The family of vertebrate Crumbs
proteins, homologous to Drosophila Crumbs (Crb), share large extracellular domains with
epidermal growth factor-like repeats and
laminin-globular domains, a single transmembrane domain, and a short intracellular C-terminus containing a single membrane proximal 4.1/
ezrin/
radixin/
moesin-binding domain and PSD-95/Discs large/ZO-1-binding motifs. There are 3 Crb genes in humans - Crumbs homolog-1 (CRB1), Crumbs homolog-2 (CRB2), and Crumbs homolog-3 (CRB3). Bilallelic loss-of-function mutations in CRB1 cause
visual impairment, with Leber's congenital
amaurosis and
retinitis pigmentosa, whereas CRB2 mutations are associated with raised maternal serum and amniotic fluid alpha feto-
protein levels, ventriculomegaly/
hydrocephalus, and renal disease, ranging from
focal segmental glomerulosclerosis to congenital Finnish
nephrosis. CRB3 has not yet been associated with human disease. In this review, we summarize the phenotypic findings associated with deleterious sequence variants in CRB1 and CRB2. We discuss the mutational spectrum, animal models of loss of function for both genes and speculate on the likely mechanisms of disease.