GDAP1
protein-codingganglioside induced differentiation associated protein 1
Gene summary
This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]
- CMT4A
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~197.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008961
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012014
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012014
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011916
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0015626
Submitter: ClinGen
GDAP1 was first reported in relation to Charcot-Marie-Tooth Disease in 2002 (Baxter et al., PMID: 11743579, Cuesta et al., PMID: 11743580). Variants in this gene are inherited in both autosomal recessive and autosomal dominant fashions, with phenotypes presenting as a spectrum of severity depending on the specific mutation and number of alleles present in trans. The phenotypes associated with GDAP1 variants include both axonal, intermediate, and demyelinating neuropathy (based on the nerve conduction velocities), with the clinical features of symmetric muscle weakness, atrophy of feet and hands, reduced to normal motor and sensory nerve conduction studies, mild sensory loss, areflexia, vocal cord paresis, and pes cavus. GDAP1 is also expressed in peroxisomes as a tail-anchored protein and is thought to function as a peroxisomal fission factor and to be involved in regulating peroxisome morphology (PMID: 30669311). GDAP1 is also reported to increase cellular glutathione-s-transferase in neuronal cells, decrease reactive oxygen species production and protect against oxidative stress (PMID: 26848201). Experimentally, GDAP1 knockdown was shown to result in more cells with elongated peroxisomes, due to the decrease in fission. No peroxisome biochemical functions were measured. Re-introduction of wild-type GDAP1 and CMT-related GDAP1 N-terminal variants into knockdown cells restored peroxisomal morphology, while CMT-related C-terminal variants of GDAP1 did not (PMID: 23628762). This gene has been included in a few sequencing panels testing for peroxisomal disorders, but till date, no GDAP1 variants have been reported in patients showing a peroxisome biogenesis disorder phenotype, to the best of our knowledge. At least 10 unique variants have been reported in humans, including nonsense, missense, and frameshift variants. Evidence supporting this gene-disease relationship includes case-level data, segregation and experimental data. Variants in this gene have been reported in at least 15 probands in at least 5 publications (PMIDs:11743579, 15805163, 11743580, 12499475, 18492089). Variants in this gene segregated with disease in 19 additional family members across three different families. This gene-disease relationship is supported by expression studies, functional studies, and animal models. GDAP1 has been shown to be predominantly expressed in neural tissue, with expression in both neurons and Schwann cells (PMIDs: 11743580, 16172208). Functional studies have revealed that GDAP1 overexpression increases mitochondrial fragmentation, while GDAP1 knockdown increased mitochondrial fusion, therefore confirming the role of GDAP1 as a mitochondrial fission-inducing factor (PMID: 16172208). In a drosophila model, both overexpression and knockdown of the fly ortholog, Gdap1, was shown to result in neuromuscular degeneration and alterations of mitochondrial morphology and dynamics (PMID: 25122658). A Gda1 knockout mouse model resulted in late onset hypomyelinating peripheral neuropathy with changes in mitochondrial morphology and dynamics (PMID: 24480485). In summary, GDAP1 is DEFINITIVELY associated with recessive and dominant Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on June 9, 2020. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, it was determined that variants in this gene result in a spectrum of the similars pathophysiology and lead to similar phenotypes underlying the disease entities: (1) Charcot-Marie-Tooth disease, axonal, type 2K (MIM:607831), (2) Charcot-Marie-Tooth disease, axonal, with vocal cord paresis (MIM:607706), (3) Charcot-Marie-Tooth disease, recessive intermediate, A (MIM:608340), (4) Charcot-Marie-Tooth disease, type 4A (MIM:214400). Therefore, all of the disease entities have been lumped into one disease entity, Charcot-Marie-Tooth Disease.
Inheritance Pattern: AD
Disease ID:MONDO:0020558
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011916
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012014
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011916
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008961
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0011898
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GDAP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018972.4. 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 | 87 | 1 | 88 | |||
| missense | 8 | 45 | 236 | 2 | 291 | |
| nonsense | 13 | 11 | 3 | 27 | ||
| start loss | 1 | 2 | 3 | |||
| frameshift | 22 | 15 | 8 | 45 | ||
| splice donor/acceptor (+/-2bp) | 3 | 6 | 3 | 12 | ||
| Total | 47 | 79 | 250 | 89 | 1 | 466 |
Highest pathogenic variant AF is 0.0003453758
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_061845.2 | 6 | MANE Select | |
| Ensembl | ENSP00000220822.7 | 6 | MANE Select | |
| RefSeq | NP_001035808.1 | 5 | Standard | |
| RefSeq | NP_001349858.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gdap1 | Danio rerio | Structure: peripheral neuron Quality: branchiness abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- mitochondrial fission
- protein targeting to mitochondrion
- mitochondrion organization
- mitochondrial fusion
- response to retinoic acid
Cellular Component
- nucleus
- mitochondrion
- cytosol
- membrane
- integral component of mitochondrial outer membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000220822
- Coding exons
- 6
- Length
- 167743
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 52
- Defined
- 125748
- p
- 0.000207
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.00 | 150 | 189 | 0.795 | 0.0000104 | 2339 |
| Missense (PolyPhen) | 67 | 87.536 | 0.7654 | 1046 | ||
| Synonymous | -0.510 | 77 | 71.5 | 1.08 | 0.00000398 | 682 |
| Loss of Function | 1.03 | 14 | 18.8 | 0.743 | 0.00000115 | 217 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00064 | 0.00064 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00020 | 0.00020 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Regulates the mitochondrial network by promoting mitochondrial fission. {ECO:0000269|PubMed:16172208}.;
- Disease
- DISEASE: Charcot-Marie-Tooth disease 4A (CMT4A) [MIM:214400]: A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4A is a severe form characterized by early age of onset and rapid progression leading to inability to walk in late childhood or adolescence. {ECO:0000269|PubMed:11743579, ECO:0000269|PubMed:12601710, ECO:0000269|PubMed:15772096, ECO:0000269|PubMed:16172208}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (CMT2RV) [MIM:607706]: A form of Charcot-Marie-Tooth disease characterized by the association of axonal neuropathy with vocal cord paresis. Charcot-Marie-Tooth disease is a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. {ECO:0000269|PubMed:12868504, ECO:0000269|PubMed:16172208}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2K (CMT2K) [MIM:607831]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Charcot-Marie-Tooth disease type 2K onset is in early childhood (younger than 3 years). This phenotype is characterized by foot deformities, kyphoscoliosis, distal limb muscle weakness and atrophy, areflexia, and diminished sensation in the lower limbs. Weakness in the upper limbs is observed in the first decade, with clawing of the fingers. Inheritance can be autosomal dominant or recessive. {ECO:0000269|PubMed:15772096, ECO:0000269|PubMed:20685671, ECO:0000269|PubMed:22206013, ECO:0000269|PubMed:26525999, ECO:0000269|PubMed:28244113}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, A (CMTRIA) [MIM:608340]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:12499475, ECO:0000269|PubMed:12566285, ECO:0000269|PubMed:15772096, ECO:0000269|PubMed:16172208}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.163
Intolerance Scores
- LoFtool
- 0.213
- RVIS EVS
- -0.69
- RVIS percentile EVS
- 14.97
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.808
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |