ABHD5
protein-codingabhydrolase domain containing 5, lysophosphatidic acid acyltransferase, the group of Abhydrolase domain containing
Gene summary
The protein encoded by this gene belongs to a large family of proteins defined by an alpha/beta hydrolase fold, and contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. It differs from other members of this subfamily in that its putative catalytic triad contains an asparagine instead of the serine residue. Mutations in this gene have been associated with Chanarin-Dorfman syndrome, a triglyceride storage disease with impaired long-chain fatty acid oxidation. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~44.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010155
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0010155
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010155
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0010155
Submitter: ClinGen
The relationship between the ABHD5 gene and Chanarin-Dorfman syndrome (CDS), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of July 23, 2022. ABHD5 encodes abhydrolase domain-containing protein 5, lysophosphatidic acid acyltransferase, an acyltransferase that is involved in the synthesis of phosphatidic acid via acylating lysophosphatidic acid to phosphatidic acid, the major intermediate in membrane and storage lipid biosynthesis, and also functions as a coactivator of adipocyte triglyceride lipase to help regulate triacylglycerol homeostasis in adipocytes (PMID: 18606822). Individuals with CDS show impaired ABHD5-mediated lipolysis, reflecting impaired ABHD5 activation of PNPLA2 (PMID: 16679289), resulting in the characteric disease manifestation of triacylglycerol accumulation in multiple tissues (as reviewed in PMID: 33455044). The disease mechanism of CDS is loss of function. CDS was first reported in 1966 by Rosenszajin (PMID: 5330405), and the first report of biallelic variants in ABHD5 among CDS patients was in 2001 by Lefevre (PMID: 11590543). Both case-level (genetic) and experimental evidence support the relationship between ABHD5 and CDS. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 11590543; PMID: 18339307; PMID: 25682902; PMID: 21122093). In total, nine variants from eight probands in four publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between ABHD5 and CDS includes: the biochemical function of the gene product (abhydrolase domain-containing protein 5, lysophosphatidic acid acyltransferase) being consistent with the clinical and biochemical findings identified individuals with CDS (as reviewed in PMID: 33455044, PMID: 19061969); the protein-protein interaction between ABHD5 and adipose triglyceride lipase (encoded by the PNPLA2 gene) (PMID: 16679289), which has been curated by the LD GCEP as Definitively associated with Neutral lipid storage disease with myopathy; functional alteration (impaired lipolysis in COS-7 cells transfected with variants of ABHD5 in which key binding pocket amino acid residues were altered (PMID: 35173175); the biochemical and clinical features of ABHD5 knockout animal models (PMID: 20023287: knockout mouse model; PMID: 25202121: knockout C. elegans model); and rescue of CDS patient fibroblasts (harboring a loss of function ABHD5 variant) via infection with an adenovirus harboring wild-type ABHD5 (PMID: 16679289). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, ABHD5 is definitively associated with CDS. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on August 2, 2022 (SOP v9).
Inheritance Pattern: AR
Disease ID:MONDO:0010155
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Dermatologic
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
Comments: Manifestations can include severe hepatic sequelae
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ABHD5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016006.6. 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 | 3 | 67 | 70 | |||
| missense | 3 | 2 | 94 | 7 | 1 | 107 |
| nonsense | 8 | 4 | 12 | |||
| start loss | 1 | 1 | ||||
| frameshift | 6 | 3 | 9 | |||
| splice donor/acceptor (+/-2bp) | 3 | 3 | 1 | 7 | ||
| Total | 20 | 13 | 98 | 74 | 1 | 206 |
Highest pathogenic variant AF is 0.00001239076
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057090.2 | 7 | MANE Select | |
| Ensembl | ENSP00000495778.1 | 7 | MANE Select | |
| RefSeq | NP_001342115.1 | 7 | Standard | |
| RefSeq | NP_001352578.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of lipolysis in adipocytes - Homo sapiens (human)
- Lipid Metabolism Pathway
- Liver steatosis AOP
- Metabolism of lipids
- Metabolism
Biological Process
- fatty acid metabolic process
- phosphatidic acid biosynthetic process
- negative regulation of sequestering of triglyceride
- positive regulation of triglyceride catabolic process
- cell differentiation
Molecular Function
- 1-acylglycerol-3-phosphate O-acyltransferase activity
- triglyceride lipase activity
- lysophosphatidic acid acyltransferase activity
- carboxylic ester hydrolase activity
Cellular Component
- lipid droplet
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000458276
- Coding exons
- 7
- Length
- 44259
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125748
- p
- 0.000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.474 | 166 | 184 | 0.902 | 0.00000933 | 2261 |
| Missense (PolyPhen) | 32 | 47.916 | 0.66784 | 614 | ||
| Synonymous | -1.98 | 86 | 65.6 | 1.31 | 0.00000343 | 679 |
| Loss of Function | 1.63 | 13 | 21.1 | 0.618 | 0.00000150 | 218 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000088 | 0.000088 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Lysophosphatidic acid acyltransferase which functions in phosphatidic acid biosynthesis (PubMed:18606822). May regulate the cellular storage of triacylglycerol through activation of the phospholipase PNPLA2 (PubMed:16679289). Involved in keratinocyte differentiation (PubMed:18832586). Regulates lipid droplet fusion (By similarity). {ECO:0000250|UniProtKB:Q9DBL9, ECO:0000269|PubMed:16679289, ECO:0000269|PubMed:18606822, ECO:0000269|PubMed:18832586}.;
- Disease
- DISEASE: Chanarin-Dorfman syndrome (CDS) [MIM:275630]: An autosomal recessive inborn error of lipid metabolism with multisystemic accumulation of triglycerides although plasma concentrations are normal. Clinical characteristics are congenital generalized ichthyosis, vacuolated leukocytes, hepatomegaly, myopathy, cataracts, neurosensory hearing loss and developmental delay. The disorder presents at birth with generalized, fine, white scaling of the skin and a variable degree of erythema resembling non-bullous congenital ichthyosiform erythroderma. {ECO:0000269|PubMed:11590543, ECO:0000269|PubMed:16679289, ECO:0000269|PubMed:17495960, ECO:0000269|PubMed:18606822}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.163
Intolerance Scores
- LoFtool
- 0.469
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.283
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |