title: Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization.
abstract: Correct morphogenesis and differentiation are critical in development and maintenance of the lens, which is a classic model system for epithelial development and disease. Through germline genomic analyses in patients with lens and eye abnormalities, we discovered functional mutations in the Signal Induced Proliferation Associated 1 Like 3 (SIPA1L3) gene, which encodes a previously uncharacterized member of the Signal Induced Proliferation Associated 1 (SIPA1 or SPA1) family, with a role in Rap1 signalling. Patient 1, with a de novo balanced translocation, 46,XY,t(2;19)(q37.3;q13.1), had lens and ocular anterior segment abnormalities. Breakpoint mapping revealed transection of SIPA1L3 at 19q13.1 and reduced SIPA1L3 expression in patient lymphoblasts. SIPA1L3 downregulation in 3D cell culture revealed morphogenetic and cell polarity abnormalities. Decreased expression of Sipa1l3 in zebrafish and mouse caused severe lens and eye abnormalities. Sipa1l3(-/-) mice showed disrupted epithelial cell organization and polarity and, notably, abnormal epithelial to mesenchymal transition in the lens. Patient 2 with cataracts was heterozygous for a missense variant in SIPA1L3, c.442G>T, p.Asp148Tyr. Examination of the p.Asp148Tyr mutation in an epithelial cell line showed abnormal clustering of actin stress fibres and decreased formation of adherens junctions. Our findings show that abnormalities of SIPA1L3 in human, zebrafish and mouse contribute to lens and eye defects, and we identify a critical role for SIPA1L3 in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organization.
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Greenlees
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Marija
authors.initials: M
authors.lastname: Mihelec
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Saira
authors.initials: S
authors.lastname: Yousoof
authors.affiliation: Cell Transformation Group, Children's Medical Research Institute, Sydney Medical School.
authors.forename: Daniel
authors.initials: D
authors.lastname: Speidel
authors.affiliation: Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
authors.forename: Selwin K
authors.initials: SK
authors.lastname: Wu
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School.
authors.forename: Silke
authors.initials: S
authors.lastname: Rinkwitz
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Prokudin
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Oxford Rd, Manchester, UK and.
authors.forename: Rahat
authors.initials: R
authors.lastname: Perveen
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Anson
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: Ma
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nash
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Oxford Rd, Manchester, UK and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Gillespie
authors.affiliation: Embryology Unit, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.
authors.forename: David A F
authors.initials: DA
authors.lastname: Loebel
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Oxford Rd, Manchester, UK and Central Manchester Hospital NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, Oxford Rd, Manchester, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Oxford Rd, Manchester, UK and Central Manchester Hospital NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, Oxford Rd, Manchester, UK.
authors.forename: I Christopher
authors.initials: IC
authors.lastname: Lloyd
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Grigg
authors.affiliation: Embryology Unit, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
authors.affiliation: Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
authors.forename: Alpha S
authors.initials: AS
authors.lastname: Yap
authors.affiliation: Brain and Mind Research Institute, Sydney Medical School.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Becker
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Oxford Rd, Manchester, UK and Central Manchester Hospital NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, Oxford Rd, Manchester, UK.
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Semina
authors.affiliation: Eye Genetics Research Group, Children's Medical Research Institute, The University of Sydney; The Children's Hospital at Westmead; and Save Sight Institute, Sydney, NSW, Australia, rjamieson@cmri.org.au.
authors.forename: Robyn V
authors.initials: RV
authors.lastname: Jamieson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016764:Cell Polarity / Q000235:genetics; D003599:Cytoskeleton / Q000648:ultrastructure*; D004252:DNA Mutational Analysis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; C430803:RAP1A protein, human; C000609021:SIPA1L3 protein, mouse; C000609022:SIPA1L3 protein, zebrafish; D029961:Zebrafish Proteins; C000609020:signal-induced proliferation-associated 1-like protein 3, human; D020827:rap1 GTP-Binding Proteins