Human Disease Model Report: cardiofaciocutaneous syndrome 3

General Information

Name

cardiofaciocutaneous syndrome 3

FlyBase ID

FBhh0001021

Disease Ontology Term

cardiofaciocutaneous syndrome 3

Parent Disease

cardiofaciocutaneous syndrome

OMIM

CARDIOFACIOCUTANEOUS SYNDROME 3; CFC3

Overview

This report describes cardiofaciocutaneous syndrome 3 (CFC3); CFC3 exhibits autosomal dominant inheritance. The human gene implicated in this disease is MAP2K1 (Mitogen-Activated Protein Kinase Kinase 1, also known as MEK1), a dual-specificity protein kinase that is a component of the MAP kinase signal transduction pathway. There is a single orthologous gene in flies, Dsor1, for which amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Dsor1 is also orthologous to a second gene in human, MAP2K2; MAP2K2 has also been implicated in cardiofaciocutaneous syndrome (in this case, CFS4).

The human MAP2K1 gene has not been introduced into flies.

Several disease-implicated variants associated with cardiofaciocutaneous syndrome have been investigated in Drosophila using the fly gene Dsor1; see the 'Disease-implicated Variants' table below. Dsor1 is the sole high-scoring fly ortholog of both MAP2K1 and MAP2K2 and both of these human genes are implicated in cardiofaciocutaneous syndrome. In some cases a characterized Dsor1 mutation is analogous to disease-implicated variants in both genes. For example, Y149C in the fly Dsor1 gene corresponds to Y130C in the human MAP2K1 gene, which is implicated in CFC3, and Y134C in the human MAP2K2 gene, which is implicated in CFC4.

Additional information can be found in the Human Disease Model report 'RASopathies, MAP2K1,2-related' (FBhh0001509).

[updated Apr. 2023 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: cardiofaciocutaneous syndrome

Symptoms and phenotype

Cardiofaciocutaneous syndrome is a disorder that affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). People with this condition also have delayed development and intellectual disability, usually ranging from moderate to severe. Infants with cardiofaciocutaneous syndrome typically have weak muscle tone (hypotonia), feeding difficulties, and a failure to grow and gain weight at the normal rate (failure to thrive). The symptoms of cardiofaciocutaneous syndrome overlap significantly with those of two other genetic conditions, Costello syndrome and Noonan syndrome. [MedlinePlus, Cardiofaciocutaneous syndrome; 2023.04.07]

(FlyBase Curators, 2013-)

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects, and mental retardation (summary by Niihori et al., 2006; pubmed:16474404). [from MIM:115150; 2023.04.07]

(OMIM, 2013-)

Specific Disease Summary: cardiofaciocutaneous syndrome 3

OMIM report

[CARDIOFACIOCUTANEOUS SYNDROME 3; CFC3](https://omim.org/entry/615279)

Human gene(s) implicated

[MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1](https://omim.org/entry/176872)

Symptoms and phenotype

Genetics

Cardiofaciocutaneous syndrome-3 (CFC3) is caused by heterozygous mutation in the MAP2K1 gene. [from MIM:615279; 2019.05.13]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

MAP2K1 (Mitogen-Activated Protein Kinase Kinase 1) encodes a dual-specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway (also called the MAPK/ERK pathway). [Gene Cards, MAP2K1; 2019.05.13]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): MAP2K1
Gene Cards: MAP2K1
GeneReviews, NCBI Bookshelf: Cardiofaciocutaneous Syndrome
MedlinePlus (condition): Cardiofaciocutaneous syndrome
MedlinePlus (gene): MAP2K1
MARRVEL (human gene): MAP2K1
NCBI MedGen: Cardiofaciocutaneous syndrome 3 (CFC3)
NCBI (Entrez) gene: MAP2K1; mitogen-activated protein kinase kinase 1

Disease synonyms

CFC3

CFC syndrome

Search term: RASopathy

Related Diseases

Related human health report(s)

cancer, multiple, MAP2K1,2-related

RASopathies, MAP2K1,2-related

Related Specific Diseases

OMIM phenotypic series

Cardiofaciocutaneous syndrome

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[CFC1](https://omim.org/entry/115150)

[BRAF](https://omim.org/entry/164757)

[CFC2](https://omim.org/entry/615278)

[KRAS](https://omim.org/entry/190070)

[CFC3](https://omim.org/entry/615279)

