Page 193 - Read Online

Page 8 of 15 Levy et al. Vessel Plus 2024;8:4 https://dx.doi.org/10.20517/2574-1209.2023.55

PRKG: Exome sequencing identified a variant gain-of-function mutation in PRKG1, which encodes a type I
cGMP-dependent protein kinase for signal transduction in VSMCs. The missense mutation in PRKG1
(c.530G>A) demonstrates complete penetrance in > 18 years of age and correlates with TAAD. Of the 31
family members carrying the PRKG1 gene, 63% presented with an acute aortic dissection. There was no
gender difference in the age of dissection, and the average age of dissection for females and males was 31
years old. The mutation results in increased PKG-1 activity, leading to decreased VSMC contraction,
although the subsequent mechanism leading to TAAD has yet to be elucidated .
[46]

FOXE3: Kuang et al. performed exome sequencing and identified pathologic variants of the FOXE3 gene
expressed in eight members of a large family presenting in an autosomal dominant pattern with incomplete
penetrance. Mutations in the N-terminal end of FOXE3, a forkhead transcription factor, have been
previously found in association with a spectrum of eye disorders [47,48] . However, none of the TAAD-affected
individuals demonstrated eye abnormalities associated with a missense mutation in the C-terminal end of
the DNA-binding domain (p.Asp153His). This novel mutation in FOXE3 led to limited VSMC
proliferation, differentiation, and survival in the ascending aorta and aortic arch during development,
suggesting that FOXE3 deficiency predisposes to ns-TAAD through heritable stress-induced VSMC
apoptosis .
[48]

MAT2A: Whole-genome linkage analysis and exome sequencing of a large family with AD TAAD and BAV
disease identified missense mutations in MAT2A (p.Glu344Ala, p.Arg356His), which encodes methionine
adenosyltransferase II alpha, a critical enzyme in VSMC metabolism. Within one family of 18 members,
24% of those individuals were also found to have BAV. The study concluded that the risk of acute aortic
dissection was low but still overall uncertain in the presence of BAV in these individuals [37,49] . These loss-of-
function variants decrease enzyme function, leading to global hypomethylation that modulates phenotype
and proliferation. The data suggests a potential epigenetic factor in the development of ns-TAAD.

Gene mutations in extracellular matrix
LOX: Lysyl oxidases, including those encoded by the LOX gene, are extracellular copper enzymes that
catalyze lysine cross-linking in elastin and collagen. Whole-genome and exome sequencing identified a
heterozygous loss-of-function mutation in LOX in individuals with TAAD who present with some
syndromic features of MFS (pectus deformities, striae, etc.) but fail to meet true MFS diagnostic criteria [50,51] .
Several missense mutations in LOX result in decreased lysyl oxidase activity, which is proposed to result in
fewer elastin cross-links and thus less organized, more fragmented elastic fibers within the thoracic aorta
ECM that predisposes to TAAD. Interestingly, Guo et al. identified three of the 20 LOX mutation carriers
also presented with a BAV, which posits the hypothesis that LOX defects may contribute to BAV disease
and associated aortopathy .
[51]

MFAP5: Barbier et al. utilized whole-exome sequencing and mutation screening to identify a nonsense
(p.Arg158*) and a missense (p.Trp21Leu) mutation in MFAP5 in two families with ns-TAAD . The gene
[52]
encodes microfibril-associated glycoprotein 2 (MAGP-2), a component of the ECM found in fibrillin-
containing and elastin-associated microfibrils. Both families presented with aortic root dilation without the
other phenotypic features of s-TAAD. Aortic tissue collected at the time of surgery from one affected
individual in the studied proband exhibited disorganization of the media with loss of VSMCs and
proteoglycan accumulation on histology - typical features of TAAD. Barbier et al. propose that the loss-of-
function of MFAP5 disrupts ECM fibers, which affects the structural integrity of the aorta, leading to
dilation, aneurysm formation, and dissection .
[52]