Human Disease Model Report: pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

General Information

Name

pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

FlyBase ID

FBhh0001486

Disease Ontology Term

pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

Parent Disease

OMIM

CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 15; CDCBM15

Overview

This report describes pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, a neurological disorder that exhibits autosomal recessive inheritance. The human gene implicated is TUBGCP2, which encodes a component of the gamma-tubulin complex. There is one high-scoring fly ortholog, Dmel\Grip84 and one moderate-scoring ortholog, Dmel\t-Grip84, for which amorphic or loss of function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

The human Hsap\TUBGCP2 gene has been introduced into flies, but has not been characterized; a stock is available.

Double mutants bearing both Dmel\Grip84 and Dmel\t-Grip84 are lethal at mid-pupariation, and exhibit developmental delay and decreased brain size at larval and pupal stages.

[updated Nov. 2022 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

OMIM report

[CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 15; CDCBM15](https://omim.org/entry/618737)

Human gene(s) implicated

[TUBULIN-GAMMA COMPLEX-ASSOCIATED PROTEIN 2; TUBGCP2](https://omim.org/entry/617817)

Symptoms and phenotype

Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS) is an autosomal recessive neurologic disorder characterized by progressive microcephaly associated with abnormal facial features, hypotonia, and variable global developmental delay with impaired intellectual development. Brain imaging shows variable malformation of cortical development on the lissencephaly spectrum, mainly pachygyria and thin corpus callosum (summary by Mitani et al., 2019; pubmed:31630790). [from MIM:618737; 2022.11.08]

(OMIM, 2013-)

Genetics

Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS) is caused by homozygous or compound heterozygous mutation in the TUBGCP2 gene. [from MIM:618737; 2022.11.08]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The TUBGCP2 gene encodes tubulin gamma complex associated protein 2, a component of the gamma-tubulin complex which is necessary for microtubule nucleation at the centrosome [from Uniprot:Q9BSJ2; 2022.11.09]

(FlyBase Curators, 2013-)

TUBGCP2 is to enable gamma-tubulin binding activity. Predicted to contribute to microtubule minus-end binding activity. Involved in brain development and neuron migration. Located in centrosome and nucleoplasm. [from Alliance of Genome Resources: gene/HGNC:18599; 2022.11.09]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): TUBGCP2
Gene Cards: TUBGCP2
MedlinePlus (condition): Lissencephaly with cerebellar hypoplasia
MedlinePlus (condition): autosomal recessive primary microcephaly
MedlinePlus (gene): TUBGCP2
MARRVEL (human gene): TUBGCP2
NCBI MedGen: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures (PAMDDFS)
NCBI (Entrez) gene: TUBGCP2; tubulin gamma complex component 2
National Organization for Rare Disorders: Pachygyria

Disease synonyms

PAMDDFS

TUBGCP2-associated microcephaly

Related Diseases

Related human health report(s)

microcephaly, primary

Ortholog Information

Human gene(s) in FlyBase

Hsap\TUBGCP2

Human gene (HGNC)

Symbol / Name

TUBGCP2; tubulin gamma complex component 2

D. melanogaster ortholog (based on DIOPT)

Dmel\Grip84

(DIOPT, 2013-)

Dmel\t-Grip84

(DIOPT, 2013-)

Comments on ortholog(s)

One to two (1 human to 2 Drosophila); TUBGCP2 has one high-scoring Drosophila ortholog, Grip84, and one moderate-scoring Drosophila ortholog, t-Grip84.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\Grip84

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human TUBGCP2 (2 Drosophila to 1 human).

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\t-Grip84

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

T-G-TURC

Comments on ortholog(s)

Moderate-scoring ortholog of human TUBGCP2 (2 Drosophila to 1 human).

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 (16 groups)

Grip84

protein-protein

Interacting group

Assay

References

Grip84 - cnn

anti bait coimmunoprecipitation, western blot, pull down, Identification by mass spectrometry, peptide massfingerprinting

(Tovey et al., 2021, Habermann et al., 2012)

Grip84 - fzr

anti tag coimmunoprecipitation, peptide massfingerprinting

(Meghini et al., 2016)

Grip84 - γTub23C

two hybrid, cosedimentation through density gradient, western blot, anti bait coimmunoprecipitation, molecular weight estimation by staining, pull down, autoradiography

(Alzyoud et al., 2021, Gopalakrishnan et al., 2012, Wiese, 2008, Oegema et al., 1999)

Grip84 - γTub37C

anti bait coimmunoprecipitation, cosedimentation through density gradient, molecular weight estimation by staining, western blot, anti tag coimmunoprecipitation

(Tariq et al., 2020, Gopalakrishnan et al., 2012, Wiese, 2008, Kawaguchi and Zheng, 2004, Gunawardane et al., 2003, Oegema et al., 1999)

Grip84 - Grip71

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, molecular weight estimation by staining

(Gunawardane et al., 2003)

Grip84 - Grip75

cosedimentation through density gradient, molecular weight estimation by staining, western blot

(Gopalakrishnan et al., 2012, Oegema et al., 1999)

Grip84 - Grip91

pull down, autoradiography, cosedimentation through density gradient, western blot, molecular weight estimation by staining, two hybrid, anti bait coimmunoprecipitation

(Alzyoud et al., 2021, Gopalakrishnan et al., 2012, Wiese, 2008, Kawaguchi and Zheng, 2004, Oegema et al., 1999)

Grip84 - Grip128

cosedimentation through density gradient, molecular weight estimation by staining, western blot

(Gopalakrishnan et al., 2012, Wiese, 2008, Oegema et al., 1999)

Grip84 - Grip163

cosedimentation through density gradient, western blot, molecular weight estimation by staining

(Gopalakrishnan et al., 2012, Wiese, 2008, Oegema et al., 1999)

Grip84 - Plp

anti bait coimmunoprecipitation, western blot

(Kawaguchi and Zheng, 2004)

Grip84 - Rab2

pull down, peptide massfingerprinting

(Gillingham et al., 2014)

Grip84 - Rab4

pull down, peptide massfingerprinting

(Gillingham et al., 2014)

Grip84 - Sas-4

anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient

(Gopalakrishnan et al., 2012)

Grip84 - t-Grip84

two hybrid

(Alzyoud et al., 2024)

Grip84 - t-Grip91

two hybrid

(Alzyoud et al., 2024)

t-Grip84

protein-protein

Interacting group

Assay

References

t-Grip84 - Grip84

two hybrid

(Alzyoud et al., 2024)

t-Grip84 - Grip91

pull down, autoradiography, two hybrid

(Alzyoud et al., 2024)

Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)

Grip84

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

Grip84^PG36

model of pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

CEA

(Bartoszewski et al., 2022)

CEA with t-Grip84^MB07394

(Bartoszewski et al., 2022)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

t-Grip84

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

t-Grip84^MB07394

model of pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures

CEA with Grip84^PG36

(Bartoszewski et al., 2022)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

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\TUBGCP2^UAS.cBa

PBac{UAS-hTUBGCP2.B}

y¹ w^*; PBac{UAS-hTUBGCP2.B}VK00037/SM6a

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Grip84^GD11106

P{GD11106}

w¹¹¹⁸; P{GD11106}v34731

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00627}attP2

t-Grip84^HMS06240

P{TRiP.HMS06240}

y¹ v¹; P{TRiP.HMS06240}attP40/CyO

t-Grip84^GD9944

P{GD9944}

w¹¹¹⁸; P{GD9944}v25526

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Grip84^PG66

loss of function allele

Delta2-3 transposase

Grip84^PG36

Delta2-3 transposase

t-Grip84^MB07394

amorphic allele - molecular evidence

w¹¹¹⁸; Mi{ET1}t-Grip84^MB07394

References (4)

Report Sections

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