FA2H explained

Fatty acid 2-hydroxylase is a protein that in humans is encoded by the FA2H gene.^[1]

Function

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.

Clinical significance

Mutations in this gene have been associated with leukodystrophy dysmyelinating with hereditary spastic paraplegia type 35 (SPG35) with or without dystonia as well as fatty acid hydroxylase-associated neurodegeneration.^[2] The largest cohort with a detailed phenotypical description and a highly sensitive imaging phenotype ('WHAT'- acronym for: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum) was recently published.^[3]

FA2H has been shown to modulate cell differentiation in vitro. FA2H is may be a Δ⁹-THC-regulated gene, as Δ⁹-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.^[4]

Further reading

• Alderson NL, Rembiesa BM, Walla MD, Bielawska A, Bielawski J, Hama H . The human FA2H gene encodes a fatty acid 2-hydroxylase . The Journal of Biological Chemistry . 279 . 47 . 48562–8 . November 2004 . 15337768 . 10.1074/jbc.M406649200 . free .
• Uchida Y, Hama H, Alderson NL, Douangpanya S, Wang Y, Crumrine DA, Elias PM, Holleran WM . Fatty acid 2-hydroxylase, encoded by FA2H, accounts for differentiation-associated increase in 2-OH ceramides during keratinocyte differentiation . The Journal of Biological Chemistry . 282 . 18 . 13211–9 . May 2007 . 17355976 . 10.1074/jbc.M611562200 . free .
• Dick KJ, Al-Mjeni R, Baskir W, Koul R, Simpson MA, Patton MA, Raeburn S, Crosby AH . A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23 . Neurology . 71 . 4 . 248–52 . July 2008 . 18463364 . 10.1212/01.wnl.0000319610.29522.8a . 207102944 .
• Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, Korman SH, Taustein I, Saada A, Elpeleg O . Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia . American Journal of Human Genetics . 83 . 5 . 643–8 . November 2008 . 19068277 . 2668027 . 10.1016/j.ajhg.2008.10.010 .
• Wheeler HE, Metter EJ, Tanaka T, Absher D, Higgins J, Zahn JM, Wilhelmy J, Davis RW, Singleton A, Myers RM, Ferrucci L, Kim SK . Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging . PLOS Genetics . 5 . 10 . e1000685 . October 2009 . 19834535 . 2752811 . 10.1371/journal.pgen.1000685 . Gibson . Greg . free .
• Dastani Z, Pajukanta P, Marcil M, Rudzicz N, Ruel I, Bailey SD, Lee JC, Lemire M, Faith J, Platko J, Rioux J, Hudson TJ, Gaudet D, Engert JC, Genest J . Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects . European Journal of Human Genetics . 18 . 3 . 342–7 . March 2010 . 19844255 . 2824775 . 10.1038/ejhg.2009.157 .
• Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH . Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35) . Human Mutation . 31 . 4 . E1251-60 . April 2010 . 20104589 . 10.1002/humu.21205 . 5344306 .
• Dan P, Edvardson S, Bielawski J, Hama H, Saada A . 2-Hydroxylated sphingomyelin profiles in cells from patients with mutated fatty acid 2-hydroxylase . Lipids in Health and Disease . 10 . 84 . May 2011 . 21599921 . 3107802 . 10.1186/1476-511X-10-84 . free .

Notes and References

1. Web site: Entrez Gene: Fatty acid 2-hydroxylase. 2011-12-30 .
2. Pierson TM, Simeonov DR, Sincan M, Adams DA, Markello T, Golas G, Fuentes-Fajardo K, Hansen NF, Cherukuri PF, Cruz P, Mullikin JC, Blackstone C, Tifft C, Boerkoel CF, Gahl WA . 6 . Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration . European Journal of Human Genetics . 20 . 4 . 476–9 . April 2012 . 22146942 . 3306865 . 10.1038/ejhg.2011.222 .
3. Rattay TW, Lindig T, Baets J, Smets K, Deconinck T, Söhn AS, Hörtnagel K, Eckstein KN, Wiethoff S, Reichbauer J, Döbler-Neumann M, Krägeloh-Mann I, Auer-Grumbach M, Plecko B, Münchau A, Wilken B, Janauschek M, Giese AK, De Bleecker JL, Ortibus E, Debyser M, Lopez de Munain A, Pujol A, Bassi MT, D'Angelo MG, De Jonghe P, Züchner S, Bauer P, Schöls L, Schüle R . 6 . FAHN/SPG35: a narrow phenotypic spectrum across disease classifications . Brain . 142 . 6 . 1561–1572 . June 2019 . 31135052 . 6536916 . 10.1093/brain/awz102 .
4. Takeda S, Harada M, Su S, Okajima S, Miyoshi H, Yoshida K, Nishimura H, Okamoto Y, Amamoto T, Watanabe K, Omiecinski CJ, Aramaki H . Induction of the fatty acid 2-hydroxylase (FA2H) gene by Δ(9)-tetrahydrocannabinol in human breast cancer cells . The Journal of Toxicological Sciences . 38 . 2 . 305–8 . 2013 . 10.2131/jts.38.305 . 23535410 . 4018719 .