Alternative titles; symbols
HGNC Approved Gene Symbol: FA2H
SNOMEDCT: 764688002;
Cytogenetic location: 16q23.1 Genomic coordinates (GRCh38): 16:74,712,969-74,774,820 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q23.1 | Spastic paraplegia 35, autosomal recessive | 612319 | Autosomal recessive | 3 |
Sphingolipids are a large class of lipids found in all eukaryotic cells and are involved in numerous cellular processes. The structural diversity of sphingolipids stems from more than 300 distinct head groups, as well as from modifications of the hydrophobic ceramide moiety. FA2H catalyzes a common modification of the ceramide moiety: hydroxylation at the 2 position of the N-acyl chain. Sphingolipids containing 2-hydroxy fatty acid are common in nervous and epidermal tissue. Glycosphingolipids containing a high proportion of 2-hydroxy fatty acid are critical components of myelin, and several very long chain ceramides with 2-hydroxy fatty acids are important for the permeability barrier function of epidermis (summary by Alderson et al., 2004).
By searching databases for homologs of yeast Fah1, Alderson et al. (2004) identified human FA2H. The deduced 372-amino acid protein has a calculated molecular mass of 42.8 kD and shares 36% identity with yeast Fah1. FA2H contains an N-terminal cytochrome b5 (613218) domain, 4 transmembrane domains, and an iron-binding histidine motif conserved among membrane-bound desaturases and hydroxylases. Northern blot analysis showed highest expression of a 3-kb transcript in brain and colon, with lower levels in testis, prostate, pancreas, and kidney. FA2H was detected exclusively in the membrane fraction of transfected COS-7 cells.
Eckhardt et al. (2005) identified mouse Fa2h. Both mouse and human FA2H have a C-terminal endoplasmic reticulum (ER) retention motif, and immunofluorescence analysis showed that mouse Fa2h colocalized with calnexin (CANX; 114217), an ER marker protein, in transfected Chinese hamster ovary cells. Northern blot analysis detected Fa2h expression in mouse brain, stomach, skin, kidney, testis, and small intestine. In mouse brain, Fa2h expression increased strongly between 1 and 2 weeks of age, reached maximal level between 2 and 3 weeks of age, and decreased slightly in older animals. In situ hybridization of mouse brain showed highest expression in white matter.
Kruer et al. (2010) stated that the FA2H gene maps to chromosome 16q23.1.
Eckhardt et al. (2005) mapped the mouse Fa2h gene to chromosome 8.
Alderson et al. (2004) found that COS-7 cells expressing human FA2H had 3- to 20-fold higher levels of 2-hydroxyceramides and 2-hydroxy fatty acids compared with control cells, and they observed a 40-fold increase in 2-hydroxyceramides in cells incubated 72 hrs. Deletion of the cytochrome b5 domain sharply reduced FA2H enzyme activity.
Using RT-PCR and Western blot analysis, Uchida et al. (2007) showed that FA2H was expressed in human keratinocytes and epidermis. FA2H expression and fatty acid 2-hydroxylase activity increased during differentiation. Downregulation of FA2H by small interfering RNA suppressed 2-hydroxylase activity and decreased levels of 2-hydroxyceramide and 2-hydroxyglucosylceramide in keratinocytes. Uchida et al. (2007) demonstrated that 2-hydroxylation of fatty acid by FA2H occurred before formation of ceramides and glucosylceramides, and that these lipids were required for formation of epidermal lamellar membranes.
In affected members of 2 unrelated consanguineous families with a complicated form of autosomal recessive spastic paraplegia (SPG35; 612319), Edvardson et al. (2008) identified a homozygous mutation in the FA2H gene (611026.0001). The patients had early onset of progressive spasticity, ataxia, dystonia, and cognitive decline associated with white matter abnormalities on brain MRI. Affected individuals from a third family with a less severe phenotype were found to have a different homozygous mutation in the FA2H gene (611026.0002). The relatively late onset of the disorders was consistent with the proposed need for FA2H at later stages of myelin maturation.
In affected members of an Omani family and a Pakistani family with complicated SPG35, Dick et al. (2010) identified 2 different homozygous mutations in the FA2H gene (611026.0003 and 611026.0004, respectively). The findings indicated that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated SPG and radiological features of leukodystrophy.
Kruer et al. (2010) identified 2 different homozygous mutations in the FA2H gene (611026.0005 and 611026.0006) in affected members from 2 unrelated families with progressive complicated spastic paraplegia associated with brain iron deposition in the globus pallidus. The authors noted the connection between leukodystrophy and neurodegeneration with brain iron accumulation (NBIA).
