Human Disease Model Report: retinal disease, CRB1-related

General Information

Name

retinal disease, CRB1-related

FlyBase ID

FBhh0000572

Disease Ontology Term

retinal disease

Parent Disease

OMIM

Overview

A number of retinal diseases are associated with defects in the CRB1 gene, which plays a role in the morphogenesis of photoreceptor cells. In humans, there is a second similar gene, CRB2. There is a single fly gene, crb, that is orthologous to both CRB1 and CRB2, and for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Many of the human genes associated with retinal disease are implicated in multiple related diseases, such as retinitis pigmentosa, cone-rod dystrophy, and forms of macular degeneration. In some cases, a single molecular variant is implicated in more than one form of retinal disease. CRB1 is implicated in retinitis pigmentosa 12 (RP12; MIM:600105; FBhh0000201), Leber congenital amaurosis 8 (LCA8; MIM:613835, FBhh0000566), and pigmented paravenous chorioretinal atrophy (MIM:172870).

A UAS construct with the intracellular domain of the human Hsap\CRB1 gene has been introduced into flies; when expressed in the developing eye it results in a weak and variable rough eye phenotype. This is very similar to the phenotype observed for over-expression of the fly crb gene in the eye.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C749W in the fly crb gene (corresponds to C250W in the human CRB1 gene, implicated in RP12); T1283M in the fly crb gene (corresponds to T745M in the human CRB1 gene, implicated in RP12); N1486S in the fly crb gene (corresponds to N894S in the human CRB1 gene, implicated in RP12); C1540Y in the fly crb gene (corresponds to C948Y in the human CRB1 gene, implicated in RP12 and LCA8).

Amorphic and loss-of-function mutations of Dmel\crb are lethal during embryonic or larval development. Phenotypes of over-expression constructs have been characterized, using either the entire coding sequence or the intracellular domain only. Physical interactions of the crb protein product have been described; see below and in the gene report for crb.

[updated Apr. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: retinal disease, CRB1-related

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

External links

Gene2Function (human gene): CRB1
Gene Cards: CRB1
MedlinePlus (gene): CRB1
MARRVEL (human gene): CRB1
NCBI MedGen: Leber congenital amaurosis 8 (LCA8)
NCBI (Entrez) gene: CRB1; crumbs cell polarity complex component 1

Disease synonyms

Related Diseases

Related human health report(s)

Leber congenital amaurosis 8

retinal disease, inherited (fly models overview)

retinitis pigmentosa 12

Ortholog Information

Human gene(s) in FlyBase

Hsap\CRB1

Human gene (HGNC)

Symbol / Name

CRB1; crumbs cell polarity complex component 1

D. melanogaster ortholog (based on DIOPT)

Dmel\crb

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila; the second orthologous human gene is CRB2.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\crb

Gene Snapshot

crumbs (crb) encodes a transmembrane protein that binds to multiple proteins such as those encoded by sdt, par-6, AP-2α, yrt, ex and Moe. It contributes to organization of zonula adherens, epithelial morphogenesis, apico-basal cell polarity, and is a negative regulator of Notch activity and growth control via the Hippo pathway. In photoreceptor cells it is involved in morphogenesis, the trafficking of the product of ninaE and prevention of light-dependent photoreceptor degeneration. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate-scoring ortholog of human CRB1 (reciprocal best hit) and CRB2 (1 Drosophila to 2 human). Dmel\crb shares 28-30% identity and 40-43% similarity with the human genes. In invertebrates, the orthologous genes are longer than in vertebrates, with additional laminin and EGF-like domains.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (24 groups)

crb

protein-protein

Interacting group

Assay

References

crb - aPKC

phenotype-based detection assay, fluorescence microscopy, inferred by author, pull down, western blot, anti tag western blot

(Kempkens et al., 2006, Sotillos et al., 2004)

crb - apn

proximity ligation assay, fluorescence microscopy, anti bait coimmunoprecipitation, western blot, ubiquitin reconstruction

