FB2026_03 , released September 17, 2026
Human Disease Model Report: focal segmental glomerulosclerosis 1
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General Information
Name
focal segmental glomerulosclerosis 1
FlyBase ID
FBhh0001506
Disease Ontology Term
Parent Disease
OMIM
FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1; FSGS1
Overview

This report describes focal segmental glomerulosclerosis 1, a renal disorder that exhibits autosomal dominant inheritance. The human gene implicated is ACTN4, which encodes Actinin Alpha 4. There is one high-scoring fly ortholog, Dmel\Actn, for which amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

UAS constructs of the human Hsap\ACTN4 gene, including wild-type ACTN4 and variants implicated in disease (M240T, W59R, K255E), have been introduced into flies. See the 'Disease-Implicated Variants' table below. Heterologous rescue (functional complementation) is observed for phenotypes associated with nephrocyte-specific RNAi knockdown of Dmel\Actn.

Nephrocyte-specific RNAi knockdown of Dmel\Actn results in decreased nephrocyte diaphragm length, and reduced filtration function. These phenotypes are rescued by coexpression of the wild-type Hsap\ACTN4 gene, but not by disease-implicated variants.

[updated Apr. 2024 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: focal segmental glomerulosclerosis
Symptoms and phenotype

Focal segmental glomerulosclerosis is one of many diseases and conditions can affect kidney function by attacking and damaging the glomeruli. "Glomerulosclerosis" refers to a hardening and scarring of the glomeruli. The scarring of FSGS takes place in small sections of each glomerulus, and only a limited number of glomeruli are damaged initially (https://www.kidney.org/atoz/content/focal).

(FlyBase Curators, 2013-)

A definitive diagnosis of FSGS is established only by histopathology findings (http://emedicine.medscape.com/article/245915-overview).

(FlyBase Curators, 2013-)

Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in several renal disorders that manifest clinically as proteinuria and progressive decline in renal function. Some patients with FSGS develop nephrotic syndrome, which includes massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. However, patients with FSGS may have proteinuria in the nephrotic range without other features of the nephrotic syndrome (summary by D'Agati et al., 2004, pubmed:14750104; Mathis et al., 1998, pubmed:9461087). [from MIM:603278; 2017.09.14]

(OMIM, 2013-)

Focal segmental glomerulosclerosis is a common cause of end-stage renal disease (Meyrier, 2005; pubmed:16932363). [from MIM:607832; 2017.09.14]

(OMIM, 2013-)

In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. [from MIM:607832; 2017.09.14]

(OMIM, 2013-)
Specific Disease Summary: focal segmental glomerulosclerosis 1
OMIM report

[FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1; FSGS1](https://omim.org/entry/603278)

Human gene(s) implicated

[ACTININ, ALPHA-4; ACTN4](https://omim.org/entry/604638)

Symptoms and phenotype

Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in several renal disorders that manifest clinically as proteinuria and progressive decline in renal function. Focal segmental glomerulosclerosis 1 (FSGS1) is an autosomal dominant glomerular disease associated with asymptomatic proteinuria and normal renal function (7 patients) or significant proteinuria leading to progressive renal failure (11 patients). Histopathologic changes were variable, but included focal segmental glomerulosclerosis and diffuse glomerulosclerosis. Renal failure usually occurred in the fifth decade of life. The most consistent clinical finding was proteinuria without microscopic hematuria or other significant urinary sediment elements (Mathis et al., 1992, pubmed:1429048; Mathis et al., 1998, pubmed:9461087). [from MIM:603278; 2023.03.20]

(OMIM, 2013-)
Genetics

FSGS1 is caused by heterozygous mutation in the gene ACTN4, encoding alpha-actinin-4, on chromosome 19q13. [from MIM:603278; 2023.03.20]

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

Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

(FlyBase Curators, 2013-)
External links
Disease synonyms
FSGS1
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
ACTN4; actinin alpha 4
D. melanogaster ortholog (based on DIOPT)
Dmel\Actn
(DIOPT, 2013-)
Comments on ortholog(s)

Many to one (4 human to 1 Drosophila); ACTN4 has one high-scoring Drosophila ortholog, Actn.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Dmel\Actn
    Gene Snapshot
    α actinin (Actn) encodes an actin cross-linking protein with muscle and non-muscle specific isoforms, which are produced by alternative spicing. The muscle isoform has a role in muscle development while the non-muscle isoform localizes to ovarian ring canals and has a role in cytoskeletal remodeling of follicle cells. [Date last reviewed: 2019-03-07]
    Molecular function (GO)
    Cellular component (GO)
    Gene Groups / Pathways
    Comments on ortholog(s)

