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Hum Mol Genet. 2015 Oct 15;24(20):5789-804. doi: 10.1093/hmg/ddv298. Epub 2015 Jul 30.

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

Author information

1
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.
2
Cell Transformation Group, Children's Medical Research Institute, Sydney Medical School.
3
Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, Queensland, Australia.
4
Brain and Mind Research Institute, Sydney Medical School.
5
Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Oxford Rd, Manchester, UK and.
6
Embryology Unit, Children's Medical Research Institute, University of Sydney, Sydney, NSW, Australia.
7
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.
8
Medical College of Wisconsin, Milwaukee, WI, USA.
9
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.

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.

PMID:
26231217
DOI:
10.1093/hmg/ddv298
[Indexed for MEDLINE]

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