(Skouloudaki et al., 2019)

crb - baz

pull down, autoradiography

(Kolsch et al., 2007)

crb - Ciao1

pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot

(Jung et al., 2020)

crb - dind

anti tag coimmunoprecipitation, western blot

(Zhao et al., 2023)

crb - Drep2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Andlauer et al., 2014)

crb - ebi

pull down, autoradiography, two hybrid, anti tag coimmunoprecipitation, anti tag western blot

(Nguyen et al., 2016)

crb - ex

pull down, anti tag western blot, anti tag coimmunoprecipitation

(Ribeiro et al., 2014, Ling et al., 2010)

crb - galla-1

anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot

(Yeom et al., 2015)

crb - galla-2

anti tag coimmunoprecipitation, western blot, pull down, anti tag western blot

(Yeom et al., 2015)

crb - Klp61F

pull down, anti tag western blot, anti tag coimmunoprecipitation

(Hwang et al., 2020)

crb - kst

anti bait coimmunoprecipitation, western blot

(Medina et al., 2002)

crb - Mbs

anti tag coimmunoprecipitation, western blot

(Sen et al., 2015)

crb - Moe

anti bait coimmunoprecipitation, western blot

(Medina et al., 2002)

crb - N

proximity ligation assay, fluorescence microscopy

(Nemetschke and Knust, 2016)

crb - par-6

nuclear magnetic resonance, pull down, western blot, anti tag coimmunoprecipitation, two hybrid, x-ray crystallography, phenotype-based detection assay, fluorescence microscopy, inferred by author

(Nunes de Almeida et al., 2019, Whitney et al., 2016, Kempkens et al., 2006)

crb - Patj

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, peptide massfingerprinting, proximity ligation assay, fluorescence microscopy, pull down, autoradiography

(Portela et al., 2018, Sen et al., 2015, Pocha et al., 2011, Sotillos et al., 2004, Medina et al., 2002, Pellikka et al., 2002, Klebes and Knust, 2000, Bhat et al., 1999)

crb - Sar1

pull down, anti tag western blot

(Kumichel et al., 2015)

crb - sdt

two hybrid, anti bait coimmunoprecipitation, western blot, peptide massfingerprinting, anti tag coimmunoprecipitation, pull down, autoradiography, coimmunoprecipitation

(Koch et al., 2016, Sen et al., 2015, Pocha et al., 2011, Li et al., 2008, Kolsch et al., 2007, Kempkens et al., 2006, Bachmann et al., 2001, Hong et al., 2001)

crb - Sec24CD

anti tag coimmunoprecipitation, anti tag western blot

(Kumichel et al., 2015)

crb - Vps26

anti tag coimmunoprecipitation, anti tag western blot

(Zhou et al., 2011)

crb - Vps35

anti tag coimmunoprecipitation, anti tag western blot

(Zhou et al., 2011)

crb - Xpd

anti tag coimmunoprecipitation, anti tag western blot

(Yeom et al., 2015)

crb - yrt

far western blotting, autoradiography, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, pull down

(Gamblin et al., 2024, Gamblin et al., 2018, Laprise et al., 2006)

Alleles Reported to Model Human Disease (Disease Ontology) (12 alleles)

crb

Models Based on Experimental Evidence ( 7 )

Allele

Disease

Evidence

References

crb^11A22

model of Leber congenital amaurosis

CEA

(Izaddoost et al., 2002)

CEA with crb^C749W.UAS

(Pellikka and Tepass, 2017)

CEA with crb^T1283M.UAS

(Pellikka and Tepass, 2017)

CEA with crb^N1486S.UAS

(Pellikka and Tepass, 2017)

CEA with crb^C1540Y.UAS

(Pellikka and Tepass, 2017)

model of retinitis pigmentosa

CEA

(Izaddoost et al., 2002)

CEA with crb^C749W.UAS

(Pellikka and Tepass, 2017)

CEA with crb^T1283M.UAS

(Pellikka and Tepass, 2017)

CEA with crb^N1486S.UAS

(Pellikka and Tepass, 2017)

