GDF6
protein-codinggrowth differentiation factor 6, the group of Transforming growth factor beta superfamily
Gene summary
This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis. [provided by RefSeq, Sep 2016]
- SGM1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007306
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007306
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0021129
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0054752
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0014145
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013130
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016520
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018998
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Ophthalmologic
Intervention: General
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development
Comments: Deafness, autosomal recessive 118, with cochlear aplasia is due to variants in a downstream regulatory element affecting GDF6 expression; Digenic inheritance (with GDF3) has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GDF6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001001557.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 140 | 1 | 142 | ||
| missense | 1 | 231 | 31 | 9 | 272 | |
| nonsense | 1 | 3 | 4 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 2 | 235 | 171 | 10 | 419 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001001557.1 | 2 | MANE Select | |
| Ensembl | ENSP00000287020.4 | 2 | MANE Select | |
| Ensembl | ENSP00000804642.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gdf6a | Danio rerio | Structure: Muller cell Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TGF-beta signaling pathway - Homo sapiens (human)
- Hippo signaling pathway - Homo sapiens (human)
- TGF-Core
- GPCR signaling-G alpha q
- GPCR signaling-cholera toxin
Biological Process
- apoptotic process
- regulation of signaling receptor activity
- positive regulation of pathway-restricted SMAD protein phosphorylation
- BMP signaling pathway
- positive regulation of chondrocyte differentiation
Molecular Function
- cytokine activity
- transforming growth factor beta receptor binding
- growth factor activity
- protein homodimerization activity
Cellular Component
- extracellular space
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000287020
- Coding exons
- 2
- Length
- 18459
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125725
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.934 | 204 | 245 | 0.832 | 0.0000118 | 2856 |
| Missense (PolyPhen) | 62 | 94.742 | 0.65441 | 1065 | ||
| Synonymous | -0.394 | 119 | 114 | 1.05 | 0.00000593 | 989 |
| Loss of Function | 3.39 | 0 | 13.4 | 0.00 | 5.81e-7 | 149 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000093 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Growth factor that controls proliferation and cellular differentiation in the retina and bone formation. Plays a key role in regulating apoptosis during retinal development. Establishes dorsal-ventral positional information in the retina and controls the formation of the retinotectal map (PubMed:23307924). Required for normal formation of bones and joints in the limbs, skull, digits and axial skeleton. Plays a key role in establishing boundaries between skeletal elements during development. Regulation of GDF6 expression seems to be a mechanism for evolving species-specific changes in skeletal strucutres. Seems to positively regulates differentiation of chondrogenic tissue through the growth factor receptors subunits BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the activation of SMAD1-SMAD5-SMAD8 complex. The regulation of chondrogenic differentiation is inhibited by NOG (PubMed:26643732). Also involved in the induction of adipogenesis from mesenchymal stem cells. This mechanism acts through the growth factor receptors subunits BMPR1A, BMPR2 and ACVR2A and the activation of SMAD1-SMAD5-SMAD8 complex and MAPK14/p38 (By similarity). {ECO:0000250|UniProtKB:P43028, ECO:0000269|PubMed:23307924, ECO:0000269|PubMed:26643732}.;
- Disease
- DISEASE: Klippel-Feil syndrome 1, autosomal dominant (KFS1) [MIM:118100]: A skeletal disorder characterized by congenital fusion of cervical vertebrae. It is due to a failure in the normal segmentation of vertebrae during the early weeks of fetal development. The clinical triad consists of short neck, low posterior hairline, and limited neck movement. Deafness is a feature in some cases and may be of sensorineural, conductive, or mixed type. {ECO:0000269|PubMed:18425797, ECO:0000269|PubMed:19129173}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving GDF6 has been found in a patient with Klippel-Feil syndrome (KFS). Paracentric inv(8)(q22;2q23.3). {ECO:0000269|PubMed:18425797}.; DISEASE: Microphthalmia, isolated, 4 (MCOP4) [MIM:613094]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. {ECO:0000269|PubMed:19129173, ECO:0000269|PubMed:24033328}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leber congenital amaurosis 17 (LCA17) [MIM:615360]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or almost absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:23307924}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple synostoses syndrome 4 (SYNS4) [MIM:617898]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. SYNS4 inheritance is autosomal dominant. {ECO:0000269|PubMed:26643732, ECO:0000269|PubMed:29130651}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.214
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.984
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |