FB2024_03 , released June 25, 2024
Human Disease Model Report: microcephaly 6, primary, autosomal recessive
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General Information
Name
microcephaly 6, primary, autosomal recessive
FlyBase ID
FBhh0000777
Disease Ontology Term
Parent Disease
OMIM
MICROCEPHALY 6, PRIMARY, AUTOSOMAL RECESSIVE; MCPH6
Overview

This report describes microcephaly 6, primary, autosomal recessive (MCPH6), which is a subtype of primary microcephaly. The human gene implicated in this disease is centromeric protein J (CENPJ), which plays a role in centrosome function. There is a single fly ortholog, Dmel\Sas-4, for which RNAi-targeting constructs, over-expression constructs, and alleles caused by insertional mutagenesis have been generated.

A Dmel\Sas-4 mutation analogous to a variant implicated in human disease has characterized; see the 'Disease-Implicated Variants' table below.

A UAS construct of the wild-type human Hsap\CENPJ gene has been introduced into flies and is available, but has not been characterized to date.

A related fly disease model is described in 'microcephaly, centrosome-SAC dysfunction' (FBhh0000778). In this model, a mutation of Dmel\Sas-4 has been combined with mutations in components of the spindle assembly checkpoint (SAC).

[updated Jan. 2023 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 6, primary, autosomal recessive
OMIM report

[MICROCEPHALY 6, PRIMARY, AUTOSOMAL RECESSIVE; MCPH6](https://omim.org/entry/608393)

Human gene(s) implicated

[CENTROMERIC PROTEIN J; CENPJ](https://omim.org/entry/609279)

Symptoms and phenotype

Although MCHP and Seckel syndrome (SCKS) were previously distinguished by height (maximum height in SCKS was equivalent to the minimum height in MCPH), stature is no longer a discriminating feature, leading to the conclusion that these phenotypes constitute a spectrum rather than distinct entities. [Medgen, 330770; 2018.03.29]

(FlyBase Curators, 2013-)
Genetics

Primary microcephaly 6 (MCPH6) is caused by homozygous mutation in the gene encoding centromeric protein J (CENPJ). [from MIM:608393; 2018.03.29]

(OMIM, 2013-)
Cellular phenotype and pathology
Molecular information

CENPJ encodes a protein that belongs to the centromere protein family. During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. [Gene Cards, CENJ; 2018.03.29]

(FlyBase Curators, 2013-)

The CENPJ gene encodes a centrosomal protein with a putative role in regulation of microtubule assembly and nucleation (Hung et al., 2000, pubmed:11003675). [from MIM:609279; 2018.03.29]

(OMIM, 2013-)
External links
Disease synonyms
MCPH6
MCPH6/SCKL4
MCPH-SCKS
MCPH-SCKS spectrum disorders
microcephaly, 6, primary, autosomal recessive
SCKS
Seckel syndrome
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
CENPJ; centromere protein J
D. melanogaster ortholog (based on DIOPT)
Dmel\Sas-4
(DIOPT, 2013-)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila; additional low-scoring orthologs in human.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Dmel\Sas-4
    Gene Snapshot
    Spindle assembly abnormal 4 (Sas-4) encodes a centriole protein that is essential for centriole assembly. It is recruited to centrioles through an interaction with the centriole protein encoded by ana2, and it helps recruit microtubules to the centriole. [Date last reviewed: 2019-03-14]
    Molecular function (GO)
    Cellular component (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)

      High-scoring ortholog of human CENPJ (1 Drosophila to 1 human); additional low-scoring orthologous genes in 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 (27 groups)
        Sas-4
        protein-protein
        Interacting group
        Assay
        References
        Sas-4
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - ana1
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - ana2
        anti tag coimmunoprecipitation, anti tag western blot, x-ray crystallography, pull down, two hybrid, bio-layer interferometry, predetermined participant, autoradiography, anti bait coimmunoprecipitation, western blot
        (McLamarrah et al., 2020, Moyer and Holland, 2019, McLamarrah et al., 2018, Galletta et al., 2016, Dzhindzhev et al., 2014, Zheng et al., 2014, Cottee et al., 2013)
        Sas-4 - ana3
        anti bait coimmunoprecipitation, peptide massfingerprinting, western blot
        (Gopalakrishnan et al., 2011)
        Sas-4 - asl
        anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, cosedimentation through density gradient, two hybrid, anti tag western blot, pull down, autoradiography, peptide massfingerprinting
        (Galletta et al., 2016, Galletta et al., 2016, Klebba et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011, Conduit et al., 2010, Dzhindzhev et al., 2010)
        Sas-4 - aurA
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - βTub56D
        pull down, western blot, anti tag coimmunoprecipitation, anti bait coimmunoprecipitation, cosedimentation through density gradient
        (Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)
        Sas-4 - Cep135
        two hybrid, pull down, western blot, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, anti tag western blot
        (Galletta et al., 2016, Zheng et al., 2014)
        Sas-4 - CG13920
        experimental knowledge based
        (Guruharsha et al., 2011)
        Sas-4 - Cnb
        anti tag coimmunoprecipitation, peptide massfingerprinting
        (Januschke et al., 2013)
        Sas-4 - cnn
        pull down, western blot, anti bait coimmunoprecipitation, peptide massfingerprinting, anti tag coimmunoprecipitation, anti tag western blot, cosedimentation through density gradient, two hybrid
        (Galletta et al., 2016, Conduit et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011, Conduit et al., 2010)
        Sas-4 - Cp110
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - Cp190
        anti bait coimmunoprecipitation, peptide massfingerprinting, pull down, western blot, anti tag coimmunoprecipitation
        (Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)
        Sas-4 - γTub23C
        anti bait coimmunoprecipitation, western blot, pull down, cosedimentation through density gradient, anti tag coimmunoprecipitation
        (Conduit et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)
        Sas-4 - γTub37C
        anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, cosedimentation through density gradient, pull down
        (Conduit et al., 2015, Zheng et al., 2014, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)
        Sas-4 - Grip75
        anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient
        (Gopalakrishnan et al., 2012)
        Sas-4 - Grip84
        anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot
        (Gopalakrishnan et al., 2012)
        Sas-4 - Grip91
        anti bait coimmunoprecipitation, western blot, cosedimentation through density gradient
        (Gopalakrishnan et al., 2012)
        Sas-4 - Grip128
        anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot, peptide massfingerprinting, pull down
        (Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)
        Sas-4 - Grip163
        anti bait coimmunoprecipitation, cosedimentation through density gradient, western blot
        (Gopalakrishnan et al., 2012)
        Sas-4 - Lk6
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - Nek2
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - Plp
        anti bait coimmunoprecipitation, peptide massfingerprinting, two hybrid, western blot, pull down, cosedimentation through density gradient, anti tag coimmunoprecipitation
        (Galletta et al., 2016, Gopalakrishnan et al., 2012, Gopalakrishnan et al., 2011)
        Sas-4 - polo
        two hybrid
        (Galletta et al., 2016)
        Sas-4 - SAK
        pull down, anti tag western blot, isothermal titration calorimetry, predetermined participant, anti tag coimmunoprecipitation, autoradiography
        (Ábrahám et al., 2023, McLamarrah et al., 2020)
        Sas-4 - Sas-6
        experimental knowledge based
        (Guruharsha et al., 2011)
        Sas-4 - spd-2
        two hybrid
        (Galletta et al., 2016)
        Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)
        Sas-4
        Models Based on Experimental Evidence ( 2 )
        Modifiers Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Interaction
        References
        Sas-4s2214
        exacerbates  microcephaly
        modeled by Mad11
        (Poulton et al., 2017)
        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
        Primary microcephaly
        Related mammalian, viral, bacterial, or synthetic transgenes
        Allele
        Transgene
        Publicly Available Stocks
        Hsap\CENPJUAS.cBa
        PBac{UAS-hCENPJ.B}
        y1 w*; PBac{UAS-hCENPJ.B}VK00037
        Selected Drosophila transgenes
        Allele
        Transgene
        Publicly Available Stocks
        Sas-4ΔTCP.GFP
        P{Sas-4.DeltaTCP.GFP}
        RNAi constructs available
        Allele
        Transgene
        Publicly Available Stocks
        Sas-4GD6852
        P{GD6852}
        w1118; P{GD6852}v17975
        Sas-4KK100878
        P{KK100878}
        P{KK100878}VIE-260B
        Sas-4HMS01463
        P{TRiP.HMS01463}
        y1 sc* v1 sev21; P{TRiP.HMS01463}attP2
        Selected Drosophila classical alleles
        Allele
        Allele class
        Mutagen
        Publicly Available Stocks
        Sas-4s2214
        loss of function allele
        P-element activity
        w1118; P{lacW}Sas-4s2214/TM3, Sb1
        References (10)