[MAP2K1](https://omim.org/entry/176872)

cardiofaciocutaneous syndrome 3

[CFC4](https://omim.org/entry/615280)

[MAP2K2](https://omim.org/entry/601263)

cardiofaciocutaneous syndrome 4

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

MAP2K1; mitogen-activated protein kinase kinase 1

D. melanogaster ortholog (based on DIOPT)

Dmel\Dsor1

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human to 1 Drosophila. The second human gene is MAP2K2.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Dsor1

Gene Snapshot

Downstream of raf1 (Dsor1) encodes a serine/threonine kinase that phosphorylates MAP kinase. It is activated by the product of Raf and acts downstream of receptor tyrosine kinases such as those encoded by tor, Egfr, and sev. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human MAP2K1 and MAP2K2 (1 Drosophila to 2 human). Dmel\Dsor1 shares 55-64% identity and 69-78% similarity with the human genes.

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 (78 groups)

Dsor1

protein-protein

Interacting group

Assay

References

Dsor1 - 14-3-3ε

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - 14-3-3ζ

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Akap200

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - αTub84D

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - arm

proximity ligation assay, fluorescence microscopy

(Hall and Verheyen, 2015)

Dsor1 - AspRS-m

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - ave

pull down, anti tag western blot, electron microscopy, molecular sieving, molecular weight estimation by staining

(Maisonneuve et al., 2024)

Dsor1 - βCOP

anti tag coimmunoprecipitation, anti tag western blot

(Friedman et al., 2011)

Dsor1 - blanks

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - brm

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - caz

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - CG1416

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - CG4972

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - CG12948

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - cindr

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - cnk

pull down, anti tag western blot, electron microscopy, molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, peptide massfingerprinting

(Maisonneuve et al., 2024, Friedman et al., 2011)

Dsor1 - cpa

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - CSN8

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Dp1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Droj2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - eIF3a

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - eIF3l

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - eIF4E1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - GCS2β

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - glo

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Gmppb

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Golgin97

experimental knowledge based

(Guruharsha et al., 2011)

Dsor1 - HDAC1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Hsp83

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Imp

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - krz

anti tag coimmunoprecipitation, anti tag western blot

(Tipping et al., 2010)

Dsor1 - ksr

molecular sieving, molecular weight estimation by staining, electron microscopy, anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting

(Maisonneuve et al., 2024, Friedman et al., 2011)

Dsor1 - kuk

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Lamtor3

pull down, autoradiography

(Mouchel-Vielh et al., 2008)

Dsor1 - larp

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Map60

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Mbs

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Mcad

anti tag coimmunoprecipitation, anti tag western blot

(Friedman et al., 2011)

Dsor1 - Mcm7

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Mec2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Mkk4

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Nepl3

experimental knowledge based

(Guruharsha et al., 2011)

Dsor1 - nesd

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Ostm1

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - ptch

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Pyk

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Raf

anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting, two hybrid

(Maisonneuve et al., 2024, Friedman et al., 2011, Therrien et al., 1998)

Dsor1 - Rbcn-3A

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RfC4

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RhoGAP18B

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - rl

anti tag coimmunoprecipitation, western blot, proximity ligation assay, fluorescence microscopy

(Hall and Verheyen, 2015, Tipping et al., 2010)

Dsor1 - RpL9

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpL10

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpL15

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpL24

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpL28

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpL32

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpS2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpS20

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpS28b

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - RpS30

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Rpt4

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Rpt6

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Saf-B

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - scny

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - ScsβA

anti tag coimmunoprecipitation, anti tag western blot, peptide massfingerprinting

(Friedman et al., 2011, Friedman et al., 2011)

Dsor1 - ScsβG

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - Sec13

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - SERCA

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - sesB

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - sip2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - SkpA

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - sqd

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - UQCR-C2

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - vlc

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - vret

experimental knowledge based

(Guruharsha et al., 2011)

Dsor1 - wal

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Dsor1 - ZAP3

anti tag coimmunoprecipitation, peptide massfingerprinting

(Friedman et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (20 alleles)

Dsor1

Models Based on Experimental Evidence ( 12 )

Allele

Disease

Evidence

References

Dsor1^F53S.UASp

model of RASopathy

CEA

(Marmion et al., 2021)

model of cancer

CEA

(Jindal et al., 2017)

Dsor1^F53L.UASp

model of cancer

CEA

(Jindal et al., 2017)

