Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1Ndr/Ndr mice, using retina as a model. Jag1Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1Ndr/Ndr mice represent a new model for vascular compromise in ALGS.

CEITEC Central European Institute of Technology Brno University of Technology Brno Czech Republic

Department of Cell and Molecular Biology Karolinska Institutet Stockholm Sweden

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Experimental Biology Masaryk University Brno Czech Republic

Department of Medical Biochemistry and Biophysics Karolinska Institutet Stockholm Sweden

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Ophthalmology University of Muenster Medical Center Münster Germany

Department of Orthodontics Faculty of Dentistry Assiut University Assiut Egypt

Department of Pediatric Ophthalmology Strabismus Electrophysiology and Ocular Oncology St Erik Eye Hospital Karolinska Institutet Stockholm Sweden

Department of Pediatrics Clinical Science Intervention and Technology Karolinska Institutet and Karolinska University Hospital Huddinge Sweden

EM Unit Institute of Biomedicine University of Gothenburg Gothenburg Sweden

Travere Therapeutics San Diego CA USA

University of Applied Sciences Utrecht Utrecht The Netherlands

University of San Francisco San Francisco CA USA

Zobrazit více v PubMed

Agrawal S, Chennuri V, Agrawal P (2015) Genetic diagnosis in an Indian child with Alagille syndrome. Indian J Pediatr 82: 653–654 PubMed

Alagille D, Odièvre M, Gautier M, Dommergues JP (1975) Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 86: 63–71 PubMed

Alagille D, Estrada A, Hadchouel M, Gautler M, Odièvre M, Dommergues JP (1987) Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 110: 195–200 PubMed

Alten F, Motte J, Ewering C, Osada N, Clemens CR, Kadas EM, Eter N, Paul F, Marziniak M (2014) Multimodal retinal vessel analysis in CADASIL patients. PLoS One 9: e112311 PubMed PMC

Andersson ER, Chivukula IV, Hankeova S, Sjöqvist M, Tsoi YL, Ramsköld D, Masek J, Elmansuri A, Hoogendoorn A, Vazquez E et al (2018) Mouse model of Alagille syndrome and mechanisms of jagged1 missense mutations. Gastroenterology 154: 1080–1095 PubMed PMC

Appelros P, Åsberg S (2020) Sex differences in stroke. Handb Clin Neurol 175: 299–312 PubMed

Arboleda‐Velasquez JF, Manent J, Lee JH, Tikka S, Ospina C, Vanderburg CR, Frosch MP, Rodríguez‐Falcón M, Villen J, Gygi S et al (2011) Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small‐vessel disease. Proc Natl Acad Sci U S A 108: E128 PubMed PMC

Armulik A, Genove G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K et al (2010) Pericytes regulate the blood–brain barrier. Nature 468: 557–561 PubMed

Baird LC, Smith ER, Ichord R, Piccoli DA, Bernard TJ, Spinner NB, Scott RM, Kamath BM (2015) Moyamoya syndrome associated with Alagille syndrome: outcome after surgical revascularization. J Pediatr 166: 470–473 PubMed

Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137: 1124–1135 PubMed

Berard E, Sarles J, Triolo V, Gagnadoux MF, Wernert F, Hadchouel M, Niaudet P (1998) Renovascular hypertension and vascular anomalies in Alagille syndrome. Pediatr Nephrol 12: 121–124 PubMed

Bucuvalas JC, Horn JA, Carlsson L, Balistreri WF, Chernausek SD (1993) Growth hormone insensitivity associated with elevated circulating growth hormone‐binding protein in children with Alagille syndrome and short stature. J Clin Endocrinol Metab 76: 1477–1482 PubMed

Carpenter CD, Linscott LL, Leach JL, Vadivelu S, Abruzzo T (2018) Spectrum of cerebral arterial and venous abnormalities in Alagille syndrome. Pediatr Radiol 48: 602–608 PubMed

Chen RF (1973) The fluorescence of bilirubin‐albumin complexes. In Fluorescence techniques in cell biology, Thaer AA, Sernetz M (eds), pp 273–282. Berlin, Heidelberg: Springer Berlin Heidelberg;

