title: Generation of heterozygous fibrillin-1 mutant cloned pigs from genome-edited foetal fibroblasts.
abstract: Marfan syndrome (MFS) is an autosomal dominant genetic disease caused by abnormal formation of the extracellular matrix with an incidence of 1 in 3, 000 to 5, 000. Patients with Marfan syndrome experience poor quality of life caused by skeletal disorders such as scoliosis, and they are at high risk of sudden death from cardiovascular impairment. Suitable animal models of MFS are essential for conquering this intractable disease. In particular, studies employing pig models will likely provide valuable information that can be extrapolated to humans because of the physiological and anatomical similarities between the two species. Here we describe the generation of heterozygous fibrillin-1 (FBN1) mutant cloned pigs (+/Glu433AsnfsX98) using genome editing and somatic cell nuclear transfer technologies. The FBN1 mutant pigs exhibited phenotypes resembling those of humans with MFS, such as scoliosis, pectus excavatum, delayed mineralization of the epiphysis and disrupted structure of elastic fibres of the aortic medial tissue. These findings indicate the value of FBN1 mutant pigs as a model for understanding the pathogenesis of MFS and for developing treatments.
authors.affiliation: Meiji University International Institute for Bio-Resource Research, Kawasaki, 214-8571, Japan.|Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Umeyama
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Meiji University International Institute for Bio-Resource Research, Kawasaki, 214-8571, Japan.|Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.|Anti-aging Orthopaedic Research, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.affiliation: Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Kitashiro
authors.affiliation: Meiji University International Institute for Bio-Resource Research, Kawasaki, 214-8571, Japan.|Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Matsunari
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Arima
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Oltea
authors.initials: O
authors.lastname: Sampetrean
authors.affiliation: Meiji University International Institute for Bio-Resource Research, Kawasaki, 214-8571, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagaya
authors.affiliation: Division of Operative Dentistry, Department of Restorative Dentistry, Tohoku University Graduate School of Dentistry, Sendai, 980-8575, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Saito
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Center for Medical Genetics, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
authors.affiliation: Meiji University International Institute for Bio-Resource Research, Kawasaki, 214-8571, Japan.|Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagashima
authors.affiliation: Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Morio
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D002999:Clone Cells; D004195:Disease Models, Animal; D000071838:Fibrillin-1 / Q000235:genetics*; D005347:Fibroblasts / Q000502:physiology; D000072669:Gene Editing; D006579:Heterozygote; D008382:Marfan Syndrome / Q000235:genetics / Q000473:pathology; D053652:Nuclear Transfer Techniques; D030781:Organisms, Genetically Modified; D013552:Swine / Q000235:genetics*
chemical_list: D000071838:Fibrillin-1