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The Family of Crumbs Genes and Human Disease
1Department of Pediatrics, UCSF School of Medicine, University of California San Francisco, San Francisco, Calif., USA.
Insights
Deleterious mutations in Crumbs homolog-1 (CRB1) and Crumbs homolog-2 (CRB2) genes cause distinct human diseases. This review summarizes CRB1 and CRB2 associated phenotypes, genetic variations, and disease mechanisms.
Area of Science:
- Genetics
- Molecular Biology
- Human Disease
Background:
- Vertebrate Crumbs (Crb) proteins are homologous to Drosophila Crb and possess conserved structural domains.
- The human genome contains three Crumbs homolog genes: CRB1, CRB2, and CRB3.
- CRB1 and CRB2 are implicated in human diseases, while CRB3 has no known disease association.
Approach:
- This review summarizes phenotypic findings from deleterious sequence variants in CRB1 and CRB2.
- It discusses the mutational spectrum and loss-of-function animal models for CRB1 and CRB2.
- The review speculates on potential disease mechanisms.
Key Points:
- Loss-of-function mutations in CRB1 cause Leber's congenital amaurosis and retinitis pigmentosa.
- CRB2 mutations are associated with elevated maternal alpha-fetoprotein, ventriculomegaly/hydrocephalus, and renal diseases.
- CRB3 is not yet linked to human disease.
Conclusions:
- CRB1 and CRB2 play critical roles in human health, with distinct disease associations.
- Understanding the mutational landscape and disease mechanisms of CRB1 and CRB2 is crucial for diagnosis and potential therapeutic strategies.
- Further research into CRB3 may reveal its role in human health and disease.
Abstract:
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.
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