Cowan JA, Barkhoudarian G, Yang LJS, Thompson BG (2004) Progression of a posterior communicating artery infundibulum into an aneurysm in a patient with Alagille syndrome. Case report. J Neurosurg 101: 694–696 PubMed

Crosnier C, Attié‐Bitach T, Encha‐Razavi F, Audollent S, Soudy F, Hadchouel M, Meunier‐Rotival M, Vekemans M (2000) JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology 32: 574–581 PubMed

Doberentz E, Kuchelmeister K, Madea B (2015) Subarachnoid hemorrhage due to aneurysm rupture in a young woman with Alagille syndrome ‐ a rare cause of sudden death. Leg Med 17: 309–312 PubMed

El‐Koofy NM, El‐Mahdy R, Fahmy ME, El‐Hennawy A, Farag MY, El‐Karaksy HM (2011) Alagille syndrome: clinical and ocular pathognomonic features. Eur J Ophthalmol 21: 199–206 PubMed

Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA (1999) Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 29: 822–829 PubMed

Emerick KM, Krantz ID, Kamath BM, Darling C, Burrowes DM, Spinner NB, Whitington PF, Piccoli DA (2005) Intracranial vascular abnormalities in patients with Alagille syndrome. J Pediatr Gastroenterol Nutr 41: 99–107 PubMed

Fahnehjelm KT, Wide K, Ygge J, Hellström A, Tomson T, Winbladh B, Strömland K (1999) Visual and ocular outcome in children after prenatal exposure to antiepileptic drugs. Acta Ophthalmol Scand 77: 530–535 PubMed

Fahnehjelm KT, Fischler B, Martin L, Nemeth A (2011) Occurrence and pattern of ocular disease in children with cholestatic disorders. Acta Ophthalmol 89: 143–150 PubMed

Fiorda‐Diaz J, Shabsigh M, Dimitrova G, Soghomonyan S, Sandhu G (2017) Perioperative management of subarachnoid hemorrhage in a patient with alagille syndrome and unrepaired tetralogy of fallot: case report. Front Surg 4: 72 PubMed PMC

Frongillo F, Bianco G, Silvestrini N, Lirosi MC, Sanchez AM, Nure E, Gaspari R, Avolio AW, Sganga G, Agnes S (2015) Acute liver failure in an adult, a rare complication of Alagille syndrome: case report and brief review. Transplant Proc 47: 2179–2181 PubMed

Fuentes AM, Du X, Pandey DK, Ansari SA, Amin‐hanjani S (2022) Abstract WP149: Mechanical thrombectomy for ischemic stroke: evaluating outcome associations with race. Stroke 53: AWP149 PubMed

Gaba RC, Shah RP, Muskovitz AA, Guzman G, Michals EA (2008) Synchronous moyamoya syndrome and ruptured cerebral aneurysm in Alagille syndrome. J Clin Neurosci 15: 1395–1398 PubMed

Han HC (2012) Twisted blood vessels: Symptoms, etiology and biomechanical mechanisms. J Vasc Res 49: 185–197 PubMed PMC

Hankeova S, Salplachta J, Zikmund T, Kavkova M, Hul V, Brinek A, Smekalova V, Laznovsky J, Lendahl U, Ellis E et al (2021) DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome. eLife 10: e60916 PubMed PMC

Henshall TL, Keller A, He L, Johansson BR, Wallgard E, Raschperger E, Andaloussi Mae M, Jin S, Betsholtz C, Lendahl U (2015) Notch3 is necessary for blood vessel integrity in the central nervous system. Arterioscler Thromb Vasc Biol 35: 409–420 PubMed

High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci U S A 105: 1955–1959 PubMed PMC

Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli‐Vergani G, Bird AC, Aclimandos WA (1999) Ocular abnormalities in Alagille syndrome. Ophthalmology 106: 330–337 PubMed

Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ (1995) Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 127: 220–224 PubMed

Hughes AD, Falaschetti E, Witt N, Wijetunge S, Thom SAMG, Tillin T, Aldington SJ, Chaturvedi N (2016) Association of retinopathy and retinal microvascular abnormalities with stroke and cerebrovascular disease. Stroke 47: 2862–2864 PubMed PMC

Jin S, Hansson EM, Tikka S, Lanner F, Sahlgren C, Farnebo F, Baumann M, Kalimo H, Lendahl U (2008) Notch signaling regulates platelet‐derived growth factor receptor‐β expression in vascular smooth muscle cells. Circ Res 102: 1483–1491 PubMed

Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E et al (1996) Notch3 mutations in CADASIL, a hereditary adult‐onset condition causing stroke and dementia. Nature 383: 707–710 PubMed

Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID (2004) Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 109: 1354–1358 PubMed

Kazi R, Fakhoury J, Beck R (2018) A case of recurrent intracranial bleeds in the setting of Alagille syndrome. Pediatrics 142: 52

Kergoat H, Herard M‐E, Lemay M (2006) RGC sensitivity to mild systemic hypoxia. Invest Ophthalmol Vis Sci 47: 5423–5427 PubMed

Kim BJ, Fulton AB (2007) The genetics and ocular findings of Alagille syndrome. Semin Ophthalmol 22: 205–210 PubMed

Kwa VIH, van der Sande JJ, Stam J, Tijmes N, Vrooland JL, Amsterdam Vascular Medicine Group (2002) Retinal arterial changes correlate with cerebral small‐vessel disease. Neurology 59: 1536–1540 PubMed

Lentz R, Merrick C, Rickman O, Maldonado F (2016) Endobronchial Nd:YAP laser ablation of a bleeding dieulafoy lesion of the bronchus. Chest 150: 989A PubMed

Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J et al (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16: 243–251 PubMed

Lykavieris P, Crosnier C, Trichet C, Meunier‐Rotival M, Hadchouel M (2003) Bleeding tendency in children with Alagille syndrome. Pediatrics 111: 167–170 PubMed

Machuca‐Parra AI, Bigger‐Allen AA, Sanchez A v, Boutabla A, Cardona‐Vélez J, Amarnani D, Saint‐Geniez M, Siebel CW, Kim LA, D'Amore PA et al (2017) Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exp Med 214: 282 PubMed PMC

Martin G, Wefelmeyer KL, Bucher F, Schlunck G, Agostini HT (2020) Arteriovenous crossing in retinal vessels of mice, rats, and pigs. Mol Vis 26: 731–741 PubMed PMC

Mašek J, Andersson ER (2017) The developmental biology of genetic Notch disorders. Development 144: 1743–1763 PubMed

Matsuura G, Higashimoto Y, Iwai J, Murayama K, Horie H, Suzuki T (2013) A case of Alagille syndrome with hepatic‐duct obliteration presenting intracranial hemorrhage. Chiba Med J 89: 181–185

McDaniell R, Warthen DM, Sanchez‐Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79: 169–173 PubMed PMC

Mhurchu CN, Anderson C, Jamrozik K, Hankey G, Dunbabin D (2001) Hormonal factors and risk of aneurysmal subarachnoid hemorrhage: an international population‐based, case–control study cliona. Stroke 32: 606–612 PubMed

Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, Chen J, He J (2016) Global disparities of hypertension prevalence and control: a systematic analysis of population‐based studies from 90 countries. Circulation 134: 441–450 PubMed PMC

Narula P, Gifford J, Steggall MA, Lloyd C, Van Mourik IDM, Mckiernan PJ, Willshaw HE, Kelly D (2006) Visual loss and idiopathic intracranial hypertension in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 43: 348–352 PubMed

Nelis P, Kleffner I, Burg MC, Clemens CR, Alnawaiseh M, Motte J, Marziniak M, Eter N, Alten F (2018) OCT‐angiography reveals reduced vessel density in the deep retinal plexus of CADASIL patients. Sci Rep 8: 1–7 PubMed PMC

O'Connell D, Kaliaperumal C, Fanning N, Wyse G, Kaar G (2012) Superior cerebellar aneurysm causing subarachnoid haemorrhage in a 17‐year‐old with alagille syndrome. Br J Neurosurg 26: 287–289 PubMed

Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS et al (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16: 235–242 PubMed

O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao‐Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ et al (2010) Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case–control study. Lancet 376: 112–123 PubMed

Ong YT, de Silva DA, Cheung CY, Chang HM, Chen CP, Wong MC, Wong TY, Ikram MK (2013) Microvascular structure and network in the retina of patients with ischemic stroke. Stroke 44: 2121–2127 PubMed

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev 10: 89 PubMed PMC

Petaros A, Miletic D, Stifter S, Slaus M, Stemberga V (2015) Alagille syndrome case report: implications for forensic pathology and anthropology. Int J Legal Med 129: 543–549 PubMed

Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16: 196–208 PubMed

Pippucci T, Maresca A, Magini P, Cenacchi G, Palombo F, Papa V, Incensi A, Gasparre G, Lucia M, Preziuso C et al (2015) Homozygous NOTCH 3 null mutation and impaired NOTCH 3 signaling in recessive early‐onset arteriopathy and cavitating leukoencephalopathy. EMBO Mol Med 7: 848–858 PubMed PMC

Qiao CZ, Richter GT, Pan WJ, Jin YB, Lin XX (2019) Extracranial arteriovenous malformations: from bedside to bench. Mutagenesis 34: 299–306 PubMed

Quiros‐Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall TR, McDiarmid SV, Vargas JH (1999) Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 29: 431–437 PubMed

Qureshi AI, Malik AA, Saeed O, Defillo A, Sherr GT, Suri MFK (2016) Hormone replacement therapy and the risk of subarachnoid hemorrhage in postmenopausal women. J Neurosurg 124: 45–50 PubMed

Rachmel A, Zeharia A, Neuman‐Levin M, Weitz R, Shamir R, Dinari G (1989) Alagille syndrome associated with Moyamoya disease. Am J Med Genet 33: 89–91 PubMed

Reagan AM, Gu X, Paudel S, Ashpole NM, Zalles M, Sonntag WE, Ungvari Z, Csiszar A, Otalora L, Freeman WM et al (2018) Age‐related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin‐1 deficiency. Neurobiol Aging 71: 1–12 PubMed PMC

Renier N, Adams EL, Kirst C, Wu Z, Azevedo R, Kohl J, Autry AE, Kadiri L, Umadevi Venkataraju K, Zhou Y et al (2016) Mapping of brain activity by automated volume analysis of immediate early genes. Cell 165: 1789–1802 PubMed PMC

Rensen SSM, Doevendans PAFM, van Eys GJJM (2007) Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J 15: 100–108 PubMed PMC

Rim TH, Teo AWJ, Yang HHS, Cheung CY, Wong TY (2020) Retinal vascular signs and cerebrovascular diseases. J Neuroophthalmol 40: 44–59 PubMed

Rocha R, Soro MI, Leitão A, Luís M, Md S, Leão MM (2012) Moyamoya vascular pattern in Alagille syndrome. Pediatr Neurol 47: 125–128 PubMed

de Rooij NK, Linn FHH, van der Plas JA, Algra A, Rinkel GJE (2007) Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 78: 1365–1372 PubMed PMC

Ruchoux MM, Domenga V, Brulin P, Maciazek J, Limol S, Tournier‐Lasserve E, Joutel A (2003) Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol 162: 329–342 PubMed PMC

Ruigrok YM, Buskens E, Rinkel GJE (2001) Attributable risk of common and rare determinants of subarachnoid hemorrhage. Stroke 32: 1173–1175 PubMed

Sanada Y, Naya I, Katano T, Hirata Y, Yamada N, Okada N, Ihara Y, Onishi Y, Mizuta K (2019) Visceral artery anomalies in patients with Alagille syndrome. Pediatr Transplant 23: e13352 PubMed

Sanes JR, Masland RH (2015) The types of retinal ganglion cells: current status and implications for neuronal classification. Annu Rev Neurosci 38: 221–246 PubMed

Santamaria R, Lopez‐Aguilera J, Gonzalez De Caldas R, Sanchez‐Frias M, Garcia‐Rios A, Buendia P, Aljama P (2016) Vascular abnormalities as predominant feature in alagille syndrome patients with a novel mutation in JAG1 gene. J Hypertens 34: e180

Schlosser H‐G, Kerner T, Woiciechowsky C, Benndorf G (2004) Multiple cerebral aneurysms and subarachnoid hemorrhage in a patient with Alagille syndrome. AJNR Am J Neuroradiol 25: 1366–1367 PubMed PMC

Seals DR, Jablonski KL, Donato AJ (2011) Aging and vascular endothelial function in humans. Clin Sci 120: 357–375 PubMed PMC

Secomb TW (2016) Hemodynamics. Compr Physiol 6: 975–1003 PubMed PMC

Sheth HS, Maldonado F, Lentz RJ (2018) Two cases of Dieulafoy lesions of the bronchus with novel comorbid associations and endobronchial ablative management. Medicine 97: e9754 PubMed PMC

Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI et al (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51: 2813–2826 PubMed PMC

Thakurdas SM, Lopez MF, Kakuda S, Fernandez‐Valdivia R, Zarrin‐Khameh N, Haltiwanger RS, Jafar‐Nejad H (2016) Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63: 550–565 PubMed PMC

Tiede A, Zieger B, Lisman T (2022) Acquired bleeding disorders. Haemophilia 28: 68–76 PubMed

Tumialán LM, Dhall SS, Tomak PR, Barrow DL (2006) Alagille syndrome and aneurysmal subarachnoid hemorrhage. Pediatr Neurosurg 42: 57–61 PubMed

Vandriel SM, Li L‐T, She H, Wang J‐S, Gilbert MA, Jankowska I, Czubkowski P, Gliwicz‐Miedzińska D, Gonzales EM, Jacquemin E et al (2022) Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA study. Hepatology 10.1002/hep.32761 PubMed DOI PMC

Vlak MHM, Rinkel GJE, Greebe P, Greving JP, Algra A (2013) Lifetime risks for aneurysmal subarachnoid haemorrhage: multivariable risk stratification. J Neurol Neurosurg Psychiatry 84: 619–623 PubMed

Volz KS, Jacobs AH, Chen HI, Poduri A, McKay AS, Riordan DP, Kofler N, Kitajewski J, Weissman I, Red‐Horse K (2015) Pericytes are progenitors for coronary artery smooth muscle. eLife 4: e10036 PubMed PMC

Vorstman EBA, Anslow P, Keeling DM, Haythornthwaite G, Bilolikar H, McShane MT (2003) Brain haemorrhage in five infants with coagulopathy. Arch Dis Child 88: 1119–1121 PubMed PMC

Wang G‐X, Zhang D, Wang Z‐P, Yang L‐Q, Yang H, Li W (2018) Risk factors for ruptured intracranial aneurysms. Indian J Med Res 147: 51–57 PubMed PMC

Wang X, Carcel C, Woodward M, Schutte AE (2022) Blood pressure and stroke: a review of sex‐ and ethnic/racial‐specific attributes to the epidemiology, pathophysiology, and management of raised blood pressure. Stroke 53: 1114–1133 PubMed

Woolfenden AR, Albers GW, Steinberg GK, Hahn JS, Johnston DCC, Farrell K (1999) Moyamoya syndrome in children with Alagille syndrome: additional evidence of a vasculopathy. Pediatrics 103: 505–508 PubMed

Xiromerisiou G, Marogianni C, Dadouli K, Zompola C, Georgouli D, Provatas A, Theodorou A, Zervas P, Nikolaidou C, Stergiou S et al (2020) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: genotype–phenotype correlations of all published cases. Neurol Genet 6: e434 PubMed PMC

Zuurbier CCM, Molenberg R, Mensing LA, Wermer MJH, Juvela S, Lindgren AE, Jääskeläinen JE, Koivisto T, Yamazaki T, Uyttenboogaart M et al (2022) Sex difference and rupture rate of intracranial aneurysms: an individual patient data meta‐analysis. Stroke 53: 362–369 PubMed PMC

Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects