Human Disease Model Report: Pitt-Hopkins syndrome

General Information

Name

Pitt-Hopkins syndrome

FlyBase ID

FBhh0000433

Disease Ontology Term

Pitt-Hopkins syndrome

Parent Disease

OMIM

PITT-HOPKINS SYNDROME; PTHS

Overview

This report describes Pitt-Hopkins syndrome (PTHS), a condition characterized by intellectual disability and developmental delay, recurrent seizures, distinctive facial features, and intermittent hyperventilation followed by apnea. PTHS is inherited as an autosomal dominant. The human gene implicated in this disease is TCF4, which encodes a basic helix-loop-helix (bHLH) transcription factor. There is a single ortholog in flies, Dmel\da, for which for which classical amorphic and hypomorphic alleles, RNAi targeting constructs, alleles caused by insertional mutagenesis have been generated. TCF4 is also implicated in a second disease, Fuchs endothelial corneal dystrophy-3 (MIM:613267). Dmel\da is orthologous to two other bHLH transcription factors in human, TCF3 and TCF12, both of which are implicated in specific diseases (see MIM:147141 and MIM:600480).

UAS constructs of the human Hsap\TCF4 gene have been introduced into flies; heterologous rescue (functional complementation) has been demonstrated.

Reflecting its key role in early transcriptional regulation of multiple developmental processes, amorphic alleles of Dmel\da result in lethality. The first allele isolated, a hypomorphic insertion of a transposable element, results in maternal-effect lethality of female offspring of homozygous mothers (hence the name of the gene). Extensive physical and genetic interactions have been described; see below and in the gene report for da.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R564H in the fly da gene [R574H (R578H) in the human TCF4 gene]; R566W in the fly da gene [R576W (R580W) in the human TCF4 gene]; R568P in the fly da gene [R578P (R582P) in the human TCF4 gene]; A600V in the fly da gene [R578P (R582P) in the human TCF4 gene]; all are conserved residues within the helix-loop helix domain. The variant R566L in the fly da gene [R576L (R580L) in the human TCF4 gene] was also characterized and found to have effects comparable to the known pathogenic Trp variant at the same position.

[updated Jul. 2017 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: Pitt-Hopkins syndrome

OMIM report

[PITT-HOPKINS SYNDROME; PTHS](https://omim.org/entry/610954)

Human gene(s) implicated

[TRANSCRIPTION FACTOR 4; TCF4](https://omim.org/entry/602272)

Symptoms and phenotype

Pitt-Hopkins syndrome is a condition characterized by intellectual disability and developmental delay, breathing problems, recurrent seizures (epilepsy), and distinctive facial features (Genetics Home Reference, Pitt-Hopkins syndrome; 2016.11.16).

(FlyBase Curators, 2013-)

Pitt-Hopkins syndrome is characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea (Zweier et al., 2007; pubmed:17436255). [from MIM:610954; 2016.11.16]

(OMIM, 2013-)

Genetics

Pitt-Hopkins syndrome (PTHS) is caused by heterozygous mutation in the TCF4 gene; inherited as an autosomal dominant. [from MIM:610954; 2016.11.16]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

TCF4 encodes a broadly expressed transcription factor, a basic helix-loop-helix (bHLH) protein that that binds to E-box DNA sequences and functions as a homodimer or as a heterodimer with other bHLH proteins. Alternative splicing produces numerous N-terminally distinct TCF4 isoforms that differ in their subcellular localization and activity (summary by Sepp et al., 2012; pubmed:22460224). [from MIM:602272; 2016.11.16]

(OMIM, 2013-)

External links

Gene2Function (human gene): TCF4
Gene Cards: TCF4
GeneReviews, NCBI Bookshelf: Pitt-Hopkins Syndrome
MedlinePlus (condition): pitt-hopkins-syndrome
MedlinePlus (gene): TCF4
MARRVEL (human gene): TCF4
NCBI MedGen: Pitt-Hopkins syndrome
NCBI (Entrez) gene: TCF4; transcription factor 4

Disease synonyms

encephalopathy, severe epileptic, with autonomic dysfunction

mental retardation, syndromal, with intermittent hyperventilation

Pitt Hopkins syndrome

PTHS

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Hsap\TCF4

Human gene (HGNC)

Symbol / Name

TCF4; transcription factor 4

D. melanogaster ortholog (based on DIOPT)

Dmel\da

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila; the additional human genes are TCF3 and TCF12.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\da

Gene Snapshot

daughterless (da) encodes a class I bHLH protein important for sex determination and dosage compensation by controlling the feminizing switch gene Sxl. It participates in transcriptional regulation of a wide variety processes, including oogenesis, neurogenesis, myogenesis and cell proliferation. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

BHLH

Comments on ortholog(s)

Moderate-scoring ortholog of human TCF4, TCF3 and TCF12 (1 Drosophila to 3 human). Dmel\da shares 29-32% identity and 39-44% 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 (46 groups)

protein-protein

Interacting group

Assay

References

two hybrid

(Liu and Belote, 1995)

da - abd-A

bimolecular fluorescence complementation, fluorescence microscopy

(Bischof et al., 2018)

da - ac

electrophoretic mobility shift assay, autoradiography, anti bait coimmunoprecipitation

(Lai et al., 2000, Cabrera and Alonso, 1991)

da - Act5C

anti tag coimmunoprecipitation, western blot

(Hsiao et al., 2014)

da - Act42A

anti tag coimmunoprecipitation, western blot

(Hsiao et al., 2014)

da - amos

electrophoretic mobility shift assay, autoradiography

(Huang et al., 2000)

da - ase

electrophoretic mobility shift assay, autoradiography

(Jarman et al., 1993)

da - ato

two hybrid, anti tag coimmunoprecipitation, autoradiography, pull down, electrophoretic mobility shift assay

(Quan et al., 2016, Witt et al., 2010, Allan et al., 2005, Quan et al., 2004, Jarman et al., 1993)

da - Blos1

two hybrid array

(Shokri et al., 2019)

da - btn

two hybrid array

(Shokri et al., 2019)

da - caup

two hybrid array

(Shokri et al., 2019)

da - CG8314

two hybrid array

(Shokri et al., 2019)

da - CG8478

two hybrid array

(Shokri et al., 2019)

da - CG31955

two hybrid array

(Shokri et al., 2019)

da - CG32772

two hybrid array

(Shokri et al., 2019)

da - Chi

anti tag coimmunoprecipitation, anti tag western blot

(Biryukova and Heitzler, 2005)

da - dimm

pull down, autoradiography

(Allan et al., 2005)

da - dpn

two hybrid

(Liu and Belote, 1995)

da - drm

two hybrid array

(Shokri et al., 2019)

da - E(spl)m5-HLH

one hybrid, two hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

da - E(spl)m7-HLH

one hybrid, two hybrid, anti tag coimmunoprecipitation, anti tag western blot

(Kiparaki et al., 2015, Zarifi et al., 2012, Alifragis et al., 1997)

da - E(spl)m8-HLH

two hybrid, one hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

da - E(spl)mβ-HLH

one hybrid, two hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

da - E(spl)mγ-HLH

two hybrid, one hybrid

(Zarifi et al., 2012, Alifragis et al., 1997)

da - Eip78C

two hybrid array

(Shokri et al., 2019)

da - emc

proximity ligation assay, fluorescence microscopy, two hybrid

(Waddell et al., 2019, Spratford and Kumar, 2015, Alifragis et al., 1997, Georgias et al., 1997)

da - esg

pull down, anti tag western blot, anti tag coimmunoprecipitation

(Yang et al., 2010)

da - Ets65A

two hybrid array

(Shokri et al., 2019)

da - ey

pull down, autoradiography

(Tanaka-Matakatsu et al., 2014)

da - foxo

two hybrid array

(Shokri et al., 2019)

da - GATAd

two hybrid array

(Shokri et al., 2019)

da - Hand

two hybrid

(Tögel et al., 2013)

da - HLH54F

two hybrid

(Georgias et al., 1997)

da - Hr78

two hybrid array

(Shokri et al., 2019)

da - Irbp18

two hybrid array

(Shokri et al., 2019)

da - l(1)sc

electrophoretic mobility shift assay, autoradiography, anti bait coimmunoprecipitation, two hybrid

(Jennings et al., 1999, Georgias et al., 1997, Cabrera et al., 1994, Oellers et al., 1994, Jarman et al., 1993, Cabrera and Alonso, 1991)

da - mbf1

two hybrid array

(Shokri et al., 2019)

da - NC2β

two hybrid array

(Shokri et al., 2019)

da - nvy

pull down, western blot

(Wildonger and Mann, 2005)

da - sage

pull down, autoradiography

(Chandrasekaran and Beckendorf, 2003)

da - sc

anti bait coimmunoprecipitation, autoradiography, electrophoretic mobility shift assay, two hybrid, western blot

(Giagtzoglou et al., 2005, Lai et al., 2000, Georgias et al., 1997, Deshpande et al., 1995, Liu and Belote, 1995, Cabrera et al., 1994, Jarman et al., 1993, Jarman et al., 1993, Cabrera and Alonso, 1991)

da - sisA

two hybrid

(Liu and Belote, 1995)

da - Su(H)

two hybrid

(Cave et al., 2005)

da - twi

pull down, autoradiography, electrophoretic mobility shift assay

(Nowak et al., 2012, Castanon et al., 2001)

da - tx

two hybrid

(Georgias et al., 1997)