Human Disease Model Report: Leber congenital amaurosis 8

General Information

Name

Leber congenital amaurosis 8

FlyBase ID

FBhh0000566

Disease Ontology Term

Leber congenital amaurosis 8

Parent Disease

Leber congenital amaurosis

OMIM

LEBER CONGENITAL AMAUROSIS 8; LCA8

Overview

This report describes Leber congenital amaurosis 8 (LCA8), which is a subtype of Leber congenital amaurosis; both autosomal dominant and autosomal recessive forms of LCA8 have been reported. The human gene implicated in this disease is CRB1. CRB1 is also implicated in other diseases associated with retinal degeneration (MIM:604210). 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. See also the report for 'retinal disease, CRB1-related' (FBhh0000572) for additional information on experimental results using Drosophila models of this and related diseases.

Experiments characterizing mutations in the fly gene analogous to variants implicated in human retinal disease include one implicated in Leber congenital amaurosis 8. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): C1540Y in the fly crb gene (corresponds to C948Y in the human CRB1 gene, implicated in LCA8 and retinitis pigmentosa 12).

[updated Apr. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: Leber congenital amaurosis

Symptoms and phenotype

Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. (summary by Chung and Traboulsi, 2009; pubmed:20006823). [from MIM:204000; 2016.08.27]

(OMIM, 2013-)

Leber congenital amaurosis (LCA) is an inherited retinal degenerative disease characterized by severe loss of vision at birth. Affected infants are often blind at birth. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or a cone shape to the front of the eye (keratoconus). [NORD, Leber Congenital Amaurosis; 2016.08.27]

(FlyBase Curators, 2013-)

Specific Disease Summary: Leber congenital amaurosis 8

OMIM report

[LEBER CONGENITAL AMAUROSIS 8; LCA8](https://omim.org/entry/613835)

Human gene(s) implicated

[CRUMBS CELL POLARITY COMPLEX COMPONENT 1; CRB1](https://omim.org/entry/604210)

Symptoms and phenotype

Genetics

Leber congenital amaurosis-8 (LCA8) is caused by homozygous or compound heterozygous mutation in the CRB1 gene. [from MIM:613835; 2017.06.30]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

External links

Gene2Function (human gene): CRB1
Gene Cards: CRB1
GeneReviews, NCBI Bookshelf: Leber Congenital Amaurosis
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

LCA8

Related Diseases

Related human health report(s)

retinal disease, CRB1-related

Related Specific Diseases

OMIM phenotypic series

Leber congenital amaurosis

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[LCA1](https://omim.org/entry/204000)

[GUCY2D](https://omim.org/entry/600179)

[LCA2](https://omim.org/entry/204100)

[RPE65](https://omim.org/entry/180069)

[LCA3](https://omim.org/entry/604232)

[SPATA7](https://omim.org/entry/609868)

[LCA4](https://omim.org/entry/604393)

[AIPL1](https://omim.org/entry/604392)

[LCA5](https://omim.org/entry/604537)

[LCA5](https://omim.org/entry/611408)

[LCA6](https://omim.org/entry/613826)

[RPGRIP1](https://omim.org/entry/605446)

[LCA7](https://omim.org/entry/613829)

[CRX](https://omim.org/entry/602225)

Leber congenital amaurosis 7

[LCA8](https://omim.org/entry/613835)

[CRB1](https://omim.org/entry/604210)

Leber congenital amaurosis 8

[LCA9](https://omim.org/entry/608553)

[NMNAT1](https://omim.org/entry/608700)

[LCA10](https://omim.org/entry/611755)

[CEP290](https://omim.org/entry/610142)

[LCA11](https://omim.org/entry/613837)

[IMPDH1](https://omim.org/entry/146690)

[LCA12](https://omim.org/entry/610612)

[RD3](https://omim.org/entry/180040)

[LCA13](https://omim.org/entry/612712)

[RDH12](https://omim.org/entry/608830)

[LCA14](https://omim.org/entry/613341)

[LRAT](https://omim.org/entry/604863)

[LCA15](https://omim.org/entry/613843)

[TULP1](https://omim.org/entry/602280)

[LCA16](https://omim.org/entry/614186)

[KCNJ13](https://omim.org/entry/603208)

[LCA17](https://omim.org/entry/615360)

[GDF6](https://omim.org/entry/601147)

[RP7](https://omim.org/entry/608133)

[PRPH2](https://omim.org/entry/179605)

[RP7](https://omim.org/entry/608133)

[ROM1](https://omim.org/entry/180721)

Ortholog Information

Human gene(s) in FlyBase

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

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

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

crb - apn

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

(Skouloudaki et al., 2019)

crb - baz

pull down, autoradiography

(Kolsch et al., 2007)

crb - Ciao1

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

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

(Nguyen et al., 2016)

crb - ex

anti tag coimmunoprecipitation, anti tag western blot, pull down

(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

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

(Yeom et al., 2015)

crb - Klp61F

anti tag coimmunoprecipitation, anti tag western blot, pull down

(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

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

(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, anti tag coimmunoprecipitation, coimmunoprecipitation, pull down, autoradiography, peptide massfingerprinting

(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

anti tag coimmunoprecipitation, anti tag western blot, far western blotting, autoradiography, anti bait coimmunoprecipitation, 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 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 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 retinal disease

CEA

(Gurudev et al., 2014)

crb^D88-3

model of retinitis pigmentosa

CEA

(Izaddoost et al., 2002)

model of Leber congenital amaurosis

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 retinal disease

CEA

(Kraut and Knust, 2019)

model of Leber congenital amaurosis 8

CEA

(Kraut and Knust, 2019)

model of retinitis pigmentosa 12

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

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