Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization

Greenlees, Rebecca, Mihelec, Marija, Yousoof, Saira, Speidel, Daniel, Wu, Selwin K., Rinkwitz, Silke, Prokudin, Ivan, Perveen, Rahat, Cheng, Anson, Ma, Alan, Nash, Benjamin, Gillespie, Rachel, Loebel, David A. F., Clayton-Smith, Jill, Lloyd, I. Christopher, Grigg, John R., Tam, Patrick P. L., Yap, Alpha S., Becker, Thomas S., Black, Graeme C. M., Semina, Elena and Jamieson, Robyn V. (2015) Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization. Human Molecular Genetics, 24 20: 5789-5804. doi:10.1093/hmg/ddv298

Author Greenlees, Rebecca
Mihelec, Marija
Yousoof, Saira
Speidel, Daniel
Wu, Selwin K.
Rinkwitz, Silke
Prokudin, Ivan
Perveen, Rahat
Cheng, Anson
Ma, Alan
Nash, Benjamin
Gillespie, Rachel
Loebel, David A. F.
Clayton-Smith, Jill
Lloyd, I. Christopher
Grigg, John R.
Tam, Patrick P. L.
Yap, Alpha S.
Becker, Thomas S.
Black, Graeme C. M.
Semina, Elena
Jamieson, Robyn V.
Title Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 1460-2083
Publication date 2015-06-05
Sub-type Article (original research)
DOI 10.1093/hmg/ddv298
Open Access Status Not Open Access
Volume 24
Issue 20
Start page 5789
End page 5804
Total pages 16
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 8 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 27 Oct 2015, 12:19:21 EST by System User on behalf of Scholarly Communication and Digitisation Service