SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract

Abstract

Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1-q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation-associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase-activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens-enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts.

A 16.7 kb deletion in Sipa1l3 is associated with juvenile cataract in mice

“…It is less clear if the early cataract is a result of the truncated protein being abnormally folded or if the missing domains influence interactions with other critical proteins such as Rap1 or 14-3-3ζ. Evers et al (2015) found that a truncated Sipa1l3, lacking the last 249 amino acids of the C-terminal domain of the SPAR protein, was sufficient to cause cataracts. Future studies will need to establish the specific impact of each domain in eye development and pathways that lead to early cataract formation.…”

“…A recent study employing exome sequencing uncovered a nonsense variant (c.4489C>T; p.R1497*) in Sipa1l3 in siblings with congenital cataract (Evers et al 2015). The peptide encoded by this variant is truncated and contains the Rap-GAP and PDZ domains, but includes only a small fragment of the C-terminal domain of the SPAR protein.…”

“…The Rap-GAP domain is specific for Rap1, which is a GTP-binding protein and suggested, like other small GTPases, to be involved in functions associated with lens development (Rao et al 1997). The PDZ domain was predicted to interact with 14-3-3ζ (YWHAZ), an isoform from a family of essential intracellular signaling molecules in human lenses (Evers et al 2015) and suggested to be involved in cataract formation (Lichtstein et al 2000). The role of the Cterminal domain of the SPAR protein is less known.…”

“…A large proportion of congenital or juvenile cataract conditions have a genetic source that is usually monogenic, but also characterized by heterogeneity (Pichi et al 2016). Currently, there are more than 20 known genes involved in congenital, infantile or juvenile cataract (Evers et al 2015). Mouse models have been used extensively in genetic research of these conditions, with over 400 reported loci associated with cataract across different strains including spontaneous and chemically or radiation-induced mutations (http://www.informatics.jax.org/).…”

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation

“…Recently, the SIPA1L3 gene has also been associated with congenital human cataracts (Evers et al, 2015;Greenlees et al, 2015). SIPA1L3 is a member of the signal-induced proliferationassociated [SIPA, also known as the spine-associated rap-gap (SPAR)] proteins.…”