@article {962, title = {Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 06 04}, pages = {779-792}, abstract = {

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.

}, keywords = {Alleles, Base Sequence, Child, Child, Preschool, Cilia, Developmental Disabilities, Female, Hedgehog Proteins, Humans, Infant, Male, Models, Molecular, Neoplasms, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, Signal Transduction, Smoothened Receptor, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.04.010}, author = {Le, Thuy-Linh and Sribudiani, Yunia and Dong, Xiaomin and Huber, Celine and Kois, Chelsea and Baujat, Genevi{\`e}ve and Gordon, Christopher T and Mayne, Valerie and Galmiche, Louise and Serre, Val{\'e}rie and Goudin, Nicolas and Zarhrate, Mohammed and Bole-Feysot, Christine and Masson, Cecile and Nitschk{\'e}, Patrick and Verheijen, Frans W and Pais, Lynn and Pelet, Anna and Sadedin, Simon and Pugh, John A and Shur, Natasha and White, Susan M and El Chehadeh, Salima and Christodoulou, John and Cormier-Daire, Val{\'e}rie and Hofstra, R M W and Lyonnet, Stanislas and Tan, Tiong Yang and Atti{\'e}-Bitach, Tania and Kerstjens-Frederikse, Wilhelmina S and Amiel, Jeanne and Thomas, Sophie} } @article {794, title = {Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {2020 10}, pages = {1046-1056}, abstract = {

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14\% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

}, keywords = {Animals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-020-0695-1}, author = {Jin, Sheng Chih and Lewis, Sara A and Bakhtiari, Somayeh and Zeng, Xue and Sierant, Michael C and Shetty, Sheetal and Nordlie, Sandra M and Elie, Aureliane and Corbett, Mark A and Norton, Bethany Y and van Eyk, Clare L and Haider, Shozeb and Guida, Brandon S and Magee, Helen and Liu, James and Pastore, Stephen and Vincent, John B and Brunstrom-Hernandez, Janice and Papavasileiou, Antigone and Fahey, Michael C and Berry, Jesia G and Harper, Kelly and Zhou, Chongchen and Zhang, Junhui and Li, Boyang and Zhao, Hongyu and Heim, Jennifer and Webber, Dani L and Frank, MAHlia S B and Xia, Lei and Xu, Yiran and Zhu, Dengna and Zhang, Bohao and Sheth, Amar H and Knight, James R and Castaldi, Christopher and Tikhonova, Irina R and L{\'o}pez-Gir{\'a}ldez, Francesc and Keren, Boris and Whalen, Sandra and Buratti, Julien and Doummar, Diane and Cho, Megan and Retterer, Kyle and Millan, Francisca and Wang, Yangong and Waugh, Jeff L and Rodan, Lance and Cohen, Julie S and Fatemi, Ali and Lin, Angela E and Phillips, John P and Feyma, Timothy and MacLennan, Suzanna C and Vaughan, Spencer and Crompton, Kylie E and Reid, Susan M and Reddihough, Dinah S and Shang, Qing and Gao, Chao and Novak, Iona and Badawi, Nadia and Wilson, Yana A and McIntyre, Sarah J and Mane, Shrikant M and Wang, Xiaoyang and Amor, David J and Zarnescu, Daniela C and Lu, Qiongshi and Xing, Qinghe and Zhu, Changlian and Bilguvar, Kaya and Padilla-Lopez, Sergio and Lifton, Richard P and Gecz, Jozef and MacLennan, Alastair H and Kruer, Michael C} } @article {576, title = {Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {213-228}, abstract = {

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61\%) individuals. In addition to TBX4, the overlapping \~{}2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