    High-scoring ortholog of human ACTN1, ACTN2, ACTN3, and ACTN4 (1 Drosophila to 4 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 (36 groups)
      Actn
      protein-protein
      Interacting group
      Assay
      References
      Actn - Act79B
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Adh
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Aldo
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Argk1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - CG14207
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - CG14315
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Cs1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Cyt-c1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - dos
      anti tag coimmunoprecipitation, peptide massfingerprinting
      (Friedman et al., 2011)
      Actn - Gdh
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Gpdh1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Idh3a
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - kirre
      two hybrid
      (Kreiskother et al., 2006)
      Actn - Lasp
      tandem affinity purification, western blot, anti tag coimmunoprecipitation, peptide massfingerprinting
      (Fernandes and Schöck, 2014)
      Actn - mAcon1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Mdh2
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Mf
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Mhc
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Mlc1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Mlc2
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Mlp84B
      anti tag coimmunoprecipitation, western blot, two hybrid
      (Clark and Kadrmas, 2013)
      Actn - ND-PDSW
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Ogdh1
      experimental knowledge based, anti tag coimmunoprecipitation, western blot
      (González Morales et al., 2023, Guruharsha et al., 2011)
      Actn - osk
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Hurd et al., 2016)
      Actn - Prm
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Rheb
      anti tag coimmunoprecipitation, Identification by mass spectrometry
      (Vinayagam et al., 2016)
      Actn - rols
      two hybrid
      (Kreiskother et al., 2006)
      Actn - Scp1
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Smn
      anti bait coimmunoprecipitation, western blot, pull down, anti tag coimmunoprecipitation, peptide massfingerprinting
      (Rajendra et al., 2007)
      Actn - Tm2
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - TpnC41C
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Tppl
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - up
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - wupA
      experimental knowledge based
      (Guruharsha et al., 2011)
      Actn - Zasp52
      anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based, anti bait coimmunoprecipitation, western blot
      (Liao et al., 2016, Rhee et al., 2014, Katzemich et al., 2013, Jani and Schock, 2007)
      Actn - Zasp66
      anti tag coimmunoprecipitation, western blot
      (Katzemich et al., 2013)
      Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
      Hsap\ACTN4
      Models Based on Experimental Evidence ( 3 )
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      Hsap\ACTN4UAS.WT.Tag:HA
      ameliorates  focal segmental glomerulosclerosis 1
      modeled by ActnKK102286
      (Odenthal et al., 2023)
      Actn
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      ActnKK102286
      model of  focal segmental glomerulosclerosis 1
      CEC
      (Odenthal et al., 2023)
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      ActnKK102286
      model of  focal segmental glomerulosclerosis 1
      is ameliorated by Hsap\ACTN4UAS.WT.Tag:HA
      (Odenthal et al., 2023)
      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\ACTN4UAS.WT.Tag:HA
      P{UAS-hACTN4.WT.HA}
      Hsap\ACTN4M240T.UAS.Tag:HA
      P{UAS-hACTN4.M240T.HA}
      Hsap\ACTN4W59R.UAS.Tag:HA
      P{UAS-hACTN4.W59R.HA}
      Hsap\ACTN4K255E.UAS.Tag:HA
      P{UAS-hACTN4.K255E.HA}
      Hsap\ACTN4UAS.Tag:HA
      M{UAS-hACTN4.HA}
      y1 w*; M{UAS-hACTN4.HA}ZH-86Fb
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      ActnRNAi.13xlexAop.cZa
      P{13xlexAop-Actn.RNAi.Z}
      ActnGD1354
      P{GD1354}
      w1118; P{GD1354}v7760
      ActnKK102286
      P{KK102286}
      P{KK102286}VIE-260B
      ActnHMS00193
      P{TRiP.HMS00193}
      y1 sc* v1 sev21; P{TRiP.HMS00193}attP2
      ActnNIG.4376R
      P{NIG.4376R}
      P{NIG.4376R}1
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      Actn8
      amorphic allele - genetic evidence
      X ray
      In(1)HC207, Actn8/FM7a
      Actn5
      amorphic allele - genetic evidence
      X ray
      Actn6
      amorphic allele - genetic evidence
      X ray
      Actn9
      amorphic allele - genetic evidence
      X ray
      References (5)