FA2H
protein-codingfatty acid 2-hydroxylase, the group of Fatty acid hydroxylase domain containing
Gene summary
This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.[provided by RefSeq, Mar 2010]
- FAXDC1
- SPG35
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~61.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012866
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012866
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012866
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012866
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012866
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012866
Submitter: ClinGen
The FA2H gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play a role in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia. FA2H was first reported in relation to autosomal recessive hereditary spastic paraplegia in 2004 (Anderson et al. PMID: 15337768). FA2H is characterized by childhood to adolescent onset of progressive spastic paraplegia, often presenting with gait disturbances as an early symptom. Additional features include cerebellar ataxia, dysarthria, dystonia, and extrapyramidal signs such as tremors or rigidity. Peripheral neuropathy is common and may manifest as distal weakness or sensory loss. Cognitive decline ranges from mild learning difficulties to progressive dementia, and seizures are reported in some cases. Brain MRI findings typically reveal cerebellar atrophy, particularly in the vermis and hemispheres, along with T2-weighted hyperintensities in the periventricular and deep white matter. Thinning of the corpus callosum is also observed in some patients, and involvement of the basal ganglia or brainstem may be noted. FA2H-related disorders are biochemically characterized by disruptions in sphingolipid metabolism, specifically reduced 2-hydroxy fatty acids in sphingolipids, which are critical for the structural integrity of the myelin sheath. These conditions are inherited in an autosomal recessive manner, emphasizing the importance of early diagnosis for management and genetic counseling. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the single disease entity has been maintained: hereditary spastic paraplegia (OMIM#612319). This curation included three missense, two frameshift, one nonsense, and one splice variants reported in eight probands across five publications (PMIDs: 19068277, 37410270, 20853438, 26344562, 20104589). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal model experimental evidence (PMID: 21491498). In summary, there is definitive evidence supporting the relationship between FA2H and autosomal recessive hereditary spastic paraplegia. 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 Leukodystrophy and Leukoencephalopathy GCEP on the meeting date: 12/04/2024 SOP Version #11. Evidence summary approved by Julie Cohen, 1/23/25
Clinical Genomic Database (CGD)
Manifestation: Biochemical; 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 FA2H variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024306.5. 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 | 4 | 82 | 87 | ||
| missense | 5 | 30 | 136 | 19 | 1 | 191 |
| nonsense | 9 | 4 | 13 | |||
| start loss | 2 | 1 | 1 | 4 | ||
| frameshift | 12 | 12 | 1 | 25 | ||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 29 | 54 | 142 | 101 | 1 | 327 |
Highest pathogenic variant AF is 0.00035904537
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_077282.3 | 7 | MANE Select | |
| Ensembl | ENSP00000219368.3 | 7 | MANE Select | |
| Ensembl | ENSP00000455126.1 | 3 | Standard | |
| Ensembl | ENSP00000464576.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Metabolism of lipids
- Metabolism
- fatty acid &alpha
- -oxidation III
- Sphingolipid de novo biosynthesis
Biological Process
- sebaceous gland cell differentiation
- fatty acid metabolic process
- fatty acid biosynthetic process
- glucosylceramide biosynthetic process
- galactosylceramide biosynthetic process
Molecular Function
- iron ion binding
- heme binding
- fatty acid alpha-hydroxylase activity
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum membrane
- membrane
- integral component of membrane
- organelle membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000219368
- Coding exons
- 7
- Length
- 61877
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 11
- Defined
- 125747
- p
- 0.0000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.456 | 179 | 197 | 0.909 | 0.0000112 | 2378 |
| Missense (PolyPhen) | 51 | 68.959 | 0.73957 | 834 | ||
| Synonymous | -0.522 | 94 | 87.8 | 1.07 | 0.00000573 | 734 |
| Loss of Function | 2.96 | 5 | 18.9 | 0.265 | 0.00000107 | 190 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000091 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for alpha-hydroxylation of free fatty acids and the formation of alpha-hydroxylated sphingolipids. {ECO:0000269|PubMed:15337768, ECO:0000269|PubMed:17355976}.;
- Disease
- DISEASE: Spastic paraplegia 35, autosomal recessive (SPG35) [MIM:612319]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG35 is a complicated form characterized by childhood onset of gait difficulties. It has a rapid progression and many patients become wheelchair-bound as young adults. Patients manifest cognitive decline associated with leukodystrophy. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur. {ECO:0000269|PubMed:19068277, ECO:0000269|PubMed:20104589, ECO:0000269|PubMed:20853438}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.131
Intolerance Scores
- LoFtool
- 0.0542
- RVIS EVS
- -0.25
- RVIS percentile EVS
- 35.99
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.250
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |