Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-β-dependent homeostasis of connective tissues.

Center for Medical Genetics Ghent University Hospital 9000 Ghent Belgium

College of Health and Life Sciences Hamad Bin Khalifa University P O Box 34110 Doha Qatar

Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY 10029 USA

Department of Medical Genetics INSERM U1163 Necker Hospital for Sick Children 75015 Paris France

Division of Biology and Genetics Department of Molecular and Translational Medicine University of Brescia 25123 Brescia Italy

Faculty of Medicine and Central European Institute of Technology Masaryk University Brno 62500 Czech Republic

Howard Hughes Medical Institute Baltimore MD 21205 USA

Howard Hughes Medical Institute New York NY 10065 USA

Immunology Division Garvan Institute of Medical Research Darlinghurst New South Wales 2010 Australia

Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children 75015 Paris France

McKusick Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD 21205 USA

Molecular Genetics Laboratory Centre for Cardiovascular Surgery and Transplantation Brno 65691 Czech Republic

Pediatric Hematology Immunology Unit Necker Hospital for Sick Children 75015 Paris France

Sidra Medicine P O Box 26999 Doha Qatar

St Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY 10065 USA

St Vincent's Clinical School Faculty of Medicine University of New South Wales Sydney New South Wales 2010 Australia

The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY 10029 USA

University of Paris Imagine Institute 75015 Paris France

Erratum In

Sci Immunol. 2020 Jan 3;5(43):eaaz9320. doi: 10.1126/sciimmunol.aaz9320. PubMed

See more in PubMed

Li J, Vinh DC, Casanova JL, Puel A, Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals. Curr. Opin. Microbiol 40, 46–57 (2017). PubMed PMC

Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL, Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr. Opin. Allergy Clin. Immunol 12, 616–622 (2012). PubMed PMC

Freeman AF, Holland SM, Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes. Pediatr. Res 65, 32R–37R (2009). PubMed PMC

Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, Ouachee-Chardin M, Fouyssac F, Girisha KM, Etzioni A, Van Montfrans J, Camcioglu Y, Kerns LA, Belohradsky B, Blanche S, Bousfiha A, Rodriguez-Gallego C, Meyts I, Kisand K, Reichenbach J, Renner ED, Rosenzweig S, Grimbacher B, van de Veerdonk FL, Traidl-Hoffmann C, Picard C, Marodi L, Morio T, Kobayashi M, Lilic D, Milner JD, Holland S, Casanova JL, Puel A, S. G.-o.-F. S. G. International, Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 127, 3154–3164 (2016). PubMed PMC

Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, Alzahrani M, Al-Muhsen S, Halwani R, Ma CS, Wong N, Soudais C, Henderson LA, Marzouqa H, Shamma J, Gonzalez M, Martinez-Barricarte R, Okada C, Avery DT, Latorre D, Deswarte C, Jabot-Hanin F, Torrado E, Fountain J, Belkadi A, Itan Y, Boisson B, Migaud M, Arlehamn CS, Sette A, Breton S, McCluskey J, Rossjohn J, de Villartay JP, Moshous D, Hambleton S, Latour S, Arkwright PD, Picard C, Lantz O, Engelhard D, Kobayashi M, Abel L, Cooper AM, Notarangelo LD, Boisson-Dupuis S, Puel A, Sallusto F, Bustamante J, Tangye SG, Casanova JL, IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science 349, 606–613 (2015). PubMed PMC

Beziat V, Li J, Lin JX, Ma CS, Li P, Bousfiha A, Pellier I, Zoghi S, Baris S, Keles S, Gray P, Du N, Wang Y, Zerbib Y, Levy R, Leclercq T, About F, Lim AI, Rao G, Payne K, Pelham SJ, Avery DT, Deenick EK, Pillay B, Chou J, Guery R, Belkadi A, Guerin A, Migaud M, Rattina V, Ailal F, Benhsaien I, Bouaziz M, Habib T, Chaussabel D, Marr N, El-Benna J, Grimbacher B, Wargon O, Bustamante J, Boisson B, Muller-Fleckenstein I, Fleckenstein B, Chandesris MO, Titeux M, Fraitag S, Alyanakian MA, Leruez-Ville M, Picard C, Meyts I, Di Santo JP, Hovnanian A, Somer A, Ozen A, Rezaei N, Chatila TA, Abel L, Leonard WJ, Tangye SG, Puel A, Casanova JL, A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci. Immunol 3, (2018). PubMed PMC

Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC, Bulashevska A, Proietti M, Frobel P, Noltner C, Yang L, Rojas-Restrepo J, Langer N, Winzer S, Engelhardt KR, Glocker C, Pfeifer D, Klein A, Schaffer AA, Lagovsky I, Lachover-Roth I, Beziat V, Puel A, Casanova JL, Fleckenstein B, Weidinger S, Kilic SS, Garty BZ, Etzioni A, Grimbacher B, ZNF341 controls STAT3 expression and thereby immunocompetence. Sci. Immunol 3, (2018). PubMed PMC

Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H, Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007). PubMed

de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, Feinberg J, von Bernuth H, Samarina A, Janniere L, Fieschi C, Stephan JL, Boileau C, Lyonnet S, Jondeau G, Cormier-Daire V, Le Merrer M, Hoarau C, Lebranchu Y, Lortholary O, Chandesris MO, Tron F, Gambineri E, Bianchi L, Rodriguez-Gallego C, Zitnik SE, Vasconcelos J, Guedes M, Vitor AB, Marodi L, Chapel H, Reid B, Roifman C, Nadal D, Reichenbach J, Caragol I, Garty BZ, Dogu F, Camcioglu Y, Gulle S, Sanal O, Fischer A, Abel L, Stockinger B, Picard C, Casanova JL, Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J. Exp. Med 205, 1543–1550 (2008). PubMed PMC

Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC, Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J. Exp. Med 205, 1551–1557 (2008). PubMed PMC

Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O’Shea J, Holland SM, Paul WE, Douek DC, Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008). PubMed PMC

Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, Toubiana J, Itan Y, Audry M, Nitschke P, Masson C, Toth B, Flatot J, Migaud M, Chrabieh M, Kochetkov T, Bolze A, Borghesi A, Toulon A, Hiller J, Eyerich S, Eyerich K, Gulacsy V, Chernyshova L, Chernyshov V, Bondarenko A, Grimaldo RM, Blancas-Galicia L, Beas IM, Roesler J, Magdorf K, Engelhard D, Thumerelle C, Burgel PR, Hoernes M, Drexel B, Seger R, Kusuma T, Jansson AF, Sawalle-Belohradsky J, Belohradsky B, Jouanguy E, Bustamante J, Bue M, Karin N, Wildbaum G, Bodemer C, Lortholary O, Fischer A, Blanche S, Al-Muhsen S, Reichenbach J, Kobayashi M, Rosales FE, Lozano CT, Kilic SS, Oleastro M, Etzioni A, Traidl-Hoffmann C, Renner ED, Abel L, Picard C, Marodi L, Boisson-Dupuis S, Puel A, Casanova JL, Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med 208, 1635–1648 (2011). PubMed PMC

van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, Arts P, Rosentul DC, Carmichael AJ, Smits-van der Graaf CA, Kullberg BJ, van der Meer JW, Lilic D, Veltman JA, Netea MG, STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med 365, 54–61 (2011). PubMed

Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, Ersvaer E, Perheentupa J, Erichsen MM, Bratanic N, Meloni A, Cetani F, Perniola R, Ergun-Longmire B, Maclaren N, Krohn KJ, Pura M, Schalke B, Strobel P, Leite MI, Battelino T, Husebye ES, Peterson P, Willcox N, Meager A, Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med 207, 299–308 (2010). PubMed PMC

Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, Cobat A, Ouachee-Chardin M, Toulon A, Bustamante J, Al-Muhsen S, Al-Owain M, Arkwright PD, Costigan C, McConnell V, Cant AJ, Abinun M, Polak M, Bougneres PF, Kumararatne D, Marodi L, Nahum A, Roifman C, Blanche S, Fischer A, Bodemer C, Abel L, Lilic D, Casanova JL, Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med 207, 291–297 (2010). PubMed PMC

Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, Gumbleton M, Toulon A, Bodemer C, El-Baghdadi J, Whitters M, Paradis T, Brooks J, Collins M, Wolfman NM, Al-Muhsen S, Galicchio M, Abel L, Picard C, Casanova JL, Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011). PubMed PMC

Levy R, Okada S, Beziat V, Moriya K, Liu C, Chai LY, Migaud M, Hauck F, Al Ali A, Cyrus C, Vatte C, Patiroglu T, Unal E, Ferneiny M, Hyakuna N, Nepesov S, Oleastro M, Ikinciogullari A, Dogu F, Asano T, Ohara O, Yun L, Della Mina E, Bronnimann D, Itan Y, Gothe F, Bustamante J, Boisson-Dupuis S, Tahuil N, Aytekin C, Salhi A, Al Muhsen S, Kobayashi M, Toubiana J, Abel L, Li X, Camcioglu Y, Celmeli F, Klein C, AlKhater SA, Casanova JL, Puel A, Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc. Natl. Acad. Sci. U.S.A 113, E8277–E8285 (2016). PubMed PMC

Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y, Nepesov S, Ikinciogullari A, Dogu F, Belkadi A, Levy R, Migaud M, Boisson B, Bolze A, Itan Y, Goudin N, Cottineau J, Picard C, Abel L, Bustamante J, Casanova JL, Puel A, Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J. Exp. Med 212, 619–631 (2015). PubMed PMC

Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, Belkadi A, Picard C, Abel L, Fieschi C, Puel A, Li X, Casanova JL, An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity 39, 676–686 (2013). PubMed PMC

Bhattad S, Dinakar C, Pinnamaraju H, Ganapathy A, Mannan A, Chronic Mucocutaneous Candidiasis in an Adolescent Boy Due to a Novel Mutation in TRAF3IP2. J. Clin. Immunol 39, 596–599 (2019). PubMed

Meester JAN, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL, Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann. Cardiothorac. Surg 6, 582–594 (2017). PubMed PMC

Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B, The 2017 international classification of the Ehlers-Danlos syndromes. Am. J. Med. Genet. C Semin. Med. Genet 175, 8–26 (2017). PubMed

Blackburn PR, Xu Z, Tumelty KE, Zhao RW, Monis WJ, Harris KG, Gass JM, Cousin MA, Boczek NJ, Mitkov MV, Cappel MA, Francomano CA, Parisi JE, Klee EW, Faqeih E, Alkuraya FS, Layne MD, McDonnell NB, Atwal PS, Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome. Am. J. Hum. Genet 102, 696–705 (2018). PubMed PMC

MacFarlane EG, Haupt J, Dietz HC, Shore EM, TGF-beta Family Signaling in Connective Tissue and Skeletal Diseases. Cold Spring Harb. Perspect. Biol 9, (2017). PubMed PMC

Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, et al., Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991). PubMed

Verrecchia F, Mauviel A, Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J. Invest. Dermatol 118, 211–215 (2002). PubMed

Itan Y, Zhang SY, Vogt G, Abhyankar A, Herman M, Nitschke P, Fried D, Quintana-Murci L, Abel L, Casanova JL, The human gene connectome as a map of short cuts for morbid allele discovery. Proc. Natl. Acad. Sci. U.S.A 110, 5558–5563 (2013). PubMed PMC

Itan Y, Mazel M, Mazel B, Abhyankar A, Nitschke P, Quintana-Murci L, Boisson-Dupuis S, Boisson B, Abel L, Zhang SY, Casanova JL, HGCS: an online tool for prioritizing disease-causing gene variants by biological distance. BMC Genomics 15, 256 (2014). PubMed PMC

Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C, Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37, e67 (2009). PubMed PMC

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J, A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet 46, 310–315 (2014). PubMed PMC

Itan Y, Shang L, Boisson B, Ciancanelli MJ, Markle JG, Martinez-Barricarte R, Scott E, Shah I, Stenson PD, Gleeson J, Cooper DN, Quintana-Murci L, Zhang SY, Abel L, Casanova JL, The mutation significance cutoff: gene-level thresholds for variant predictions. Nat. Methods 13, 109–110 (2016). PubMed PMC

Itan Y, Shang L, Boisson B, Patin E, Bolze A, Moncada-Velez M, Scott E, Ciancanelli MJ, Lafaille FG, Markle JG, Martinez-Barricarte R, de Jong SJ, Kong XF, Nitschke P, Belkadi A, Bustamante J, Puel A, Boisson-Dupuis S, Stenson PD, Gleeson JG, Cooper DN, Quintana-Murci L, Claverie JM, Zhang SY, Abel L, Casanova JL, The human gene damage index as a gene-level approach to prioritizing exome variants. Proc. Natl. Acad. Sci. U.S.A 112, 13615–13620 (2015). PubMed PMC

McDonald JH, Kreitman M, Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–654 (1991). PubMed

Eilertson KE, Booth JG, Bustamante CD, SnIPRE: selection inference using a Poisson random effects model. PLoS Comput. Biol 8, e1002806 (2012). PubMed PMC

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C, Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016). PubMed PMC

Johnson GL, Nakamura K, The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim. Biophys. Acta 1773, 1341–1348 (2007). PubMed PMC

Hotamisligil GS, Davis RJ, Cell Signaling and Stress Responses. Cold Spring Harb. Perspect. Biol 8, (2016). PubMed PMC

Manning AM, Davis RJ, Targeting JNK for therapeutic benefit: from junk to gold? Nat. Rev. Drug Discov 2, 554–565 (2003). PubMed

Eckhart L, Ban J, Ballaun C, Weninger W, Tschachler E, Reverse transcription-polymerase chain reaction products of alternatively spliced mRNAs form DNA heteroduplexes and heteroduplex complexes. J. Biol. Chem 274, 2613–2615 (1999). PubMed

Gaffen SL, Jain R, Garg AV, Cua DJ, The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol 14, 585–600 (2014). PubMed PMC

Li J, Casanova JL, Puel A, Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation. Mucosal Immunol 11, 581–589 (2018). PubMed PMC

Puel A, Picard C, Cypowyj S, Lilic D, Abel L, Casanova JL, Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines? Curr. Opin. Immunol 22, 467–474 (2010). PubMed PMC

Hernandez-Santos N, Gaffen SL, Th17 cells in immunity to Candida albicans. Cell Host Microbe 11, 425–435 (2012). PubMed PMC

Dong C, Yang DD, Wysk M, Whitmarsh AJ, Davis RJ, Flavell RA, Defective T cell differentiation in the absence of Jnk1. Science 282, 2092–2095 (1998). PubMed

Conze D, Krahl T, Kennedy N, Weiss L, Lumsden J, Hess P, Flavell RA, Le Gros G, Davis RJ, Rincon M, c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J. Exp. Med 195, 811–823 (2002). PubMed PMC

Ichiyama K, Sekiya T, Inoue N, Tamiya T, Kashiwagi I, Kimura A, Morita R, Muto G, Shichita T, Takahashi R, Yoshimura A, Transcription factor Smad-independent T helper 17 cell induction by transforming-growth factor-beta is mediated by suppression of eomesodermin. Immunity 34, 741–754 (2011). PubMed

Zhang YE, Non-Smad Signaling Pathways of the TGF-beta Family. Cold Spring Harb. Perspect. Biol 9, (2017). PubMed PMC

Manel N, Unutmaz D, Littman DR, The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol 9, 641–649 (2008). PubMed PMC

Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V, A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat. Immunol 9, 650–657 (2008). PubMed

Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA, IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454, 350–352 (2008). PubMed PMC

Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, Bustamante J, Okada S, Stoddard JL, Deenick EK, Pelham SJ, Payne K, Boisson-Dupuis S, Puel A, Kobayashi M, Arkwright PD, Kilic SS, El Baghdadi J, Nonoyama S, Minegishi Y, Mahdaviani SA, Mansouri D, Bousfiha A, Blincoe AK, French MA, Hsu P, Campbell DE, Stormon MO, Wong M, Adelstein S, Smart JM, Fulcher DA, Cook MC, Phan TG, Stepensky P, Boztug K, Kansu A, Ikinciogullari A, Baumann U, Beier R, Roscioli T, Ziegler JB, Gray P, Picard C, Grimbacher B, Warnatz K, Holland SM, Casanova JL, Uzel G, Tangye SG, Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J. Allergy Clin. Immunol 136, 993–1006 e1001 (2015). PubMed PMC

Chiarelli N, Carini G, Zoppi N, Dordoni C, Ritelli M, Venturini M, Castori M, Colombi M, Transcriptome-Wide Expression Profiling in Skin Fibroblasts of Patients with Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type. PLoS One 11, e0161347 (2016). PubMed PMC

Zoppi N, Chiarelli N, Ritelli M, Colombi M, Multifaced Roles of the alphavbeta3 Integrin in Ehlers-Danlos and Arterial Tortuosity Syndromes’ Dermal Fibroblasts. Int. J. Mol. Sci. 19, (2018). PubMed PMC

Mendoza-Londono R, Chitayat D, Kahr WH, Hinek A, Blaser S, Dupuis L, Goh E, Badilla-Porras R, Howard A, Mittaz L, Superti-Furga A, Unger S, Nishimura G, Bonafe L, Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am. J. Med. Genet. A 158A, 1344–1354 (2012). PubMed

Syx D, Van Damme T, Symoens S, Maiburg MC, van de Laar I, Morton J, Suri M, Del Campo M, Hausser I, Hermanns-Le T, De Paepe A, Malfait F, Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis. Hum. Mutat 36, 535–547 (2015). PubMed

Zoppi N, Chiarelli N, Binetti S, Ritelli M, Colombi M, Dermal fibroblast-to-myofibroblast transition sustained by alphavss3 integrin-ILK-Snail1/Slug signaling is a common feature for hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Biochim. Biophys. Acta 1864, 1010–1023 (2018). PubMed

Hocevar BA, Brown TL, Howe PH, TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J. 18, 1345–1356 (1999). PubMed PMC

Piek E, Ju WJ, Heyer J, Escalante-Alcalde D, Stewart CL, Weinstein M, Deng C, Kucherlapati R, Bottinger EP, Roberts AB, Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. J. Biol. Chem 276, 19945–19953 (2001). PubMed

Lee CS, Fu H, Baratang N, Rousseau J, Kumra H, Sutton VR, Niceta M, Ciolfi A, Yamamoto G, Bertola D, Marcelis CL, Lugtenberg D, Bartuli A, Kim C, Hoover-Fong J, Sobreira N, Pauli R, Bacino C, Krakow D, Parboosingh J, Yap P, Kariminejad A, McDonald MT, Aracena MI, Lausch E, Unger S, Superti-Furga A, Lu JT, Baylor-Hopkins G Center for Mendelian, Cohn DH, Tartaglia M, Lee BH, Reinhardt DP, Campeau PM, Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with “Corner Fractures”. Am. J. Hum. Genet 101, 815–823 (2017). PubMed PMC

Verrecchia F, Chu ML, Mauviel A, Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J. Biol. Chem 276, 17058–17062 (2001). PubMed

Deere M, Rhoades Hall C, Gunning KB, LeFebvre V, Ridall AL, Hecht JT, Analysis of the promoter region of human cartilage oligomeric matrix protein (COMP). Matrix Biol. 19, 783–792 (2001). PubMed

Oleggini R, Gastaldo N, Di Donato A, Regulation of elastin promoter by lysyl oxidase and growth factors: cross control of lysyl oxidase on TGF-beta1 effects. Matrix Biol. 26, 494–505 (2007). PubMed

Shi-Wen X, Rodriguez-Pascual F, Lamas S, Holmes A, Howat S, Pearson JD, Dashwood MR, du Bois RM, Denton CP, Black CM, Abraham DJ, Leask A, Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors. Mol. Cell. Biol 26, 5518–5527 (2006). PubMed PMC

Tang W, Yang L, Yang YC, Leng SX, Elias JA, Transforming growth factor-beta stimulates interleukin-11 transcription via complex activating protein-1-dependent pathways. J. Biol. Chem 273, 5506–5513 (1998). PubMed

Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES, et al., Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat. Genet 10, 330–336 (1995). PubMed

Zhang MC, He L, Giro M, Yong SL, Tiller GE, Davidson JM, Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN). J. Biol. Chem 274, 981–986 (1999). PubMed

Gordon CT, Petit F, Kroisel PM, Jakobsen L, Zechi-Ceide RM, Oufadem M, Bole-Feysot C, Pruvost S, Masson C, Tores F, Hieu T, Nitschke P, Lindholm P, Pellerin P, Guion-Almeida ML, Kokitsu-Nakata NM, Vendramini-Pittoli S, Munnich A, Lyonnet S, Holder-Espinasse M, Amiel J, Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears. Am. J. Hum. Genet 93, 1118–1125 (2013). PubMed PMC

Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E, Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat. Genet 21, 142–144 (1999). PubMed

Gordon CT, Weaver KN, Zechi-Ceide RM, Madsen EC, Tavares AL, Oufadem M, Kurihara Y, Adameyko I, Picard A, Breton S, Pierrot S, Biosse-Duplan M, Voisin N, Masson C, Bole-Feysot C, Nitschke P, Delrue MA, Lacombe D, Guion-Almeida ML, Moura PP, Garib DG, Munnich A, Ernfors P, Hufnagel RB, Hopkin RJ, Kurihara H, Saal HM, Weaver DD, Katsanis N, Lyonnet S, Golzio C, Clouthier DE, Amiel J, Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia. Am. J. Hum. Genet 96, 519–531 (2015). PubMed PMC

Nieminen P, Morgan NV, Fenwick AL, Parmanen S, Veistinen L, Mikkola ML, van der Spek PJ, Giraud A, Judd L, Arte S, Brueton LA, Wall SA, Mathijssen IM, Maher ER, Wilkie AO, Kreiborg S, Thesleff I, Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. Am. J. Hum. Genet 89, 67–81 (2011). PubMed PMC

van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collee M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM, Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet 43, 121–126 (2011). PubMed

Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, Kempers MJ, Fishman EK, Chen Y, Myers L, Bjeda D, Oswald G, Elias AF, Levy HP, Anderlid BM, Yang MH, Bongers EM, Timmermans J, Braverman AC, Canham N, Mortier GR, Brunner HG, Byers PH, Van Eyk J, Van Laer L, Dietz HC, Loeys BL, Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet 44, 922–927 (2012). PubMed PMC

Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L, De Belder S, Waitzman K, Young L, Markham LW, Vogt J, Richer J, Beauchesne LM, Unger S, Superti-Furga A, Prsa M, Dhillon R, Reyniers E, Dietz HC, Wuyts W, Mortier G, Verstraeten A, Van Laer L, Loeys BL, Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet. Med 19, 386–395 (2017). PubMed PMC

Rincon M, Davis RJ, Regulation of the immune response by stress-activated protein kinases. Immunol. Rev 228, 212–224 (2009). PubMed

Van der Velden J, Janssen-Heininger YM, Mandalapu S, Scheller EV, Kolls JK, Alcorn JF, Differential requirement for c-Jun N-terminal kinase 1 in lung inflammation and host defense. PLoS One 7, e34638 (2012). PubMed PMC

Wang YQ, Ma X, Lu L, Zhao L, Zhang X, Xu Q, Wang Y, Defective antiviral CD8 T-cell response and viral clearance in the absence of c-Jun N-terminal kinases. Immunology 142, 603–613 (2014). PubMed PMC

Sabapathy K, Kallunki T, David JP, Graef I, Karin M, Wagner EF, c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J. Exp. Med 193, 317–328 (2001). PubMed PMC

Li H, Durbin R, Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009). PubMed PMC

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA, The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20, 1297–1303 (2010). PubMed PMC

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome S Project Data Processing, The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009). PubMed PMC

Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ, Okada S, Mandel H, Garcia P, Ciancanelli MJ, Biran A, Lafaille FG, Tsumura M, Cobat A, Luo J, Volpi S, Zimmer B, Sakata S, Dinis A, Ohara O, Garcia Reino EJ, Dobbs K, Hasek M, Holloway SP, McCammon K, Hussong SA, DeRosa N, Van Skike CE, Katolik A, Lorenzo L, Hyodo M, Faria E, Halwani R, Fukuhara R, Smith GA, Galvan V, Damha MJ, Al-Muhsen S, Itan Y, Boeke JD, Notarangelo LD, Studer L, Kobayashi M, Diogo L, Fairbrother WG, Abel L, Rosenberg BR, Hart PJ, Etzioni A, Casanova JL, Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection. Cell 172, 952–965 e918 (2018). PubMed PMC

Lahaye X, Satoh T, Gentili M, Cerboni S, Silvin A, Conrad C, Ahmed-Belkacem A, Rodriguez EC, Guichou JF, Bosquet N, Piel M, Le Grand R, King MC, Pawlotsky JM, Manel N, Nuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication. Cell Rep. 15, 879–892 (2016). PubMed PMC

Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, Torpy J, O’Young P, Deenick E, Bustamante J, Puel A, Okada S, Kobayashi M, Martinez-Barricarte R, Elliott M, Sebnem Kilic S, El Baghdadi J, Minegishi Y, Bousfiha A, Robertson N, Hambleton S, Arkwright PD, French M, Blincoe AK, Hsu P, Campbell DE, Stormon MO, Wong M, Adelstein S, Fulcher DA, Cook MC, Stepensky P, Boztug K, Beier R, Ikinciogullari A, Ziegler JB, Gray P, Picard C, Boisson-Dupuis S, Phan TG, Grimbacher B, Warnatz K, Holland SM, Uzel G, Casanova JL, Tangye SG, Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets. J. Exp. Med 213, 1589–1608 (2016). PubMed PMC

Zoppi N, Gardella R, De Paepe A, Barlati S, Colombi M, Human fibroblasts with mutations in COL5A1 and COL3A1 genes do not organize collagens and fibronectin in the extracellular matrix, down-regulate alpha2beta1 integrin, and recruit alphavbeta3 Instead of alpha5beta1 integrin. J. Biol. Chem 279, 18157–18168 (2004). PubMed

Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP, Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003). PubMed

Gautier L, Cope L, Bolstad BM, Irizarry RA, affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20, 307–315 (2004). PubMed

Alsina L, Israelsson E, Altman MC, Dang KK, Ghandil P, Israel L, von Bernuth H, Baldwin N, Qin H, Jin Z, Banchereau R, Anguiano E, Ionan A, Abel L, Puel A, Picard C, Pascual V, Casanova JL, Chaussabel D, A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4. Nat. Immunol 15, 1134–1142 (2014). PubMed PMC

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR, STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013). PubMed PMC

Anders S, Pyl PT, Huber W, HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015). PubMed PMC

Love MI, Huber W, Anders S, Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014). PubMed PMC

Gu Z, Eils R, Schlesner M, Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016). PubMed

Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israel A, Heiss NS, Klauck SM, Kioschis P, Wiemann S, Poustka A, Esposito T, Bardaro T, Gianfrancesco F, Ciccodicola A, D’Urso M, Woffendin H, Jakins T, Donnai D, Stewart H, Kenwrick SJ, Aradhya S, Yamagata T, Levy M, Lewis RA, Nelson DL, Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405, 466–472 (2000). PubMed

Ritelli M, Dordoni C, Venturini M, Chiarelli N, Quinzani S, Traversa M, Zoppi N, Vascellaro A, Wischmeijer A, Manfredini E, Garavelli L, Calzavara-Pinton P, Colombi M, Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J. Rare Dis 8, 58 (2013). PubMed PMC

von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Arostegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yague J, Anton J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Marodi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A, Casanova JL, Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691–696 (2008). PubMed PMC

van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM, van Meer BL, Pals G, Oldenburg RA, Bekkers JA, Moelker A, de Graaf BM, Matyas G, Frohn-Mulder IM, Timmermans J, Hilhorst-Hofstee Y, Cobben JM, Bruggenwirth HT, van Laer L, Loeys B, De Backer J, Coucke PJ, Dietz HC, Willems PJ, Oostra BA, De Paepe A, Roos-Hesselink JW, Bertoli-Avella AM, Wessels MW, Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J. Med. Genet 49, 47–57 (2012). PubMed