}, keywords = {DNA Copy Number Variations, Female, Fibroblast Growth Factor 10, Gene Expression Regulation, Gestational Age, Humans, Infant, Newborn, Infant, Newborn, Diseases, Lung, Lung Diseases, Male, Maternal Inheritance, Organogenesis, Paternal Inheritance, Pedigree, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Signal Transduction, T-Box Domain Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.010}, author = {Karolak, Justyna A and Vincent, Marie and Deutsch, Gail and Gambin, Tomasz and Cogn{\'e}, Benjamin and Pichon, Olivier and Vetrini, Francesco and Mefford, Heather C and Dines, Jennifer N and Golden-Grant, Katie and Dipple, Katrina and Freed, Amanda S and Leppig, Kathleen A and Dishop, Megan and Mowat, David and Bennetts, Bruce and Gifford, Andrew J and Weber, Martin A and Lee, Anna F and Boerkoel, Cornelius F and Bartell, Tina M and Ward-Melver, Catherine and Besnard, Thomas and Petit, Florence and Bache, Iben and T{\"u}mer, Zeynep and Denis-Musquer, Marie and Joubert, Madeleine and Martinovic, Jelena and B{\'e}n{\'e}teau, Claire and Molin, Arnaud and Carles, Dominique and Andr{\'e}, Gwenaelle and Bieth, Eric and Chassaing, Nicolas and Devisme, Louise and Chalabreysse, Lara and Pasquier, Laurent and Secq, V{\'e}ronique and Don, Massimiliano and Orsaria, Maria and Missirian, Chantal and Mortreux, J{\'e}r{\'e}mie and Sanlaville, Damien and Pons, Linda and K{\"u}ry, S{\'e}bastien and B{\'e}zieau, St{\'e}phane and Liet, Jean-Michel and Joram, Nicolas and Bihou{\'e}e, Tiphaine and Scott, Daryl A and Brown, Chester W and Scaglia, Fernando and Tsai, Anne Chun-Hui and Grange, Dorothy K and Phillips, John A and Pfotenhauer, Jean P and Jhangiani, Shalini N and Gonzaga-Jauregui, Claudia G and Chung, Wendy K and Schauer, Galen M and Lipson, Mark H and Mercer, Catherine L and van Haeringen, Arie and Liu, Qian and Popek, Edwina and Coban Akdemir, Zeynep H and Lupski, James R and Szafranski, Przemyslaw and Isidor, Bertrand and Le Caignec, Cedric and Stankiewicz, Pawe{\l}} } @article {541, title = {Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.}, journal = {J Clin Endocrinol Metab}, volume = {103}, year = {2018}, month = {2018 04 01}, pages = {1273-1276}, abstract = {

Context: Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders.

Case Description: A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone.

Conclusion: This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.

}, keywords = {Cryptorchidism, Follicle Stimulating Hormone, Follow-Up Studies, Humans, Infant, Kisspeptins, Luteinizing Hormone, Male, Mutation, Missense, Penis, Receptors, Kisspeptin-1, Sexual Maturation, Signal Transduction, Testosterone}, issn = {1945-7197}, doi = {10.1210/jc.2017-02636}, author = {Shahab, Muhammad and Lippincott, Margaret and Chan, Yee-Ming and Davies, Addie and Merino, Paulina M and Plummer, Lacey and Mericq, Veronica and Seminara, Stephanie} } @article {437, title = {Asprosin is a centrally acting orexigenic hormone.}, journal = {Nat Med}, volume = {23}, year = {2017}, month = {2017 Dec}, pages = {1444-1453}, abstract = {

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

}, keywords = {Adolescent, Adult, Animals, Appetite Depressants, Appetite Regulation, Female, Humans, Hypothalamus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Peptide Fragments, Peptide Hormones, Rats, Signal Transduction, Young Adult}, issn = {1546-170X}, doi = {10.1038/nm.4432}, author = {Duerrschmid, Clemens and He, Yanlin and Wang, Chunmei and Li, Chia and Bournat, Juan C and Romere, Chase and Saha, Pradip K and Lee, Mark E and Phillips, Kevin J and Jain, Mahim and Jia, Peilin and Zhao, Zhongming and Farias, Monica and Wu, Qi and Milewicz, Dianna M and Sutton, V Reid and Moore, David D and Butte, Nancy F and Krashes, Michael J and Xu, Yong and Chopra, Atul R} } @article {386, title = {De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 08 29}, pages = {E7341-E7347}, abstract = {

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95\% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, = 2.4 {\texttimes} 10). had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10\% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near increased the penetrance of mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