Dsor1^E203K.UASp

model of cancer

CEA

(Jindal et al., 2017)

Dsor1^Y130C.UASp

model of cancer

CEA

(Jindal et al., 2017)

Dsor1^D44G.UASp

model of cancer

CEA

(Jindal et al., 2017)

Dsor1^F72S

model of RASopathy

CEA

(Marmion et al., 2023)

Dsor1^Y149C

model of RASopathy

CEA

(Marmion et al., 2023)

Dsor1^E222K

model of RASopathy

CEA

(Marmion et al., 2023)

Dsor1^{F53S.UASp.SSAA}

model of RASopathy

CEA

(Marmion et al., 2021)

Dsor1^F53Y.UASp

model of cancer

CEA

(Andrianova et al., 2023)

Dsor1^G128D.UASp

model of cancer

CEA

(Andrianova et al., 2023)

Dsor1^Q56P.UASp

model of cancer

CEA

(Andrianova et al., 2023)

Modifiers Based on Experimental Evidence ( 9 )

Allele

Disease

Interaction

References

Dsor1^HMS00037

ameliorates mitochondrial DNA depletion syndrome 15

modeled by TFAM^UAS.cCa

(Duncan et al., 2018)

Dsor1^JF01697

ameliorates mitochondrial DNA depletion syndrome 15

modeled by TFAM^UAS.cCa

(Duncan et al., 2018)

Dsor1^G79

ameliorates autosomal dominant cerebellar ataxia

modeled by Hsap\ATXN1^82Q.UAS

(Park et al., 2013)

Dsor1^LH110

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

ameliorates pancreatic ductal adenocarcinoma

modeled by CycE^{UAS.Tag:HA.Medsh}, Med^{RNAi.UAS.CycE-HA}, p53^{RNAi.UAS.RasG12D}

(Sekiya et al., 2023)

Dsor1^S-1221

ameliorates Huntington's disease

modeled by Hsap\HTT^NT.128Q.UAS

(Miller et al., 2012)

Dsor1^GD9123

ameliorates Huntington's disease

modeled by Hsap\HTT^NT.128Q.UAS

(Miller et al., 2012)

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

Dsor1^KK102276

ameliorates neurofibromatosis

modeled by Nf1^E2

(Walker et al., 2013)

ameliorates colorectal cancer

modeled by SH3PX1^JF02730

(Zhang et al., 2019)

ameliorates hematologic cancer

modeled by mxc¹

(Kurihara et al., 2020)

Dsor1^F72S

model of RASopathy

is ameliorated by grk^unspecified

(Marmion et al., 2023)

Dsor1^RNAi.UAS.cUa

ameliorates cardiomyopathy

modeled by Hsap\RAF1^gof.UAS

(Yu 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

Dsor1^D44G.UASp

P{UASp-Dsor1.D44G}

Dsor1^{F53S.UASp.SSAA}

P{UASp-Dsor1.F53S.SSAA}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w¹¹¹⁸; P{GD9123}v40026

y¹ v¹; P{TRiP.JF03100}attP2

Dsor1^JF01697

P{TRiP.JF01697}

y¹ v¹; P{TRiP.JF01697}attP2

Dsor1^HMS00037

P{TRiP.HMS00037}

y¹ v¹; P{TRiP.HMS00037}attP2

Dsor1^HMS00710

P{TRiP.HMS00710}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00710}attP2/TM3, Sb¹

Dsor1^GL00096

P{TRiP.GL00096}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00096}attP2/TM3, Sb¹

Dsor1^GLV21003

P{TRiP.GLV21003}

y¹ sc^* v¹ sev²¹; P{TRiP.GLV21003}attP2

Dsor1^HMS00145

P{TRiP.HMS00145}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00145}attP2

Dsor1^GLC01824

P{TRiP.GLC01824}

y¹ sc^* v¹ sev²¹; P{TRiP.GLC01824}attP40

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Dsor1^K8C13

loss of function allele

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

ethyl methanesulfonate

y¹ w^a Dsor1^S-1221/Basc

Dsor1^LH110

amorphic allele - genetic evidence

y¹ w^* Dsor1^LH110 P{FRT(w^hs)}101/FM7a

Dsor1^G79

ethyl methanesulfonate

w¹ Dsor1^G79/FM7c/Dp(1;Y)FF1, y⁺

References (4)

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