Human Disease Model Report: microcephaly, condensin subunit insufficiency

General Information

Name

microcephaly, condensin subunit insufficiency

FlyBase ID

FBhh0001594

Disease Ontology Term

primary microcephaly

Parent Disease

microcephaly, primary

OMIM

Overview

Condensin complexes I and II play essential roles in mitotic chromosome assembly and segregation. Several genes encoding condensin subunits have been implicated in primary microcephaly, specifically microcephaly 22 (MIM:617984, human gene NCAPD3 implicated); microcephaly 21 (MIM:617983, human gene NCAPD2 implicated), and microcephaly 23 (MIM:617985, human gene NCAPH implicated). All three diseases exhibit autosomal recessive inheritance. Drosophila genes orthologous to each are Cap-D3 (orthologous to NCAPD3), Cap-D2 (orthologous to NCAPD2), and barr (orthologous to NCAPH). An additional component of the condensin complex, Dmel/SMC2 has also been studied in Drosophila; human SMC2 has not been implicated in disease.

None of these human genes has been introduced into flies.

RNAi-mediated targeted knockdown of Dmel\Cap-D3 in the developing brain results in adults with dramatically reduced head size and eye size; adult brain size is reduced. However, larval brain size is normal. Similar results are obtained with targeted knockdown of Dmel\Cap-D2, Dmel\barr, or Dmel\SMC2.

An increase in retrotransposon activity is observed in neural progenitor cells of third instar larvae expressing decreased levels of condensin proteins; the resulting adult small-head phenotypes are suppressed by ingestion of reverse transcriptase inhibitors. These observations suggest a model in which the observed microcephaly is due to increased cell death related to high levels of retrotransposon activity.

[updated Jul. 2024 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: microcephaly, primary

Symptoms and phenotype

Primary microcephaly (MCPH) refers to the clinical finding of a head circumference less than 3 standard deviations below the age- and sex-related mean, present at birth. Primary microcephaly is a static developmental anomaly, distinguished from secondary microcephaly, which refers to a progressive neurodegenerative condition. Microcephaly is a disorder of fetal brain growth; individuals with microcephaly have small brains and almost always have mental retardation; additional clinical features may include short stature or mild seizures (review by Woods et al., 2005; pubmed:15806441). [from MIM:251200; 2016.06.16]

(OMIM, 2013-)

Specific Disease Summary: microcephaly, condensin subunit insufficiency

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Autosomal recessive primary microcephaly-21 (MCPH21) is caused by homozygous mutation in the NCAPD2 gene. MIM:617983; 2024.07.30]

(OMIM, 2013-)

Autosomal recessive primary microcephaly-22 (MCPH22) is caused by homozygous or compound heterozygous mutation in the NCAPD3 gene. [from MIM:617984; 2024.07.30]

(OMIM, 2013-)

Autosomal recessive primary microcephaly-23 (MCPH23) is caused by homozygous mutation in the NCAPH gene. [from MIM:617985; 2024.07.30]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

Condensin complexes I and II play essential roles in mitotic chromosome assembly and segregation. [from MIM:609276; 2024.07.30]

(OMIM, 2013-)

External links

Disease synonyms

Related Diseases

Related human health report(s)

microcephaly, primary

Related Specific Diseases

OMIM phenotypic series

Microcephaly, primary autosomal recessive

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[MCPH1](https://omim.org/entry/251200)

[MCPH1](https://omim.org/entry/607117)

microcephaly 1, primary, autosomal recessive

[MCPH2](https://omim.org/entry/604317)

[WDR62](https://omim.org/entry/613583)

microcephaly 2, primary, autosomal recessive

[MCPH3](https://omim.org/entry/604804)

[CDK5RAP2](https://omim.org/entry/608201)

microcephaly 3, primary, autosomal recessive

[MCPH4](https://omim.org/entry/604321)

[KNL1](https://omim.org/entry/609173)

[MCPH5](https://omim.org/entry/608716)

[ASPM](https://omim.org/entry/605481)

microcephaly 5, primary, autosomal recessive

[MCPH6](https://omim.org/entry/608393)

[CENPJ](https://omim.org/entry/609279)

microcephaly 6, primary, autosomal recessive

[MCPH7](https://omim.org/entry/612703)

[STIL](https://omim.org/entry/181590)

[MCPH8](https://omim.org/entry/614673)

[CEP135](https://omim.org/entry/611423)

[MCPH9](https://omim.org/entry/614852)

[CEP152](https://omim.org/entry/613529)

[MCPH10](https://omim.org/entry/615095)

[ZNF335](https://omim.org/entry/610827)

[MCPH11](https://omim.org/entry/615414)

[PHC1](https://omim.org/entry/602978)

[MCPH12](https://omim.org/entry/616080)

[CDK6](https://omim.org/entry/603368)

[MCPH13](https://omim.org/entry/616051)

[CENPE](https://omim.org/entry/117143)

[MCPH14](https://omim.org/entry/616402)

[SASS6](https://omim.org/entry/609321)

[MCPH16](https://omim.org/entry/616681)

[ANKLE2](https://omim.org/entry/616062)

microcephaly 16, primary, autosomal recessive

[MCPH17](https://omim.org/entry/617090)

[CIT](https://omim.org/entry/605629)

microcephaly 17, primary, autosomal recessive

[MCPH18](https://omim.org/entry/617520)

[WDFY3](https://omim.org/entry/617485)

microcephaly 18, primary, autosomal dominant

[MCPH19](https://omim.org/entry/617800)

[COPB2](https://omim.org/entry/606990)

[MCPH20](https://omim.org/entry/617914)

[KIF14](https://omim.org/entry/611279)

[MCPH21](https://omim.org/entry/617983)

[NCAPD2](https://omim.org/entry/615638)

[MCPH22](https://omim.org/entry/617984)

[NCAPD3](https://omim.org/entry/609276)

[MCPH23](https://omim.org/entry/617985)

[NCAPH](https://omim.org/entry/602332)

[MCPH24](https://omim.org/entry/618179)

[NUP37](https://omim.org/entry/609264)

[MCPH25](https://omim.org/entry/618351)

[TRAPPC14](https://omim.org/entry/618350)

[NEDMISBA](https://omim.org/entry/616486)

[MFSD2A](https://omim.org/entry/614397)

Ortholog Information

Human gene(s) in FlyBase

Other mammalian ortholog(s) used

D. melanogaster Gene Information (4)

Dmel\barr

Gene Snapshot

barren (barr) encodes a chromatin binding protein involved in chromatin condensation. It regulates Malpighian tubule development and epithelial morphogenesis. [Date last reviewed: 2019-07-11]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

COND-I

Comments on ortholog(s)

High-scoring ortholog of human NCAPH (1 Drosophila gene 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\Cap-D3

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

COND-II

Comments on ortholog(s)

High-scoring ortholog of human NCAPD3 (1 Drosophila gene 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\Cap-D2

Gene Snapshot

CAP-D2 condensin subunit (Cap-D2) encodes a component of the conserved condensin I complex, together with the products of Cap-G, barr, SMC2 and glu. Condensin I associates with mitotic chromatin and plays a crucial role in shaping mitotic chromosomes and in their faithful segregation during anaphase. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

COND-I

Comments on ortholog(s)

High-scoring ortholog of human NCAPD2 (1 Drosophila gene 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\SMC2

Gene Snapshot

Structural maintenance of chromosomes 2 (SMC2) encodes a condensin subunit involved in chromosome condensation and cell division. It contributes to neurogenesis and stem cell differentiation. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human SMC2 (1 Drosophila gene to 1 human; multiple similar genes in both species.)

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 (23 groups)

barr

protein-protein

Interacting group

Assay

References

barr - AGO2

anti bait coimmunoprecipitation, western blot

(Pek and Kai, 2011)

barr - bel

anti bait coimmunoprecipitation, western blot

(Pek and Kai, 2011)

barr - Cap-D2

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, autoradiography

(Herzog et al., 2013, Pek and Kai, 2011, Pek and Kai, 2011, D'Avino et al., 2009, Savvidou et al., 2005)

barr - Cap-D3

anti tag coimmunoprecipitation, autoradiography

(Herzog et al., 2013)

barr - Cap-G

anti tag coimmunoprecipitation, western blot, autoradiography, peptide massfingerprinting

(Herzog et al., 2013, D'Avino et al., 2009)

barr - glu

anti tag coimmunoprecipitation, autoradiography, peptide massfingerprinting

(Herzog et al., 2013, D'Avino et al., 2009)

barr - ph-d

anti bait coimmunoprecipitation, western blot

(Lupo et al., 2001)

barr - ph-p

anti bait coimmunoprecipitation, western blot

(Lupo et al., 2001)

barr - SMC2

anti tag coimmunoprecipitation, peptide massfingerprinting

(D'Avino et al., 2009)

barr - spn-E

anti bait coimmunoprecipitation, western blot

(Pek and Kai, 2011)

barr - Top2

anti bait coimmunoprecipitation, western blot

(Lupo et al., 2001)

barr - vas

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot

(Pek and Kai, 2011)

Cap-D3

protein-protein

Interacting group

Assay

References

Cap-D3 - barr

anti tag coimmunoprecipitation, autoradiography

(Herzog et al., 2013)

Cap-D3 - Cap-H2

anti tag coimmunoprecipitation, autoradiography

(Herzog et al., 2013)

Cap-D3 - Rbf

anti tag coimmunoprecipitation, western blot

(Longworth et al., 2008)

Cap-D2

protein-protein

Interacting group

Assay

References

Cap-D2 - barr

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting, autoradiography

(Herzog et al., 2013, Pek and Kai, 2011, Pek and Kai, 2011, D'Avino et al., 2009, Savvidou et al., 2005)

Cap-D2 - bel

anti bait coimmunoprecipitation, western blot

(Pek and Kai, 2011)

Cap-D2 - Cap-G

anti tag coimmunoprecipitation, western blot

(Herzog et al., 2013)

Cap-D2 - Cap-H2

anti tag coimmunoprecipitation, autoradiography

(Herzog et al., 2013)

Cap-D2 - glu

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, autoradiography

(Herzog et al., 2013, Savvidou et al., 2005)

Cap-D2 - SMC2

anti bait coimmunoprecipitation, western blot

(Savvidou et al., 2005)

Cap-D2 - vas

anti bait coimmunoprecipitation, western blot

(Pek and Kai, 2011)

SMC2

protein-protein

Interacting group

Assay

References

SMC2 - barr

anti tag coimmunoprecipitation, peptide massfingerprinting

(D'Avino et al., 2009)

SMC2 - Cap-D2

anti bait coimmunoprecipitation, western blot

(Savvidou et al., 2005)

SMC2 - Cap-G

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

(Herzog et al., 2013)

SMC2 - Cap-H2

anti tag coimmunoprecipitation, western blot

(Buster et al., 2013)

SMC2 - Nelf-E

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

Alleles Reported to Model Human Disease (Disease Ontology) (0 alleles)

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

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Cap-D3^GD913

P{GD913}

w¹¹¹⁸; P{GD913}v29657

y¹ v¹; P{TRiP.HMJ23605}attP40/CyO

barr^GD12427

P{GD12427}

w¹¹¹⁸; P{GD12427}v26759

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00049}attP2

w¹¹¹⁸; P{GD9677}v33424

y¹ v¹; P{TRiP.JF01279}attP2

Cap-D2^JF01280

P{TRiP.JF01280}

y¹ v¹; P{TRiP.JF01280}attP2

Cap-D2^GL00523

P{TRiP.GL00523}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00523}attP2

SMC2^GD4489

P{GD4489}

w¹¹¹⁸; P{GD4489}v10711/CyO

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00360}attP2

SMC2^GL00440

P{TRiP.GL00440}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00440}attP40

SMC2^NIG.10212R

P{NIG.10212R}

P{NIG.10212R}2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

barr^L305

amorphic allele - genetic evidence

P-element activity

y¹ w^67c23; barr^L305/CyO

References (4)

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