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

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


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cataract / genetics
  • Cataract / metabolism
  • Cataract / physiopathology*
  • Cell Polarity* / genetics
  • Cytoskeleton / ultrastructure*
  • DNA Mutational Analysis
  • Epithelial-Mesenchymal Transition / genetics
  • Eye Abnormalities / genetics
  • Eye Abnormalities / metabolism
  • Eye Abnormalities / physiopathology*
  • GTPase-Activating Proteins / genetics*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Signal Transduction
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics*
  • rap1 GTP-Binding Proteins / metabolism


  • GTPase-Activating Proteins
  • RAP1A protein, human
  • SIPA1L3 protein, mouse
  • SIPA1L3 protein, zebrafish
  • Zebrafish Proteins
  • signal-induced proliferation-associated 1-like protein 3, human
  • rap1 GTP-Binding Proteins