Zoller et al. (2008) found that Fa2h-null mice lacked 2-hydroxylated sphingolipids in the brain and in peripheral nerves. However, nonhydroxylated galactosylceramide was increased, and oligodendrocyte differentiation, myelin formation, and peripheral nerve conduction velocities were normal up to 5 months of age. In contrast, aged 18-month-old Fa2h-null mice showed scattered axonal and myelin sheath degeneration in the spinal cord and more pronounced loss of myelin staining in sciatic nerves. These changes were associated with functional motor impairment. Zoller et al. (2008) concluded that the long-term maintenance of myelin is impaired in the absence of 2-hydroxylated sphingolipids and suggested that these lipids might be required for glial support of axon function.
In 7 affected members of 2 unrelated consanguineous Arab Muslim families with a complicated form of autosomal recessive spastic paraplegia (SPG35; 612319), Edvardson et al. (2008) identified a homozygous G-to-A transition in intron 5 of the FA2H gene, resulting in the skipping of exons 5 and 6 and predicted to abolish catalytic activity. The patients had early onset of progressive spasticity, ataxia, dystonia, and cognitive decline associated with white matter abnormalities on brain MRI.
In 2 sisters, from a consanguineous Arab Muslim family, with a complicated form of spastic paraplegia (SPG35; 612319), Edvardson et al. (2008) identified a homozygous 103G-T transversion in exon 1 of the FA2H gene, resulting in an asp35-to-tyr (D35Y) substitution. The patients had mild spasticity and difficulty walking, but did not have cerebellar signs, dystonia, or impaired cognition. Both unaffected parents were heterozygous for the mutation. In vitro expression studies showed that the transfected D35Y-mutant had enzyme activity indistinguishable from an empty vector, suggesting that the D35Y mutation inactivated FA2H.
In affected members of a consanguineous Omani family with complicated autosomal recessive spastic paraplegia-35 (SPG35; 612319), Dick et al. (2010) identified a homozygous 703C-T transition in exon 5 of the FA2H gene, resulting in an arg235-to-cys (R235C) substitution. The mutation was not found in 700 control chromosomes. In vitro functional expression studies showed that the mutation resulted in a reduction in hydroxylated ceramides to 60-80% of wildtype.
In affected members of a consanguineous Pakistani family with complicated autosomal recessive spastic paraplegia-35 (SPG35; 612319), Dick et al. (2010) identified a homozygous 18-bp deletion in exon 1 of the FA2H gene, resulting in the loss of 6 amino acids (53-58) in the cytochrome B5 domain of the protein. The mutation was not found in 200 control chromosomes. In vitro functional expression studies showed that the mutation resulted in undetectable levels of hydroxylated ceramides.
In 3 Italian brothers, born of consanguineous parents, with a complicated form of autosomal recessive spastic paraplegia-35 (SPG35; 612319) and evidence of brain iron accumulation in the globus pallidus, Kruer et al. (2010) identified a homozygous 460C-T transition in exon 3 of the FA2H gene, resulting in an arg154-to-cys (R154C) substitution in a highly conserved residue. Western blot analysis of COS-7 cells transfected with the R154C mutation showed decreased FA2H protein levels.
In 2 Albanian brothers with a complicated form of autosomal recessive spastic paraplegia-35 (SPG35; 612319) and evidence of brain iron accumulation in the globus pallidus, Kruer et al. (2010) identified a homozygous 2-bp deletion (c.509_510delAC) in the FA2H gene, resulting in a frameshift and premature termination.
Donkervoort et al. (2014) identified homozygosity for the c.509_510delAC deletion in the FA2H gene, which resulted in a frameshift and a premature stop codon (Tyr170Ter), in a brother and sister from Montenegro with SPG35. The mutation segregated with the disorder in the family; functional studies were not performed. Both children had typical features of the disorder, but no brain iron accumulation was seen on brain MRI. Because this mutation had been identified by Kruer et al. (2010) in 2 brothers from Albania with a similar neurodegenerative disorder with brain iron accumulation, Donkervoort et al. (2014) suggested that it may represent a founder mutation in individuals from the Balkan region.
