Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization. Hum Mol Genet 2015 Oct 15;24(20):5789-804
Date
08/02/2015Pubmed ID
26231217DOI
10.1093/hmg/ddv298Scopus ID
2-s2.0-84943766596 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Greenlees R, Mihelec M, Yousoof S, Speidel D, Wu SK, Rinkwitz S, Prokudin I, Perveen R, Cheng A, Ma A, Nash B, Gillespie R, Loebel DA, Clayton-Smith J, Lloyd IC, Grigg JR, Tam PP, Yap AS, Becker TS, Black GC, Semina E, Jamieson RVAuthor
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Cataract
Cell Polarity
Cytoskeleton
DNA Mutational Analysis
Epithelial-Mesenchymal Transition
Eye Abnormalities
GTPase-Activating Proteins
Humans
Mice
Molecular Sequence Data
Mutation
Signal Transduction
Zebrafish
Zebrafish Proteins
rap1 GTP-Binding Proteins