C9orf72 C9orf72-SMCR8 complex subunit [Homo sapiens (human)] - Gene

Summary

Official Symbol: C9orf72provided by HGNC
Official Full Name: C9orf72-SMCR8 complex subunitprovided by HGNC
Primary source: HGNC:HGNC:28337
See related: Ensembl:ENSG00000147894 MIM:614260; AllianceGenome:HGNC:28337
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: ALSFTD; DENND9; FTDALS; DENNL72; FTDALS1
Summary: The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]
Expression: Ubiquitous expression in appendix (RPKM 9.7), testis (RPKM 9.3) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 9p21.2

Exon count:: 12

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	9	NC_000009.12 (27546546..27573866, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	9	NC_060933.1 (27557112..27584475, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	9	NC_000009.11 (27546544..27573864, complement)

Chromosome 9 - NC_000009.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: Tissue-specific circular RNA induction during human fetal development
Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
BioProject: PRJNA270632
Publication: PMID 26076956
Analysis date: Mon Apr 2 22:54:59 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.
Title: Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids.
C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.
Title: C9orf72 gene repeat expansion phenotype profile of motor neurone disease in Portugal.
Toxic gain-of-function mechanisms in C9orf72 ALS-FTD neurons drive autophagy and lysosome dysfunction.
Title: Toxic gain-of-function mechanisms in C9orf72 ALS-FTD neurons drive autophagy and lysosome dysfunction.
Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions.
Title: Unveiling New Genetic Variants Associated with Age at Onset in Alzheimer's Disease and Frontotemporal Lobar Degeneration Due to C9orf72 Repeat Expansions.
Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.
Title: Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons.
Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand.
Title: Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand.
Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.
Title: Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.
Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.
Title: Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.
Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.
Title: Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.
Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.
Title: Neuromuscular organoids model spinal neuromuscular pathologies in C9orf72 amyotrophic lateral sclerosis.

Submit: New GeneRIF Correction See all GeneRIFs (567)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Amyotrophic lateral sclerosis MedGen: C0002736 GeneReviews: Amyotrophic Lateral Sclerosis Overview	Compare labs
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 MedGen: C5779877 OMIM: 105550 GeneReviews: Amyotrophic Lateral Sclerosis Overview, C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia	Compare labs

EBI GWAS Catalog

Description
Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. EBI GWAS Catalog EBI GWAS CatalogPubMed
Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. EBI GWAS Catalog EBI GWAS CatalogPubMed
Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies genetic determinants of urine PCA3 levels in men. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH66179 (e-PCR)
- UniSTS:87042

SHGC-36542 (e-PCR)
- UniSTS:63515

D9S1122 (e-PCR), detects polymorphism
- UniSTS:50735

D9S922 (e-PCR), detects polymorphism
- UniSTS:64876

D9S301 (e-PCR), detects polymorphism
- UniSTS:17012

SGC32711 (e-PCR)
- UniSTS:41127

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables GTPase activator activity	IMP Inferred from Mutant Phenotype more info	PubMed
contributes_to guanyl-nucleotide exchange factor activity	IDA Inferred from Direct Assay more info	PubMed
enables guanyl-nucleotide exchange factor activity	IDA Inferred from Direct Assay more info	PubMed
enables guanyl-nucleotide exchange factor activity	IEA Inferred from Electronic Annotation more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables small GTPase binding	IDA Inferred from Direct Assay more info	PubMed
enables small GTPase binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in autophagosome-lysosome fusion	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in autophagy	IBA Inferred from Biological aspect of Ancestor more info
involved_in autophagy	IEA Inferred from Electronic Annotation more info
involved_in autophagy	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in axon extension	IEA Inferred from Electronic Annotation more info
involved_in axon extension	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in endocytosis	IBA Inferred from Biological aspect of Ancestor more info
involved_in endocytosis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in late endosome to lysosome transport	IEA Inferred from Electronic Annotation more info
involved_in late endosome to lysosome transport	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of exocytosis	NAS Non-traceable Author Statement more info	PubMed
involved_in negative regulation of immune response	NAS Non-traceable Author Statement more info	PubMed
involved_in negative regulation of protein phosphorylation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of macroautophagy	IGI Inferred from Genetic Interaction more info	PubMed
involved_in positive regulation of macroautophagy	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of TORC1 signaling	IEA Inferred from Electronic Annotation more info
involved_in regulation of TORC1 signaling	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of actin filament organization	IEA Inferred from Electronic Annotation more info
involved_in regulation of actin filament organization	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of autophagosome assembly	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of autophagy	IEA Inferred from Electronic Annotation more info
involved_in regulation of autophagy	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of autophagy	NAS Non-traceable Author Statement more info	PubMed
involved_in regulation of protein localization	IEA Inferred from Electronic Annotation more info
involved_in regulation of synaptic vesicle cycle	IEA Inferred from Electronic Annotation more info
involved_in stress granule assembly	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
part_of Atg1/ULK1 kinase complex	IDA Inferred from Direct Assay more info	PubMed
located_in Flemming body	IDA Inferred from Direct Assay more info
located_in P-body	IDA Inferred from Direct Assay more info	PubMed
located_in P-body	IEA Inferred from Electronic Annotation more info
is_active_in autophagosome	IBA Inferred from Biological aspect of Ancestor more info
located_in autophagosome	IDA Inferred from Direct Assay more info	PubMed
located_in autophagosome	IEA Inferred from Electronic Annotation more info
located_in axon	IEA Inferred from Electronic Annotation more info
located_in axonal growth cone	IDA Inferred from Direct Assay more info	PubMed
located_in cell projection	IEA Inferred from Electronic Annotation more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasm	IEA Inferred from Electronic Annotation more info
located_in cytoplasm	NAS Non-traceable Author Statement more info	PubMed
located_in cytoplasmic stress granule	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasmic stress granule	IEA Inferred from Electronic Annotation more info
located_in cytoplasmic vesicle	IEA Inferred from Electronic Annotation more info
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in dendrite	IDA Inferred from Direct Assay more info	PubMed
located_in dendrite	IEA Inferred from Electronic Annotation more info
is_active_in endosome	IBA Inferred from Biological aspect of Ancestor more info
located_in endosome	IDA Inferred from Direct Assay more info	PubMed
located_in endosome	IEA Inferred from Electronic Annotation more info
located_in extracellular region	IEA Inferred from Electronic Annotation more info
located_in extracellular space	IDA Inferred from Direct Assay more info	PubMed
located_in extracellular space	IEA Inferred from Electronic Annotation more info
is_active_in glutamatergic synapse	IEA Inferred from Electronic Annotation more info
located_in growth cone	IEA Inferred from Electronic Annotation more info
part_of guanyl-nucleotide exchange factor complex	IDA Inferred from Direct Assay more info	PubMed
part_of guanyl-nucleotide exchange factor complex	IPI Inferred from Physical Interaction more info	PubMed
is_active_in hippocampal mossy fiber to CA3 synapse	IEA Inferred from Electronic Annotation more info
located_in intracellular membrane-bounded organelle	IDA Inferred from Direct Assay more info
located_in lysosome	IDA Inferred from Direct Assay more info	PubMed
located_in lysosome	IEA Inferred from Electronic Annotation more info
located_in main axon	IDA Inferred from Direct Assay more info	PubMed
located_in membrane	IEA Inferred from Electronic Annotation more info
located_in neuron projection	IEA Inferred from Electronic Annotation more info
located_in nuclear membrane	IDA Inferred from Direct Assay more info	PubMed
located_in nuclear membrane	IEA Inferred from Electronic Annotation more info
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed
located_in nucleus	IEA Inferred from Electronic Annotation more info
located_in perikaryon	IDA Inferred from Direct Assay more info	PubMed
located_in perikaryon	IEA Inferred from Electronic Annotation more info
located_in postsynapse	IEA Inferred from Electronic Annotation more info
located_in presynapse	IEA Inferred from Electronic Annotation more info
is_active_in presynaptic cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in synapse	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: guanine nucleotide exchange factor C9orf72

Names: guanine nucleotide exchange C9orf72; protein C9orf72

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_031977.2 RefSeqGene

Range

5386..32321

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_658

mRNA and Protein(s)

NM_001256054.3 → NP_001242983.1 guanine nucleotide exchange factor C9orf72 isoform a

See identical proteins and their annotated locations for NP_001242983.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) represents the longest transcript and encodes the longer isoform (a). Hexanucleotide expansions that can occur in a repeat region between the first and second exon of this variant have been associated with frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS;PMID: 21944778, PMID: 21944779 ). Variants 2 and 3 encode the same protein.

Source sequence(s)

AL832229, BQ068108, JN681271

Consensus CDS

CCDS6522.1

UniProtKB/Swiss-Prot

A8K5W0, D3DRK6, G8I0B6, Q6NUS9, Q96LT7

UniProtKB/TrEMBL

A0A2R8Y5K2

Related

ENSP00000482753.1, ENST00000619707.5

Conserved Domains (1) summary

pfam15019
Location:61 → 324

C9orf72-like; C9orf72-like protein family
NM_018325.5 → NP_060795.1 guanine nucleotide exchange factor C9orf72 isoform a

See identical proteins and their annotated locations for NP_060795.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 3. Both variants 2 and 3 encode the same protein.

Source sequence(s)

AK291425, AL832229, BC020851, BC039112, BC068445, BQ777139

Consensus CDS

CCDS6522.1

UniProtKB/Swiss-Prot

A8K5W0, D3DRK6, G8I0B6, Q6NUS9, Q96LT7

UniProtKB/TrEMBL

A0A2R8Y5K2

Related

ENSP00000369339.3, ENST00000380003.8

Conserved Domains (1) summary

pfam15019
Location:61 → 324

C9orf72-like; C9orf72-like protein family
NM_145005.7 → NP_659442.2 guanine nucleotide exchange factor C9orf72 isoform b

See identical proteins and their annotated locations for NP_659442.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) lacks multiple exons in the central and 3' coding regions, and its 3' terminal exon extends beyond a splice site that is used in variant 3 . This results in a novel 3' UTR, compared to variant 3. It encodes isoform b which is significantly shorter, and its C-terminal amino acid is distinct, compared to isoform a.

Source sequence(s)

AI141996, AK057806, BC020851, BQ068108, DA802421

Consensus CDS

CCDS6523.1

UniProtKB/Swiss-Prot

Q96LT7

Related

ENSP00000369333.3, ENST00000379997.7

Conserved Domains (1) summary

pfam15019
Location:61 → 222

C9orf72-like; C9orf72-like protein family