Human Disease Model Report: Townes-Brocks syndrome

General Information

Name

Townes-Brocks syndrome

FlyBase ID

FBhh0000257

Disease Ontology Term

Townes-Brocks syndrome

Parent Disease

OMIM

TOWNES-BROCKS SYNDROME 1; TBS1

Overview

This report describes Townes-Brocks syndrome (TBS), which is inherited as an autosomal dominant and is characterized by multiple morphological abnormalities, both external and internal (affecting anal opening, ears, thumbs, kidneys, heart, genitourinary structures, and others). The gene implicated in TBS is SALL1, a zinc-finger transcriptional repressor. There are two Drosophila orthologs, salm (spalt major) and salr (spalt-related), for which for which classical amorphic (for salm) and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The human SALL1 gene has not been introduced into flies.

In order to create a fly model for this disease, animals that carried loss-of-function mutations in both Dmel\salm and Dmel\salr were generated. Since homozygous null mutations of Dmel\salm are embryonic lethals, null clones were generated using the FLP/FRT system. Loss of both salm and salr function results in morphological defects in the testes, genitalia, and the antenna. Electrophysiological analyses indicate that salm/salr mutant flies are deaf. Thus, multiple aspects of the human disease are recapitulated.

[updated Apr. 2016 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: Townes-Brocks syndrome

OMIM report

[TOWNES-BROCKS SYNDROME 1; TBS1](https://omim.org/entry/107480)

Human gene(s) implicated

[SAL-LIKE 1; SALL1](https://omim.org/entry/602218)

Symptoms and phenotype

The absence of the anal opening (imperforate anus) is the most common feature of TBS. Small ears and a folded rim of skin and cartilage around the outer ear are usually present; hand malformations that most often affect the thumb are common. Congenital sensorineural and/or conductive hearing loss can range from mild to severe and can be progressive. Malformations of the feet may be present; kidney abnormalities may be present. Mental retardation occurs in approximately 10% of affected individuals. [from NORD, Townes Brocks Syndrome; 2016.04.22]

(FlyBase Curators, 2013-)

Genetics

Variable expressivity is observed: features vary among affected individuals, even within the same family. [from Genetics Home Reference, Townes-Brocks Syndrome; 2016.04.22]

(FlyBase Curators, 2013-)

Townes-Brocks syndrome is caused by mutation in the gene encoding the SALL1 putative transcription factor; it is inherited as an autosomal dominant. [from MIM:107480; 2016.04.13]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The SALL1 (Spalt-Like Transcription Factor 1) protein is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase complex (HDAC). [from Gene Cards, SALL1; 2016.04.22]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): SALL1
Gene Cards: SALL1
GeneReviews, NCBI Bookshelf: Townes-Brocks Syndrome
MedlinePlus (condition): Townes-Brocks Syndrome
MedlinePlus (gene): SALL1
MARRVEL (human gene): SALL1
NCBI MedGen: Townes syndrome (TBS1)
NCBI (Entrez) gene: SALL1; spalt like transcription factor 1
National Organization for Rare Disorders: Townes Brocks Syndrome

Disease synonyms

anus, imperforate, with hand, foot, and ear anomalies

deafness, sensorineural, with imperforate anus and thumb anomalies

REAR syndrome

renal-ear-anal-radial syndrome

TBS

Townes-Brocks-branchiootorenal-like syndrome

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

SALL1; spalt like transcription factor 1

D. melanogaster ortholog (based on DIOPT)

Dmel\salm

(DIOPT, 2013-)

Dmel\salr

(DIOPT, 2013-)

Comments on ortholog(s)

One to many: 1 human to 2 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\salm

Gene Snapshot

spalt major (salm) encodes a zinc finger transcriptional repressor. It mediates most dpp functions during development of the central part of the wing through regulation of the products of kni and ara. The product of salm is required for cell specification during the development of the nervous system, muscle, eye or trachea. [Date last reviewed: 2019-03-14]

Molecular function (GO)

DNA-binding transcription factor activity, RNA polymerase II-specific

Cellular component (GO)

nucleus

Gene Groups / Pathways

ZF-C2H2

Comments on ortholog(s)

One of two Drosophila orthologs of human gene SALL1 (2 Drosophila to 1 human). Dmel\salm shares 27% identity and 40% similarity with human SALL1.

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Dmel\salr

Gene Snapshot

spalt-related (salr) encodes a zinc finger transcriptional repressor that, together with the product of salm, mediates most dpp functions during development of the central part of the wing. It is repressed by the product of Ubx during haltere development. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

nucleus

Gene Groups / Pathways

ZF-C2H2

Comments on ortholog(s)

One of two Drosophila orthologs of human gene SALL1 (2 Drosophila to 1 human). Dmel\salr shares 29% identity and 41% similarity with human SALL1.

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 (13 groups)

salm

protein-protein

Interacting group

Assay

References

salm - abd-A

bimolecular fluorescence complementation, fluorescence microscopy

(Bischof et al., 2018, Baëza et al., 2015)

salm - Abd-B

bimolecular fluorescence complementation, fluorescence microscopy

(Baëza et al., 2015)

salm - Antp

bimolecular fluorescence complementation, fluorescence microscopy

(Baëza et al., 2015)

salm - CG3919

two hybrid array

(Shokri et al., 2019)

salm - CG10209

two hybrid array

(Shokri et al., 2019)

salm - CG15514

two hybrid array

(Shokri et al., 2019)

salm - exd

bimolecular fluorescence complementation, fluorescence microscopy

(Bischof et al., 2018)

salm - gro

two hybrid array

(Shokri et al., 2019)

salm - Hr78

two hybrid array

(Shokri et al., 2019)

salm - mid

two hybrid array

(Shokri et al., 2019)

salm - Scr

bimolecular fluorescence complementation, fluorescence microscopy

(Baëza et al., 2015)

salm - topi

two hybrid array

(Shokri et al., 2019)

salm - toy

two hybrid array

(Shokri et al., 2019)

Alleles Reported to Model Human Disease (Disease Ontology) (4 alleles)

salm

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

salm^FCK-25

model of Townes-Brocks syndrome

CEA with salr^FCK-25

(Si-Dong et al., 2003)

salm^UAS.cKa

model of carcinoma

CEA

(Sun et al., 2020)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

salm^UAS.cKa

model of carcinoma

is ameliorated by Timp^UAS.cPa

(Sun et al., 2020)

is ameliorated by bsk^K53R.UAS

(Sun et al., 2020)

is ameliorated by puc^UAS.cMa

(Sun et al., 2020)

salr

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

salr^FCK-25

model of Townes-Brocks syndrome

CEA with salm^FCK-25

(Si-Dong et al., 2003)

salr^UAS.cBa

model of carcinoma

CEA

(Sun et al., 2020)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

salr^UAS.cBa

model of carcinoma

is exacerbated by Myc^HMS01538

(Sun et al., 2020)

is ameliorated by Myc^UAS.cZa

(Sun et al., 2020)

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

P{UAS-salm.K}X, w^*; P{UAS-mCD8::GFP.L}LL5

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

salr^GD12797

P{GD12797}

w¹¹¹⁸; P{GD12797}v28386

salr^JF03226

P{TRiP.JF03226}

y¹ v¹; P{TRiP.JF03226}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMS06019}attP40/CyO

w¹¹¹⁸; P{GD1525}v3029

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00594}attP2

salm^HMJ22831

P{TRiP.HMJ22831}

y¹ v¹; P{TRiP.HMJ22831}attP40/CyO

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

salr^FCK-25

X ray

salm³

amorphic allele - genetic evidence

ethyl methanesulfonate

salm^FCK-25

X ray

salm²

loss of function allele

ethyl methanesulfonate

salm¹

amorphic allele - genetic evidence

ethyl methanesulfonate

salm¹ cn¹ bw¹ speck¹/CyO

salm¹⁶

loss of function allele

ethyl methanesulfonate

salm⁶⁵

loss of function allele

ethyl methanesulfonate

References (5)

Report Sections

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