In a 10-year-old boy, born of unrelated parents, with a complicated form of autosomal recessive spastic paraplegia-35 (SPG35; 612319), Pierson et al. (2012) identified compound heterozygosity for a heterozygous 707T-C transition in exon 5 of the FA2H gene, resulting in a phe236-to-ser (F236S) substitution inherited from the unaffected father, and a 28-kb deletion encompassing exons 3 to 7 of the FA2H gene (611026.0008) inherited from the unaffected mother. The F236S substitution occurred in a highly conserved residue in an iron-binding histidine motif in the catalytic site. The patient developed normally until age 3 years, when he developed progressive neurodegeneration following a febrile illness. He had lower extremity weakness and atrophy, spasticity, dystonic foot inversion, and poor balance. He also had dysarthria, neck weakness, mask-like facies, hunched posture, and mild cognitive deficits, but did not have optic atrophy or seizures. Serial brain MRIs showed progressive neurodegenerative changes, with white matter abnormalities, cerebellar and brainstem atrophy, thin corpus callosum, and evidence of demyelination. He also had an axonal sensory neuropathy.
For discussion of the 28-kb deletion in the FA2H gene that was found in compound heterozygous state in a patient with autosomal recessive spastic paraplegia-35 (SPG35; 612319) by Pierson et al. (2012), see 611026.0007.
Alderson, N. L., Rembiesa, B. M., Walla, M. D., Bielawska, A., Bielawski, J., Hama, H. The human FA2H gene encodes a fatty acid 2-hydroxylase. J. Biol. Chem. 279: 48562-48568, 2004. [PubMed: 15337768] [Full Text: https://doi.org/10.1074/jbc.M406649200]
Dick, K. J., Eckhardt, M., Paisan-Ruiz, C., Alshehhi, A. A., Proukakis, C., Sibtain, N. A., Maier, H., Sharifi, R., Patton, M. A., Bashir, W., Koul, R., Raeburn, S., Gieselmann, V., Houlden, H., Crosby, A. H. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum. Mutat. 31: E1251-1260, 2010. Note: Electronic Article. [PubMed: 20104589] [Full Text: https://doi.org/10.1002/humu.21205]
Donkervoort, S., Dastgir, J., Hu, Y., Zein, W. M., Marks, H., Blackstone, C., Bonnemann, C. G. Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. (Letter) Clin. Genet. 85: 393-395, 2014. [PubMed: 23745665] [Full Text: https://doi.org/10.1111/cge.12185]
Eckhardt, M., Yaghootfam, A., Fewou, S. N., Zoller, I., Gieselmann, V. A mammalian fatty acid hydroxylase responsible for the formation of alpha-hydroxylated galactosylceramide in myelin. Biochem. J. 388: 245-254, 2005. [PubMed: 15658937] [Full Text: https://doi.org/10.1042/BJ20041451]
Edvardson, S., Hama, H., Shaag, A., Gomori, J. M., Berger, I., Soffer, D., Korman, S. H., Taustein, I., Saada, A., Elpeleg, O. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am. J. Hum. Genet. 83: 643-648, 2008. [PubMed: 19068277] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.010]
Kruer, M. C., Paisan-Ruiz, C., Boddaert, N., Yoon, M. Y., Hama, H., Gregory, A., Malandrini, A., Woltjer, R. L., Munnich, A., Gobin, S., Polster, B. J., Palmeri, S., Edvardson, S., Hardy, J., Houlden, H., Hayflick, S. J. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann. Neurol. 68: 611-618, 2010. [PubMed: 20853438] [Full Text: https://doi.org/10.1002/ana.22122]
Pierson, T. M., Simeonov, D. R., Sincan, M., Adams, D. A., Markello, T., Golas, G., Fuentes-Fajardo, K., Hansen, N. F., Cherukuri, P. F., Cruz, P., Mullikin, J. C., Blackstone, C., Tifft, C., Boerkoel, C. F., Gahl, W. A. Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. Europ. J. Hum. Genet. 20: 476-479, 2012. [PubMed: 22146942] [Full Text: https://doi.org/10.1038/ejhg.2011.222]
Uchida, Y., Hama, H., Alderson, N. L., Douangpanya, S., Wang, Y., Crumrine, D. A., Elias, P. M., Holleran, W. M. Fatty acid 2-hydroxylase, encoded by FA2H, accounts for differentiation-associated increase in 2-OH ceramides during keratinocyte differentiation. J. Biol. Chem. 282: 13211-13219, 2007. [PubMed: 17355976] [Full Text: https://doi.org/10.1074/jbc.M611562200]
Zoller, I., Meixner, M., Hartmann, D, Bussow, H., Meyer, R., Gieselmann, V., Eckhardt, M. Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration. J. Neurosci. 28: 9741-9754, 2008. [PubMed: 18815260] [Full Text: https://doi.org/10.1523/JNEUROSCI.0458-08.2008]