}, keywords = {Adult, Animals, Bone Morphogenetic Proteins, Child, Child, Preschool, Cranial Sutures, Craniosynostoses, Exome, Female, Humans, Male, MAP Kinase Signaling System, Mutation, Osteogenesis, Penetrance, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction, Smad6 Protein, Whole Exome Sequencing}, issn = {1091-6490}, doi = {10.1073/pnas.1709255114}, author = {Timberlake, Andrew T and Furey, Charuta G and Choi, Jungmin and Nelson-Williams, Carol and Loring, Erin and Galm, Amy and Kahle, Kristopher T and Steinbacher, Derek M and Larysz, Dawid and Persing, John A and Lifton, Richard P} } @article {401, title = {A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations Dysregulation of Retinoic Acid Signaling.}, journal = {J Am Soc Nephrol}, volume = {28}, year = {2017}, month = {2017 Aug}, pages = {2364-2376}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene () in all seven affected members. encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RAR, and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RAR RNA hybridization confirmed expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in confirmed an evolutionarily conserved role for in renal development. These data indicate that dominant mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease.

}, keywords = {Adaptor Proteins, Signal Transducing, Animals, Mice, Mutation, Nuclear Proteins, Nuclear Receptor Interacting Protein 1, Signal Transduction, Tretinoin, Urinary Tract}, issn = {1533-3450}, doi = {10.1681/ASN.2016060694}, author = {Vivante, Asaf and Mann, Nina and Yonath, Hagith and Weiss, Anna-Carina and Getwan, Maike and Kaminski, Michael M and Bohnenpoll, Tobias and Teyssier, Catherine and Chen, Jing and Shril, Shirlee and van der Ven, Amelie T and Ityel, Hadas and Schmidt, Johanna Magdalena and Widmeier, Eugen and Bauer, Stuart B and Sanna-Cherchi, Simone and Gharavi, Ali G and Lu, Weining and Magen, Daniella and Shukrun, Rachel and Lifton, Richard P and Tasic, Velibor and Stanescu, Horia C and Cavaill{\`e}s, Vincent and Kleta, Robert and Anikster, Yair and Dekel, Benjamin and Kispert, Andreas and Lienkamp, Soeren S and Hildebrandt, Friedhelm} } @article {358, title = {Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Apr}, pages = {613-617}, abstract = {

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

}, keywords = {Abnormalities, Multiple, Animals, Bone Diseases, Developmental, Cell Line, Chromosome Disorders, Craniofacial Abnormalities, Feeding and Eating Disorders, Female, Fusion Proteins, bcr-abl, Germ-Line Mutation, Heart Defects, Congenital, HEK293 Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Limb Deformities, Congenital, Male, Mice, Mice, Knockout, Philadelphia Chromosome, Phosphorylation, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3815}, author = {Wang, Xia and Charng, Wu-Lin and Chen, Chun-An and Rosenfeld, Jill A and Al Shamsi, Aisha and Al-Gazali, Lihadh and McGuire, Marianne and Mew, Nicholas Ah and Arnold, Georgianne L and Qu, Chunjing and Ding, Yan and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Plon, Sharon E and Lupski, James R and Schaaf, Christian P and Yang, Yaping} } @article {349, title = {A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFβ signaling and cause autosomal dominant spondylocarpotarsal synostosis.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 02 16}, pages = {41803}, abstract = {

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFβ signaling, revealing a regulatory role for embryonic myosin in the TGFβ signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

}, keywords = {Abnormalities, Multiple, Alleles, Bone Morphogenetic Proteins, Cytoskeletal Proteins, Female, Genes, Dominant, Genotype, Humans, Lumbar Vertebrae, Male, Musculoskeletal Diseases, Mutation, Myosins, Phenotype, Radiography, Scoliosis, Signal Transduction, Synostosis, Thoracic Vertebrae, Transforming Growth Factor beta, Whole Exome Sequencing}, issn = {2045-2322}, doi = {10.1038/srep41803}, author = {Zieba, Jennifer and Zhang, Wenjuan and Chong, Jessica X and Forlenza, Kimberly N and Martin, Jorge H and Heard, Kelly and Grange, Dorothy K and Butler, Merlin G and Kleefstra, Tjitske and Lachman, Ralph S and Nickerson, Deborah and Regnier, Michael and Cohn, Daniel H and Bamshad, Michael and Krakow, Deborah} } @article {94, title = {Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.}, journal = {Clin Genet}, volume = {90}, year = {2016}, month = {2016 10}, pages = {351-60}, abstract = {

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.

}, keywords = {Adolescent, Adult, Animals, Child, Child, Preschool, Cohort Studies, Esophageal Achalasia, Female, Humans, Hypertension, Infant, Male, Middle Aged, Moyamoya Disease, Mutation, Nitric Oxide, Nonlinear Dynamics, Regression Analysis, Sf9 Cells, Signal Transduction, Soluble Guanylyl Cyclase}, issn = {1399-0004}, doi = {10.1111/cge.12739}, author = {Wallace, S and Guo, D-C and Regalado, E and Mellor-Crummey, L and Bamshad, M and Nickerson, D A and Dauser, R and Hanchard, N and Marom, R and Martin, E and Berka, V and Sharina, I and Ganesan, V and Saunders, D and Morris, S A and Milewicz, D M} } @article {533, title = {Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006335}, abstract = {

Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

}, keywords = {Aortic Valve, Codon, Nonsense, Constriction, Pathologic, Exome, Female, Genetic Association Studies, Genetic Linkage, Genome, Human, Heart Defects, Congenital, Humans, Male, Pedigree, Receptor, Notch1, Receptors, Notch, Sequence Deletion, Signal Transduction, Ventricular Outflow Obstruction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006335}, author = {Preuss, Christoph and Capredon, Melanie and W{\"u}nnemann, Florian and Chetaille, Philippe and Prince, Andrea and Godard, Beatrice and Leclerc, Severine and Sobreira, Nara and Ling, Hua and Awadalla, Philip and Thibeault, Maryse and Khairy, Paul and Samuels, Mark E and Andelfinger, Gregor} } @article {65, title = {Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {1001-1010}, abstract = {

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein~subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p~=~7.1~{\texttimes} 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Humans, Infant, Intellectual Disability, Male, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.011}, author = {Petrovski, Slav{\'e} and K{\"u}ry, S{\'e}bastien and Myers, Candace T and Anyane-Yeboa, Kwame and Cogn{\'e}, Benjamin and Bialer, Martin and Xia, Fan and Hemati, Parisa and Riviello, James and Mehaffey, Michele and Besnard, Thomas and Becraft, Emily and Wadley, Alexandrea and Politi, Anya Revah and Colombo, Sophie and Zhu, Xiaolin and Ren, Zhong and Andrews, Ian and Dudding-Byth, Tracy and Schneider, Amy L and Wallace, Geoffrey and Rosen, Aaron B I and Schelley, Susan and Enns, Gregory M and Corre, Pierre and Dalton, Joline and Mercier, Sandra and Latypova, X{\'e}nia and Schmitt, S{\'e}bastien and Guzman, Edwin and Moore, Christine and Bier, Louise and Heinzen, Erin L and Karachunski, Peter and Shur, Natasha and Grebe, Theresa and Basinger, Alice and Nguyen, Joanne M and B{\'e}zieau, St{\'e}phane and Wierenga, Klaas and Bernstein, Jonathan A and Scheffer, Ingrid E and Rosenfeld, Jill A and Mefford, Heather C and Isidor, Bertrand and Goldstein, David B} } @article {343, title = {An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 09 15}, pages = {3998-4011}, abstract = {

The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.

}, keywords = {Abnormalities, Multiple, Cilia, Exome, Female, Hedgehog Proteins, Humans, Infant, MAP Kinase Signaling System, Pedigree, Pregnancy, Protein-Serine-Threonine Kinases, Sequence Analysis, DNA, Short Rib-Polydactyly Syndrome, Signal Transduction, Skeleton}, issn = {1460-2083}, doi = {10.1093/hmg/ddw240}, author = {Paige Taylor, S and Kunova Bosakova, Michaela and Varecha, Miroslav and Balek, Lukas and Barta, Tomas and Trantirek, Lukas and Jelinkova, Iva and Duran, Ivan and Vesela, Iva and Forlenza, Kimberly N and Martin, Jorge H and Hampl, Ales and Bamshad, Michael and Nickerson, Deborah and Jaworski, Margie L and Song, Jieun and Ko, Hyuk Wan and Cohn, Daniel H and Krakow, Deborah and Krejci, Pavel} } @article {82, title = {Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 May}, pages = {1165-73}, abstract = {

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

}, keywords = {Autistic Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, DNA Copy Number Variations, Female, Genetic Association Studies, Humans, Male, Psychotic Disorders, Schizophrenia, Signal Transduction}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37595}, author = {Brownstein, Catherine A and Kleiman, Robin J and Engle, Elizabeth C and Towne, Meghan C and D{\textquoteright}Angelo, Eugene J and Yu, Timothy W and Beggs, Alan H and Picker, Jonathan and Fogler, Jason M and Carroll, Devon and Schmitt, Rachel C O and Wolff, Robert R and Shen, Yiping and Lip, Va and Bilguvar, Kaya and Kim, April and Tembulkar, Sahil and O{\textquoteright}Donnell, Kyle and Gonzalez-Heydrich, Joseph} } @article {70, title = {Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Apr 07}, pages = {772-81}, abstract = {

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126(*)] and c.1363A>T [p.Lys455(*)]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in~silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Brain Diseases, Child, Child, Preschool, Corpus Callosum, Female, GTPase-Activating Proteins, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Protein-Serine-Threonine Kinases, Signal Transduction, TOR Serine-Threonine Kinases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.016}, author = {Chong, Jessica X and Caputo, Viviana and Phelps, Ian G and Stella, Lorenzo and Worgan, Lisa and Dempsey, Jennifer C and Nguyen, Alina and Leuzzi, Vincenzo and Webster, Richard and Pizzuti, Antonio and Marvin, Colby T and Ishak, Gisele E and Ardern-Holmes, Simone and Richmond, Zara and Bamshad, Michael J and Ortiz-Gonzalez, Xilma R and Tartaglia, Marco and Chopra, Maya and Doherty, Dan} } @article {157, title = {Mutation of ATF6 causes autosomal recessive achromatopsia.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Sep}, pages = {941-50}, abstract = {

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.

}, keywords = {Activating Transcription Factor 6, Adolescent, Animals, Asian Continental Ancestry Group, Color Vision Defects, Consanguinity, DNA Mutational Analysis, Exome, Female, Frameshift Mutation, Genotyping Techniques, Homozygote, Humans, Limit of Detection, Male, Mice, Mice, Inbred C57BL, Pakistan, Pedigree, Phenotype, Retina, Signal Transduction}, issn = {1432-1203}, doi = {10.1007/s00439-015-1571-4}, author = {Ansar, Muhammad and Santos-Cortez, Regie Lyn P and Saqib, Muhammad Arif Nadeem and Zulfiqar, Fareeha and Lee, Kwanghyuk and Ashraf, Naeem Mahmood and Ullah, Ehsan and Wang, Xin and Sajid, Sundus and Khan, Falak Sher and Amin-ud-Din, Muhammad and Smith, Joshua D and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hameed, Abdul and Riazuddin, Saima and Ahmed, Zubair M and Ahmad, Wasim and Leal, Suzanne M} } @article {137, title = {Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Nov}, pages = {2795-9}, abstract = {

Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel{\textquoteright}s deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. {\textcopyright} 2015 Wiley Periodicals, Inc.

}, keywords = {Adolescent, Base Sequence, Female, Humans, Klippel-Feil Syndrome, Male, Molecular Sequence Data, Mutation, Pedigree, Radiography, Receptors, Notch, Signal Transduction, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37263}, author = {Karaca, Ender and Yuregir, Ozge O and Bozdogan, Sevcan T and Aslan, Huseyin and Pehlivan, Davut and Jhangiani, Shalini N and Akdemir, Zeynep C and Gambin, Tomasz and Bayram, Yavuz and Atik, Mehmed M and Erdin, Serkan and Muzny, Donna and Gibbs, Richard A and Lupski, James R} } @article {243, title = {Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jun 05}, pages = {915-23}, abstract = {

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in~vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

