Molecular Characteristics
ELOVL4 (Elongation of Very Long Chain Fatty Acids-Like 4) gene is located at 6q14.1 and encodes one of the fatty acid elongases, which catalyse the first and rate-limiting step of producing very-long-chain fatty acids (VLCFAs). VLCFAs form the main components of complex lipids, such as phospholipids and sphingolipids, which play a role in several cellular processes, such as cell signalling, protein and lipid trafficking, nuclear membrane stabilization, myelin production, photoreceptor function, and epidermal water barrier production.
Mutations and pathophysiology
Mutations in ELOVL4 disrupt the production of VLCFAs. A few selected examples of pathogenic variants are described below:
Autosomal recessive mutations:
- Aldahmesh et al. (2011) reported two ELOVL4 mutations in two unrelated individuals:
- The first individual is born to Saudi consanguineous parents with ichthyosis, spastic quadriplegia, and intellectual disability. A homozygous c.646C>T [p.Arg216X] mutation was identified in ELOVL4 (NM_022726.2). Cells with the mutation produced normal-sized ELOVL4 protein (although it was predicted to produce a truncated protein) but at a reduced level compared to control. It is suggested that nonsense read-through of the mutation is the reason behind this finding.
- The other individual is born to Asian Indian consanguineous parents with a similar phenotype to the first individual. A homozygous c.690del [p.Ile230Metfs*22] mutation causing a frameshift and premature termination was identified in this individual.
- Monies et al. (2017) identified a homozygous mutation in ELOVL4 (c.575A>G [p.His192Arg]) affecting exon 5. The affected individual displays the phenotypical features of the syndrome.
Autosomal dominant mutations:
- Zhang et al. (2001) reported Stargardt Macular Degeneration type 3 in the members of 5 families from the US and Canada with 797–801delAACTT heterozygous mutation resulting in a frameshift, loss of 51 amino acids at the C terminus, synthesis of an aberrant peptide from amino acid 264 to 271, and a premature stop codon.
- Bernstein et al. (2001) reported a complex heterozygous mutation in ELOVL4 (del (790ΔT+794ΔT) resulting in a frameshift and a premature stop codon). The mutation caused Stargardt Macular Degeneration type 3 in the affected individuals.
- Maugeri et al. (2004) identified another heterozygous mutation (c.810C>G [p.Tyr270X]) in ELOVL4 in a Belgian family with Stargardt Macular Degeneration type 3.
- Cadieux-Dion et al. (2014) identified a heterozygous mutation in ELOVL4 (c.504G>C [p. Leu168Phe]) causing Spinocerebellar Ataxia type 34 in a large French-Canadian family. The affected family was originally reported by Giroux and Barbeau (1972).
- Ozaki et al. (2015) reported a heterozygous mutation in ELOVL4 (c.736T>G [p.W246G]) causing Spinocerebellar Ataxia type 34 in two unrelated Japanese families.