The ELOVL4 gene codes for a protein that is found primarily in the retina. This protein called ELOVL Fatty Acid Elongase 4, is a member of the ELO protein family and is produced in photoreceptors. The ELOVL4 protein is also found in the brain and skin, but little is known about its expression in these structures. Inside photoreceptor cells, this protein is located in a cell structure called the endoplasmic reticulum that is involved in protein production, processing, and transport. The ELOVL4 protein plays a role in making a group of fats called very long-chain fatty acids. The protein helps add carbon molecules to long-chain fatty acids, making them very long-chain fatty acids.
Mutations in the ELOVL4 gene create a premature stop signal in the instructions used to make the ELOVL4 protein. As a result, the protein cannot be retained in the endoplasmic reticulum of photoreceptor cells. Instead, the ELOVL4 protein forms clumps (aggregates). These aggregates cannot make very long-chain fatty acids and may interfere with cell functions, ultimately leading to cell death. Studies in animal models have shown that defective ELOVL4 proteins are unable to prevent water loss from the skin in a desiccating environment leading the animals to dehydrate very quickly and die as a result. Mutations in this gene are implicated in different diseases, including ISQMR, a syndrome of ichthyosis, spastic quadriplegia and mental retardation, a subtype of spinocerebellar ataxia (SCA34), and a form of macular degeneration known as Stargadt Disease.
The ELOVL4 gene is located on the long (q) arm of chromosome 6 at position 14, spanning a length of 32.7 kb. It contains six exons. It has two putative polyadenylation sites in the 3-prime region. The ELOVL4 protein consists of 314 amino acids. This protein contains typical features for members of the ELO family. These include the presence of five transmembrane segments; a single histidine cluster motif (HXXHH) involved with fatty acid desaturase activity and other dioxy iron cluster proteins; and a dilysine motif that enables the retention of the protein within the endoplasmic reticulum. Most disease causing mutations in this gene are clustered around the C-terminal end of the protein.
Aldahmesh et al. (2011) reported on an individual born to healthy first cousin consanguineous Saudi Arabian parents with recessive ELOVL4 mutation who displayed a syndrome of congenital ichthyosis, spastic quadriplegia, and mental retardation. Biochemical analysis of fibroblast fatty aldehyde dehydrogenase (FALDH) activity was found to be normal in this patient, which suggested that this index had ‘‘pseudo-SLS’’. Whole exome sequencing performed at 303x coverage identified a truncating nonsense mutation in exon 5 of ELOVL4, c.646C>T (p.Arg216X), as the most plausible candidate for causing the disease phenotype. Sanger sequencing confirmed the homoallelic state of this mutation in the patient and the carrier state of the parents, and a screen of 192 Saudi controls was negative. Immunoblot analysis of the patient’s cells consistently showed that he produced normal-sized ELOVL4, albeit at about a 45% reduced level. This is surprising because his nonsense mutation predicted a 24 kDa protein compared to the normal 37 kDa ELOVL4. The authors emphasized the importance of VLCFA synthesis in brain and cutaneous development and the critical role of ELOVL4 and VLCFAs in early brain development and in the integrity of the epidermal water barrier. In addition, the findings demonstrated the power of combining homozygosity mapping with next-generation sequencing for identifying the cause of autosomal-recessive diseases even in simplex cases.
Monies et al. (2017) described the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One male patient suffered from contractures, ichthyosis, failure to thrive, microcephaly, fine/gross motor delay, speech delay, spasticity, seizures, optic atrophy and Sjogren Larsson syndrome. He was born premature at 34 weeks to a consanguineous family and reported a positive family history. Whole exome sequencing helped identify a homozygous mutation (c.575A>G, p.H192R) in exon 5 of the patient’s ELOVL4 gene, associated with the disorder Ichthyosis, Spastic Quadriplegia and Mental Retardation (ISQMR). As the ELOVL4 gene had previously been tentatively linked to ISQMR, this report helped confirm its association with the disorder.
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