}, keywords = {Adult, Alleles, Animals, Anophthalmos, Brain Diseases, Metabolic, Inborn, Coloboma, Corneal Opacity, Exome, Eye Proteins, Female, Gene Expression, HEK293 Cells, Heterozygote, Homozygote, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Mice, Microcephaly, Microphthalmos, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Signal Transduction}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.005}, author = {Rainger, Joe and Pehlivan, Davut and Johansson, Stefan and Bengani, Hemant and Sanchez-Pulido, Luis and Williamson, Kathleen A and Ture, Mehmet and Barker, Heather and Rosendahl, Karen and Spranger, J{\"u}rgen and Horn, Denise and Meynert, Alison and Floyd, James A B and Prescott, Trine and Anderson, Carl A and Rainger, Jacqueline K and Karaca, Ender and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Muzny, Donna M and Seawright, Anne and Soares, Dinesh C and Kharbanda, Mira and Murday, Victoria and Finch, Andrew and Gibbs, Richard A and van Heyningen, Veronica and Taylor, Martin S and Yakut, Tahsin and Knappskog, Per M and Hurles, Matthew E and Ponting, Chris P and Lupski, James R and Houge, Gunnar and FitzPatrick, David R} } @article {286, title = {Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi.}, journal = {J Invest Dermatol}, volume = {134}, year = {2014}, month = {2014 Apr}, pages = {1149-1152}, keywords = {Adherens Junctions, Child, Exome, Female, Genes, ras, Hair, Hair Diseases, Hair Follicle, Humans, Intermediate Filaments, Mosaicism, Mutation, Nevus, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction}, issn = {1523-1747}, doi = {10.1038/jid.2013.430}, author = {Levinsohn, Jonathan L and Teng, Joyce and Craiglow, Brittany G and Loring, Erin C and Burrow, T Andrew and Mane, Shrikant S and Overton, John D and Lifton, Richard P and McNiff, Jennifer M and Lucky, Anne W and Choate, Keith A} } @article {324, title = {Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Jul 08}, pages = {922-7}, abstract = {

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Disease Models, Animal, Female, Fibrillin-1, Fibrillins, Haploinsufficiency, Humans, Loeys-Dietz Syndrome, Male, Marfan Syndrome, Mice, Mice, Knockout, Mice, Mutant Strains, Microfilament Proteins, Mutation, Pedigree, Phenotype, Signal Transduction, Syndrome, Transforming Growth Factor beta2}, issn = {1546-1718}, doi = {10.1038/ng.2349}, author = {Lindsay, Mark E and Schepers, Dorien and Bolar, Nikhita Ajit and Doyle, Jefferson J and Gallo, Elena and Fert-Bober, Justyna and Kempers, Marlies J E and Fishman, Elliot K and Chen, Yichun and Myers, Loretha and Bjeda, Djahita and Oswald, Gretchen and Elias, Abdallah F and Levy, Howard P and Anderlid, Britt-Marie and Yang, Margaret H and Bongers, Ernie M H F and Timmermans, Janneke and Braverman, Alan C and Canham, Natalie and Mortier, Geert R and Brunner, Han G and Byers, Peter H and Van Eyk, Jennifer and Van Laer, Lut and Dietz, Harry C and Loeys, Bart L} } @article {319, title = {Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Nov}, pages = {1249-54}, abstract = {

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

}, keywords = {Animals, Aortic Aneurysm, Arachnodactyly, Cells, Cultured, Craniosynostoses, DNA-Binding Proteins, Fibroblasts, Humans, Loeys-Dietz Syndrome, Marfan Syndrome, Mice, Mutation, Phenotype, Phosphorylation, Proto-Oncogene Proteins, Signal Transduction, Transforming Growth Factor beta, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.2421}, author = {Doyle, Alexander J and Doyle, Jefferson J and Bessling, Seneca L and Maragh, Samantha and Lindsay, Mark E and Schepers, Dorien and Gillis, Elisabeth and Mortier, Geert and Homfray, Tessa and Sauls, Kimberly and Norris, Russell A and Huso, Nicholas D and Leahy, Dan and Mohr, David W and Caulfield, Mark J and Scott, Alan F and Destr{\'e}e, Anne and Hennekam, Raoul C and Arn, Pamela H and Curry, Cynthia J and Van Laer, Lut and McCallion, Andrew S and Loeys, Bart L and Dietz, Harry C} }