@article {340, title = {Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {21-30}, abstract = {

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

}, keywords = {Adolescent, Adult, Bone and Bones, Brachydactyly, Cell Cycle Checkpoints, Exome, Female, Fibromuscular Dysplasia, Genes, Recessive, Heterozygote, Homozygote, Humans, Learning Disorders, Male, Middle Aged, Muscle, Smooth, Vascular, Mutation, Nuclear Proteins, Pedigree, Syndactyly, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.008}, author = {Guo, Dong-Chuan and Duan, Xue-Yan and Regalado, Ellen S and Mellor-Crummey, Lauren and Kwartler, Callie S and Kim, Dong and Lieberman, Kenneth and de Vries, Bert B A and Pfundt, Rolph and Schinzel, Albert and Kotzot, Dieter and Shen, Xuetong and Yang, Min-Lee and Bamshad, Michael J and Nickerson, Deborah A and Gornik, Heather L and Ganesh, Santhi K and Braverman, Alan C and Grange, Dorothy K and Milewicz, Dianna M} } @article {86, title = {FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Mar 01}, pages = {948-61}, abstract = {

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

}, keywords = {Adult, Aneurysm, Dissecting, Animals, Aorta, Aortic Aneurysm, Thoracic, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Forkhead Transcription Factors, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree, Tumor Suppressor Protein p53, Vascular Remodeling, Zebrafish}, issn = {1558-8238}, doi = {10.1172/JCI83778}, author = {Kuang, Shao-Qing and Medina-Martinez, Olga and Guo, Dong-Chuan and Gong, Limin and Regalado, Ellen S and Reynolds, Corey L and Boileau, Catherine and Jondeau, Guillaume and Prakash, Siddharth K and Kwartler, Callie S and Zhu, Lawrence Yang and Peters, Andrew M and Duan, Xue-Yan and Bamshad, Michael J and Shendure, Jay and Nickerson, Debbie A and Santos-Cortez, Regie L and Dong, Xiurong and Leal, Suzanne M and Majesky, Mark W and Swindell, Eric C and Jamrich, Milan and Milewicz, Dianna M} } @article {56, title = {Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1082-1091}, abstract = {

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In~vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.

}, keywords = {Cell Differentiation, Cells, Cultured, Ductus Arteriosus, Patent, Epigenesis, Genetic, Female, Fluorescent Antibody Technique, Histones, Humans, Immunoblotting, Male, Muscle Proteins, Muscle, Smooth, Vascular, Mutation, Pedigree, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.022}, author = {Li, Na and Subrahmanyan, Lakshman and Smith, Emily and Yu, Xiaoqing and Zaidi, Samir and Choi, Murim and Mane, Shrikant and Nelson-Williams, Carol and Behjati, Mohaddeseh and Kazemi, Mohammad and Hashemi, Mohammad and Fathzadeh, Mohsen and Narayanan, Anand and Tian, Likun and Montazeri, Farhad and Mani, Mitra and Begleiter, Michael L and Coon, Brian G and Lynch, Henry T and Olson, Eric N and Zhao, Hongyu and Ruland, J{\"u}rgen and Lifton, Richard P and Mani, Arya} } @article {294, title = {Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {398-404}, abstract = {

Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63\%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime.

}, keywords = {Acute Disease, Adolescent, Adult, Amino Acid Sequence, Aneurysm, Dissecting, Aorta, Thoracic, Aortic Aneurysm, Thoracic, Cyclic GMP, Cyclic GMP-Dependent Protein Kinase Type I, Exome, Female, Fibroblasts, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Molecular Sequence Data, Muscle Contraction, Muscle, Smooth, Vascular, Mutation, Myosin Light Chains, Pedigree}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.06.019}, author = {Guo, Dong-Chuan and Regalado, Ellen and Casteel, Darren E and Santos-Cortez, Regie L and Gong, Limin and Kim, Jeong Joo and Dyack, Sarah and Horne, S Gabrielle and Chang, Guijuan and Jondeau, Guillaume and Boileau, Catherine and Coselli, Joseph S and Li, Zhenyu and Leal, Suzanne M and Shendure, Jay and Rieder, Mark J and Bamshad, Michael J and Nickerson, Deborah A and Kim, Choel and Milewicz, Dianna M} }