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8.A.221.  The Very Long Chain Fatty Acid Elongase (VLCFA-E) Family 

These integral membrane enzymes catalyze the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acid elongation cycle. This endoplasmic reticulum (ER)-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle (Leonard et al. 2000). The fatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum (ER) where they catalyze long-chain fatty acid elongation. A missense variant (c.689G>T, p.Gly230Val) in ELOVL5 (of 299 aas and 7 TMSs) causes Spinocerebellar Ataxia subtype 38 (SCA38), a neurodegenerative disorder characterized by autosomal dominant inheritance, cerebellar Purkinje cell demise and adult-onset ataxia (Ferrero et al. 2023). This presumably alters the activities of several transporters in the ER and the plasma membrane.

References associated with 8.A.221 family:

Ferrero, E., E. Di Gregorio, M. Ferrero, E. Ortolan, Y.A. Moon, A. Di Campli, L. Pavinato, C. Mancini, D. Tripathy, M. Manes, E. Hoxha, C. Costanzi, E. Pozzi, M. Rossi Sebastiano, N. Mitro, F. Tempia, D. Caruso, B. Borroni, M. Basso, M. Sallese, and A. Brusco. (2023). Spinocerebellar ataxia 38: structure-function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot. Hum Genet. [Epub: Ahead of Print] 37199746
Leonard, A.E., E.G. Bobik, J. Dorado, P.E. Kroeger, L.T. Chuang, J.M. Thurmond, J.M. Parker-Barnes, T. Das, Y.S. Huang, and P. Mukerji. (2000). Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids. Biochem. J. 350Pt3: 765-770. 10970790
Mueller, N., T. Sassa, S. Morales-Gonzalez, J. Schneider, D.J. Salchow, D. Seelow, E. Knierim, W. Stenzel, A. Kihara, and M. Schuelke. (2019). De novo mutation in causes ichthyosis, , hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy. J Med Genet 56: 164-175. 30487246
Ohno, Y., S. Suto, M. Yamanaka, Y. Mizutani, S. Mitsutake, Y. Igarashi, T. Sassa, and A. Kihara. (2010). ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proc. Natl. Acad. Sci. USA 107: 18439-18444. 20937905