Human Disease Model Report: spinocerebellar ataxia, autosomal recessive 25 (postulated)

General Information

Name

spinocerebellar ataxia, autosomal recessive 25 (postulated)

FlyBase ID

FBhh0000557

Disease Ontology Term

autosomal recessive spinocerebellar ataxia 25

Parent Disease

spinocerebellar ataxia, autosomal recessive

OMIM

SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 25; SCAR25

Overview

This report describes spinocerebellar ataxia, autosomal recessive 25 (postulated). In the single family in which this form of hereditary ataxia has been characterized, it exhibits autosomal recessive inheritance. The gene postulated to be implicated in this disease is autophagy 5 (ATG5), which is part of a complex involved in autophagy in apoptotic cells. There is a single ortholog of ATG5 in Drosophila, Dmel\Atg5, for which an amorphic mutation, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

UAS constructs of the human Hsap\ATG5 have been introduced into flies. Heterologous rescue (functional complementation) is observed: ubiquitous expression of the wild-type human gene almost completely rescues the mobility defect observed for animals homozygous for a Dmel\Atg5 amorphic mutation.

Variant(s) implicated in human disease introduced (as transgenic human gene, ATG5): the E122D variant form of the human gene has been introduced into flies. Based on an assay for heterologous rescue, this variant appears to retain a low level of function.

Animals homozygous for an amorphic mutation of Dmel\Atg5 are viable as adults; based on a climbing assay, they exhibit significant mobility defects. Physical and genetic interactions of Dmel\Atg5 have been described; see below and in the Atg5 gene report.

[updated Sep. 2018 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: spinocerebellar ataxia, autosomal recessive 25 (postulated)

OMIM report

[SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 25; SCAR25](https://omim.org/entry/617584)

Human gene(s) implicated

[AUTOPHAGY-RELATED 5; ATG5](https://omim.org/entry/604261)

Symptoms and phenotype

Congenital ataxia, mental retardation, and developmental delay.

(Kim et al., 2016)

Genetics

A homozygous missense mutation (E122D), changing a conserved amino acid, was identified in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay.

(Kim et al., 2016)

Evidence indicates that autosomal recessive spinocerebellar ataxia-25 (SCAR25) is caused by homozygous mutation in the ATG5 gene; one such family has been reported. [from MIM:617584; 2018.09.14]

(OMIM, 2013-)

Cellular phenotype and pathology

The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5.

(Kim et al., 2016)

Molecular information

Crystal structure of the ATG12-ATG5-ATG16L1 complex indicates that E122 is located in the vicinity of the ATG12-ATG5 interaction surface.

(Kim et al., 2016)

ATG5 plays a role in elongation of the phagophore and its subsequent maturation into the complete autophagosome.

(Kim et al., 2016)

ATG5 was originally named apoptosis-specific protein, since the ATG5 protein is found at high levels in apoptotic cells. Since levels of ATG5 mRNA are similar in viable and apoptotic cells, the increase in protein levels may be due to increased translation of preexisting ATG5 mRNA (Hammond et al., 1998; pubmed:9563500).[from MIM:604261; 2017.06.16]

(OMIM, 2013-)

External links

Gene2Function (human gene): ATG5
Gene Cards: ATG5
GeneReviews, NCBI Bookshelf: Hereditary Ataxia Overview
MedlinePlus (gene): ATG5
KEGG Disease Pathways: Autophagy - animal - Homo sapien
MARRVEL (human gene): ATG5
NCBI (Entrez) gene: ATG5; autophagy related 5

Disease synonyms

hereditary ataxia (postulated), ATG5-related

SCAR25

spinocerebellar ataxia autosomal recessive 25 (postulated)

Related Diseases

Related human health report(s)

spinocerebellar ataxia, autosomal recessive

Ortholog Information

Human gene(s) in FlyBase

Hsap\ATG5

Human gene (HGNC)

Symbol / Name

ATG5; autophagy related 5

D. melanogaster ortholog (based on DIOPT)

Dmel\Atg5

(DIOPT, 2013-)

Comments on ortholog(s)

One to one (1 human to 1 Drosophila).

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Atg5

Gene Snapshot

Contributions welcome

Molecular function (GO)

Atg8-family ligase activity

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human ATG5 (reciprocal best hit). Dmel\Atg5 shares 48% identity and 67% similarity with the human gene.

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 (8 groups)

Atg5

RNA-protein

Interacting group

Assay

References

Atg5 - orb

anti tag coimmunoprecipitation, quantitative reverse transcription pcr

(Rojas-Ríos et al., 2015)

protein-protein

Interacting group

Assay

References

Atg5 - Act5C

experimental knowledge based

(Guruharsha et al., 2011)

Atg5 - Atg16

two hybrid, experimental knowledge based

(Hu et al., 2017.6.13, Guruharsha et al., 2011)

Atg5 - Cam

experimental knowledge based

(Guruharsha et al., 2011)

Atg5 - CG4325

experimental knowledge based

(Guruharsha et al., 2011)

Atg5 - Poxn

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

Atg5 - Rab19

pull down, peptide massfingerprinting

(Gillingham et al., 2014)

Atg5 - wdb

experimental knowledge based

(Guruharsha et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)

Atg5

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

Atg5^5cc5

model of hereditary ataxia

CEA

(Kim et al., 2016)

CEA with Hsap\ATG5^{E122D.UAS.Tag:FLAG}

(Kim et al., 2016)

Modifiers Based on Experimental Evidence ( 6 )

Allele

Disease

Interaction

References

Atg5^UASp.EGFP

ameliorates Huntington's disease

modeled by Hsap\HTT^{N548.Q128.UAS}

(Prakash et al., 2022)

Atg5^RNAi.UAS

ameliorates Alzheimer's disease

modeled by Hsap\APP^{Aβ42.UAS.Tag:SS(rPENK)}

(Ling et al., 2009)

Atg5^HMS01244

ameliorates cancer

modeled by Raf^F22.hs

(Zhao et al., 2021)

Atg5^JF02703

exacerbates carcinoma

modeled by Delta^UAS.cDa, lola^GS88A8

(Pérez et al., 2015)

ameliorates C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis

modeled by Zzzz\GGGGCC^30.UAS.EGFP

(Cunningham et al., 2020)

ameliorates Parkinson's disease

modeled by Hsc70-5^KK100233

(Zhu et al., 2021)

Atg5^5cc5

model of hereditary ataxia

is ameliorated by Hsap\ATG5^UAS.Tag:FLAG

(Kim et al., 2016)

Atg5^RNAi.UAS.cUa

ameliorates Huntington's disease

modeled by Zzzz\CAG^{127Q.UAS.Tag:HA}

(Maurya and Tapadia, 2023)

Hsap\ATG5

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

Hsap\ATG5^{E122D.UAS.Tag:FLAG}

model of hereditary ataxia

CEA with Atg5^5cc5

(Kim et al., 2016)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Hsap\ATG5^UAS.Tag:FLAG

ameliorates hereditary ataxia

modeled by Atg5^5cc5

(Kim et al., 2016)

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\ATG5^UAS.Tag:FLAG

M{UAS-hATG5.WT.FLAG}

w^*; M{UAS-hATG5.WT.FLAG}ZH-51D

Hsap\ATG5^{E122D.UAS.Tag:FLAG}

M{UAS-hATG5.E122D.FLAG}

w^*; M{UAS-hATG5.E122D.FLAG}ZH-51D

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

Atg5^UASp.EGFP

P{UASp-eGFP-drAtg5}

P{hsFLP}12, y¹ w^*; Kr^If-1/CyO; P{UASp-eGFP-drAtg5}16

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

y¹ v¹; P{TRiP.JF02703}attP2

Atg5^HMS01244

P{TRiP.HMS01244}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS01244}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Atg5^5cc5

amorphic allele - molecular evidence

CRISPR/Cas9

Atg5^5cc5/FM7i, P{ActGFP}JMR3

References (12)

Report Sections

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