CEA with crb^C1540Y.UAS

(Pellikka and Tepass, 2017)

model of retinal disease

CEA

(Gurudev et al., 2014)

crb^D88-3

model of Leber congenital amaurosis

CEA

(Izaddoost et al., 2002)

model of retinitis pigmentosa

CEA

(Izaddoost et al., 2002)

crb^C749W.UAS

model of retinitis pigmentosa

CEA with crb^11A22

(Pellikka and Tepass, 2017)

model of Leber congenital amaurosis

CEA with crb^11A22

(Pellikka and Tepass, 2017)

crb^T1283M.UAS

model of retinitis pigmentosa

CEA with crb^11A22

(Pellikka and Tepass, 2017)

model of Leber congenital amaurosis

CEA with crb^11A22

(Pellikka and Tepass, 2017)

crb^N1486S.UAS

model of retinitis pigmentosa

CEA with crb^11A22

(Pellikka and Tepass, 2017)

model of Leber congenital amaurosis

CEA with crb^11A22

(Pellikka and Tepass, 2017)

crb^C1540Y.UAS

model of retinitis pigmentosa

CEA with crb^11A22

(Pellikka and Tepass, 2017)

model of Leber congenital amaurosis

CEA with crb^11A22

(Pellikka and Tepass, 2017)

crb^p13A9

model of retinitis pigmentosa 12

CEA

(Kraut and Knust, 2019)

model of Leber congenital amaurosis 8

CEA

(Kraut and Knust, 2019)

model of retinal disease

CEA

(Kraut and Knust, 2019)

Modifiers Based on Experimental Evidence ( 6 )

Allele

Disease

Interaction

References

crb^11A22

ameliorates neurodegenerative disease

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Steffensmeier et al., 2013)

model of retinal disease

is exacerbated by chp²

(Gurudev et al., 2014)

crb^{IntraΔERLI.UAS.Tag:MYC}

ameliorates neurodegenerative disease

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Steffensmeier et al., 2013)

crb^{IntraY10A.E16A.ΔERLI.UAS.Tag:MYC}

ameliorates neurodegenerative disease

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Steffensmeier et al., 2013)

crb^{IntraY10A.E16A.UAS.Tag:MYC}

ameliorates neurodegenerative disease

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Steffensmeier et al., 2013)

crb^UAS.cWa

exacerbates neurodegenerative disease

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Steffensmeier et al., 2013)

crb^GD14463

ameliorates neurodegenerative disease

modeled by Hsap\APP^{Aβ42.UAS.cUa}

(Steffensmeier et al., 2013)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\CRB1^intra.UAS

P{UAS-CRB1^intra}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

w^*; P{UAS-crb.wt}30.12e

crb^{IntraY10A.E16A.UAS.Tag:MYC}

P{UAS-crb.IntraY10A.E16A.myc}

crb^{IntraY10A.E16A.ΔERLI.UAS.Tag:MYC}

P{UAS-crb.IntraY10A.E16A.DeltaERLI.myc}

crb^{IntraΔERLI.UAS.Tag:MYC}

P{UAS-crb.IntraDeltaERLI.myc}

w^*; P{UAS-crb.IntraΔERLI.myc}14.1

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

crb^GD14463

P{GD14463}

w¹¹¹⁸; P{GD14463}v39177

y¹ v¹; P{TRiP.JF02777}attP2

crb^HMS01409

P{TRiP.HMS01409}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS01409}attP2

y¹ v¹; P{TRiP.GL00674}attP40

crb^HMS01842

P{TRiP.HMS01842}

y¹ v¹; P{TRiP.HMS01842}attP40

crb^HMS02036

P{TRiP.HMS02036}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS02036}attP2

crb^VSH330135

P{VSH330135}

P{VSH330135}attP40

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

crb^p13A9

ethyl methanesulfonate

crb^Δ325

loss of function allele

CRISPR/Cas9

crb^Δ193

loss of function allele

CRISPR/Cas9

crb^D88-3

X ray

crb^8F105