Recessive Mutations in ELOVL4 Cause Ichthyosis, Intellectual Disability, and Spastic Quadriplegia

Aldahmesh, Mohammed A.; Mohamed, Jawahir Y.; Alkuraya, Hisham; Verma, I. C.; Puri, Ratna Dua; Alaiya, Ayodele; Rizzo, William B.; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2011.10.011

Cited by 168 publications

(181 citation statements)

References 29 publications

(35 reference statements)

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“…Acylceramide is quite important for epidermal barrier formation, and impairment of its production (e.g. by ELOVL4 and CERS3 mutations) causes ichthyosis (15,20). CYP4F22 was first identified as an ARCI-causative gene by Fischer and her coworkers (21).…”

Section: Discussionmentioning

confidence: 99%

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Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

Ohno

Nakamichi

Ohkuni

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

128

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A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid ω-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the ω-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (≥C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production.acylceramide | ceramide | lipid | skin | sphingolipid

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Section: Discussionmentioning

confidence: 99%

“…The exact functions of NIPAL4, LIPN, and PNPLA1 are currently unclear. Causative genes of syndromic forms of ichthyosis also include a gene required for acylceramide synthesis: the FA elongase ELOVL4, which produces ULCFACoAs, the substrate of CERS3 (20).…”

Section: Significancementioning

confidence: 99%

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

Ohno

Nakamichi

Ohkuni

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

128

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“…30 This may suggest a different disease mechanism than we have previously shown for other genes in which biallelic loss of function results in distinct clinical phenotypes as compared with heterozygous mutations. 9,31,32 Alternatively, the susceptibility to absence seizures may have been erroneous.…”

Section: Discussionmentioning

confidence: 99%

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Shaheen

Patel

Shamseldin

et al. 2016

Genetics in Medicine

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Purpose: Dysmorphology syndromes are among the most common referrals to clinical genetics specialists. Inability to match the dysmorphology pattern to a known syndrome can pose a major diagnostic challenge. With an aim to accelerate the establishment of new syndromes and their genetic etiology, we describe our experience with multiplex consanguineous families that appeared to represent novel autosomal recessive dysmorphology syndromes at the time of evaluation. Methods:Combined autozygome/exome analysis of multiplex consanguineous families with apparently novel dysmorphology syndromes.Results: Consistent with the apparent novelty of the phenotypes, our analysis revealed a strong candidate variant in genes that were novel at the time of the analysis in the majority of cases, and 10 of these genes are published here for the first time as novel candidates (CDK9, NEK9, ZNF668, TTC28, MBL2, CADPS, CACNA1H, HYAL2, CTU2, and C3ORF17). A significant minority of the phenotypes (6/31, 19%), however, were caused by genes known to cause Mendelian phenotypes, thus expanding the phenotypic spectrum of the diseases linked to these genes. The conspicuous inheritance pattern and the highly specific phenotypes appear to have contributed to the high yield (90%) of plausible molecular diagnoses in our study cohort. Conclusion:Reporting detailed clinical and genomic analysis of a large series of apparently novel dysmorphology syndromes will likely lead to a trend to accelerate the establishment of novel syndromes and their underlying genes through open exchange of data for the benefit of patients, their families, health-care providers, and the research community.

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“…As we have shown previously, autozygome served as an extremely powerful filter of the resulting variants. 35,36 In Family MKS_F1, two variants survived filtration but TMEM237 was recently described as a novel Joubert gene. 25 Some of the original reported cases had occipital encephalocele and cystic kidney so it seems likely that our mutation is the causal variant.…”

Section: Head and Neckmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

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Recessive Mutations in ELOVL4 Cause Ichthyosis, Intellectual Disability, and Spastic Quadriplegia

Cited by 168 publications

References 29 publications

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

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