet undefined, role in the pathogenesis of intracranial aneurysms (IAs). It has been shown that up to 20% of IA patients have a positive family history, with a 7 times higher rupture rate in first-degree relatives compared with second-degree relatives. Several patterns of inheritance have been observed, but a single model of inheritance has yet to be established. IAs share many similar pathological findings with aortic aneurysms (AAs), such as degeneration of the extracellular matrix, destruction of elastic lamina, and loss of media, in addition to increased levels of matrix metalloproteinases, apoptosis, and inflammatory cell infiltration. IAs and AAs even seem to have some common genetic predisposition, as shown by the coexistence of both in some families. It has been suggested that the genetic mutations leading to thoracic aortic aneurysms and dissections (TAAD), whether as an isolated finding or as a part of Marfan and Loeys-Dietz syndromes, involve a dysregulation in the TGF-β pathway caused by mutations in the TGF-β receptor genes (TGFBR1 and TGFBR2).FIGURE: Reproduced from Front Biosci 7:d1231–1246, 2002.Based on the hypothesis that IAs and AAs might share common genetic predisposition, Santiago-Sim et al. (Stroke 40:1604–1611, 2009) from the Harvard Medical School, Brigham and Women's Hospital, and The University of Texas Health Science Center at Houston investigated the dysregulation of the TGF-β signaling pathway in 44 familial IAs. Using intron-based exon-specific primers, TGFB1, TGFBR1, TGFBR2, ACVR1, TGFBR3, and ENG were sequenced. The authors found no novel variants of TGFBR1 and TGFBR2, and none of the mutations that have been previously described for TAAD. This finding suggests that mutations in these receptors are not a major cause of IA development. Interestingly, however, 5 nonsynonymous novel variants were identified in ENG/endoglin and TGFBR3/Betaglycan, 2 of which (ENG p. A60E and TGFBR3 p. W112R) containing a mutation affecting a highly evolutionarily conserved amino acid residue in their sequence. Endoglin has been proven to be vital in vessel wall structural development, and mutations in its sequence have been associated with hemorrhagic telangiectasia 1 (HHT1), which can also be associated with intracranial aneurysms. The variant described by the authors (p. A60E) had not been previously indentified. Betaglycan has been implicated in tumor suppression and ovarian function regulation, however, the variant noted by the authors (p.W112R), has not been previously described. Endoglin has been studied by other investigators showing an association with IAs in a Japanese population. However, this could not be replicated in other populations. Endoglin may not be a major IA susceptibility gene. However, it is possible that these variants can help determine a genetic mechanism leading to the formation of IA. The road to unraveling intracranial aneurysm biology and genetics has been frustrating, but cracks in the puzzle are starting to emerge. Studies such as these will hopefully bring us closer to cost efficient individualized screening. It is conceivable that models based on genetic and environmental factors will emerge which will help predict an indivdual's risk for rupture. This may one day help refine decision-making with regards to aneurysm treatment. ARUN K. SHERMA, MD RUDY RAHME, MD BERNARD R. BENDOK, MD VASCULAR BIOLOGY RESEARCH