A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity

Abstract

BackgroundA rare neuro-ichthyotic disorder characterized by ichthyosis, spastic quadriplegia and intellectual disability and caused by recessive mutations in ELOVL4, encoding elongase-4 protein has recently been described. The objective of the study was to search for sequence variants in the gene ELOVL4 in three affected individuals of a consanguineous Pakistani family exhibiting features of neuro-ichthyotic disorder.MethodsLinkage in the family was searched by genotyping microsatellite markers linked to the gene ELOVL4, mapped at chromosome 6p14.1. Exons and splice junction sites of the gene ELOVL4 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer.ResultsDNA sequence analysis revealed a novel homozygous nonsense mutation (c.78C > G; p.Tyr26*).ConclusionsOur report further confirms the recently described ELOVL4-related neuro-ichthyosis and shows that the neurological phenotype can be absent in some individuals.

A NewELOVL4Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia

“…4 In the complex syndrome of ichthyosis, spastic quadriplegia, and mental retardation, which might be considered to be a more severe form of SCA34, the homozygous mutations are in exon 5, which encodes the fourth transmembrane domain. 5 Our report supports the notion that SCA34 causative mutations cluster in exon 4 of ELOVL4 where they disrupt the third transmembrane domain. Moreover, the finding of an ELOVL4 mutation in a patient with an SCA34 phenotype suggests that alterations in this gene lead to the same condition in separate populations.…”

Retinal Degenerative Diseases

“…He died at 17 years of age, while the Asian Indian children died at 6 months and 2 years of age. The only retinal phenotype reported in these patients was tortuous blood vessels, subtle macular changes, and mild degree of myopia with subtle peripapillary changes (Aldahmesh et al 2011;Mir et al 2014). Of the surviving Pakistani family members, intra-familial phenotypic differences were observed, suggesting the severity of the phenotypes was age-dependent or due to the degree of activity of expressed mutant ELOVL4, or both.…”

“…Interestingly, no significant retinal phenotype was observed in these patients or their heterozygous parents. In 2014, another novel homozygous recessive ELOVL4 mutation (c. 78C > G) encoding a Try26stop was reported in four Pakistani family members aged 16-24 years (Mir et al 2014), who displayed neuro-ichthyotic disorders similar to the Saudi and Asian Indian children. Much like the Asian Indian children, one of the Pakistani patients had severe intellectual disability, impaired speech and hearing, spastic quadriplegia, was constantly bed ridden, and had frequent seizures and small testicles.…”

“…Eight separate mutations in human ELOVL4 have been identified Edwards et al 2001;Zhang et al 2001;Maugeri et al 2004;Aldahmesh et al 2011;Cadieux-Dion et al 2014;Mir et al 2014). The ELOVL4 gene encodes a protein that is expressed in retina, testis, skin, meibomian gland, and brain, where it mediates tissue-specific biosynthesis of very long chain saturated fatty acids (VLC-SFA, > C26) and/or very long chain polyunsaturated fatty acids (VLC-PUFA; > C26), collectively referred to as VLC-FA .…”

An overview of inborn errors of complex lipid biosynthesis and remodelling

“…Very recently, heterozygote mutations in ELOVL4 have been reported in a large family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia(Cadieux- Dion et al 2014). Homozygous mutations in the same gene have also been reported in patients with congenital ichthyosis, spastic paraplegia and intellectual disability resembling Sjögren-Larsson syndrome(Aldahmesh et al 2011;Mir et al 2014; Aubourg in this issue). Of note, ELOVL5 heterozygote mutations have just been identified in three unrelated families with autosomal dominant spinocerebellar ataxia (SCA38)(Di Gregorio et al 2014).…”