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Year : 2020  |  Volume : 14  |  Issue : 4  |  Page : 90-94

CYP4F22 gene mutations in patients with autosomal recessive congenital ichthyosis: Identification of two novel mutations

1 Department of Medical Genetics, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
2 Department of Medical Genetics, Ege University Faculty of Medicine, Izmir, Turkey
3 Department of Dermatology, Ege University Faculty of Medicine, Izmir, Turkey
4 Department of Medical Genetics, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
5 Department of Medical Genetics, Dr. Behcet Uz Children's Hospital, Izmir, Turkey

Date of Submission12-Aug-2020
Date of Decision31-Aug-2020
Date of Acceptance22-Sep-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Dr. Esra Arslan Ates
Department of Medical Genetics, Marmara University Pendik Training and Research Hospital, Pendik, Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjd.tjd_91_20

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Background: Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous keratinization disorder, which is clinically classified into five main forms: Lamellar ichthyosis, congenital ichthyosiform erythroderma, harlequin ichthyosis, self-healing collodion baby, and bathing suit ichthyosis. Mutations in TGM1, ABCA12, ALOX12B, ALOXE3, NIPAL4, CYP4F22, PNPLA1, LIPN, and CERS3 genes have been described in patients with ARCI. However, in 20% of the ARCI patients, the genetic defect remains unknown. Materials and Methods: In this study, we investigated the mutations in the CYP4F22 gene in ARCI patients who do not have mutations in two common ARCI genes, NIPAL4 and TGM1. Twenty-two patients diagnosed with ARCI and having no mutations in TGM1 and NIPAL4 genes were included in the study. Their CYP4F22 genes were sequenced using the Sanger sequencing method. Results: In 5 of 22 (22.7%) ARCI patients, four different mutations, of which two were previously reported, were found. The two novel mutations were c.976C> T and c.1189C> T. The c.727C> T and c.1303C>T mutations were previously reported. Conclusions: This study expands the CYP4F22 mutation spectrum and to provide more accurate genetic counseling for patients at risk.

Keywords: Autosomal recessive, CYP4F22, genetic diseases/mechanisms, ichthyosis, sanger sequencing

How to cite this article:
Ates EA, Onay H, Ertam I, Ataman E, Hazan F, Durmaz A, Dereli T, Özkinay F. CYP4F22 gene mutations in patients with autosomal recessive congenital ichthyosis: Identification of two novel mutations. Turk J Dermatol 2020;14:90-4

How to cite this URL:
Ates EA, Onay H, Ertam I, Ataman E, Hazan F, Durmaz A, Dereli T, Özkinay F. CYP4F22 gene mutations in patients with autosomal recessive congenital ichthyosis: Identification of two novel mutations. Turk J Dermatol [serial online] 2020 [cited 2021 Apr 19];14:90-4. Available from: https://www.tjdonline.org/text.asp?2020/14/4/90/305748

  Introduction Top

Ichthyosis is a group of cornification disorders, which affects a part or all of the skin. It is characterized by widespread dryness and scaling. A number of etiological factors (drugs, malignancies, and autoimmune diseases) may be responsible for acquired ichthyosis.[1] Genetically determined or hereditary ichthyosis shows high genetic heterogeneity.[2] The most common hereditary form is ichthyosis vulgaris caused by the mutations in FLG gene.[3] This is followed by X-linked recessive ichthyosis (XLRI) with a prevalence of 1/6000 males.[4] Another form of hereditary ichthyosis is autosomal recessive congenital ichthyosis (ARCI) which affects 1 in 300,000 newborns worldwide.[5] The prevalence is higher in some populations due to the founder effect. ARCI patients are affected in utero and show clinical findings, such as collodion membrane, at birth.[6] There are three major clinical forms of ARCI: Lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE), and harlequin ichthyosis (HI). HI, the most severe form, shows hyperkeratosis characterized by thick plaques separated by fissures and is caused by large deletions or mutations resulting in premature stop codon in ABCA12 gene.[7],[8] LI patients present with large, dark, plate-like scales covering the whole body surface, eclabium, and ectropion.[6] CIE patients show whitish, fine, semi-adherent scales with erythrodermia.[9] The major problems in the last two forms of ARCI are the risk of severe dehydration and infections leading to morbidity and mortality.[10] Both forms of ARCI are caused by the mutations in eight different genes in 80% of patients: TGM1 and NIPAL4 gene mutations account for 50% of ARCI patients, while ALOX12B, ALOXE3, CYP4F22, ABCA12, PNPLA1, LIPN, and CERS3 gene mutations are responsible for the rest of patients.[11],[12],[13],[14] Eight percent of patients with ARCI have mutations in CYP4F22 gene located at 19p13.1.12. The CYP4F22 gene encodes for a protein that is a member of cytochrome P450 family and plays a role in the fatty acid metabolic pathway.[15],[16]

In this study, CYP4F22 mutations were investigated in 22 patients diagnosed with ARCI and previously shown that they did not have TGM1 and NIPAL4 mutations. In five patients four different mutations, two of them being novel were defined.

  Materials and Methods Top

The present study was approved by the institutional ethics review board of our institution (Decision Number: 11-6.1/3). Twenty-two patients recruited from Ege University Faculty of Medicine, Department of Dermatology and Department of Medical Genetics were included in the study. Medical history, physical examination, and pedigree analysis were evaluated to determine the heredity pattern and ichthyosis type. The type of ichthyosis was verified histopathologically only when the patient's consent was provided. Twenty-two patients (aged between 5 months and 36 years) studied had a pedigree suggestive of ARCI and did not have a mutation in TGM1 and NIPAL4 genes which are the two most common ARCI causing genes. These two genes are routinely tested as a first step in ARCI patients in our laboratory. In this study, 22 patients were sequenced for the gene CYP4F22 described as an ARCI causing gene previously. Parents of all patients having CYP4F22 mutations were screened for the mutations. A hundred control chromosomes were evaluated for novel mutations.

Molecular genetic analysis

DNA isolation was performed from peripheral blood lymphocytes using MagNa Pure LC DNA Isolation Kit I (Product No: 0300039900001; Roche, USA). In 22 patients, all exons and exon-intron boundaries of CYP4F22 gene were sequenced by ABI 3130 using the instrument protocols. When a mutation was detected, parents were analyzed. The primers used for CYP4F22 gene amplification are listed in [Table 1]. All variations detected were evaluated using Ensembl Genome Bowser and HGMD mutation database.
Table 1: Primers used for CYP4F22 gene amplification

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In slico analysis

Genomic variations which had not been reported previously were evaluated by protein sorting intolerant from tolerant (SIFT) and PolyPhen.

  Results Top

This study included 22 ARCI patients who do not have mutations in their TGM1 and NIPAL4 genes. In 5 (22.7%) out of 22 ARCI patients, homozygous CYP4F22 mutations were detected. Two patients had a known mutation, c.1303C<T and one another known mutation c.727C>T, whereas two patients had two different novel homozygous mutations [Figure 1] and [Table 2]. Novel mutations were not detected in 100 healthy control chromosomes. Parental consanguinity was declared in 4 of 5 patients. One patient had parents from a small village, but no consanguinity was described. All parents were heterozygous for the mutations detected in their children. Clinical features and the mutations detected in these five patients are given in [Table 2]. Five ARCI patients having CYP4F22 mutations presented with palmoplantar involvement, ectropion, and erythema [Figure 2]. One had a pigmentation defect in the retina. Ocular examinations of other patients were normal, and one of them had been discussed in another study.[17] A skin biopsy was performed in three mutation-positive patients, one patient showed hyperkeratosis, parakeratosis and thickened stratum corneum and one patient showed acanthosis, spongiosis in the epidermis, and perivascular eosinophilic infiltration. One patient histopathological examination showed nonspecific findings.
Figure 1: Electropherogram of detected CYP4F22 gene mutations. (a) c.1303C>T(H435Y) homozygous mutation (b) c.976C>T(p.R326X) homozygous mutation (c) c.1189C>T(p.R397C) homozygous mutation (d) c.727C>T(p.R243C) homozygous mutation

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Figure 2: Clinical findings of case 20. (a) Erythema and fine scaling on the face. (b and c) Palmoplantar keratoderma and hyperlinearity

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Table 2: Clinical findings of autosomal recessive congenital ichthyosis patients with CYP4F22 gene mutations

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  Discussion Top

ARCI is a rare form of ichthyosis with an estimated prevalence of 1:300,000 newborns.[5] It is expected more common in populations with a high rate of consanguineous marriages such as Turkey.

In this study, parents of four patients with homozygous CYP4F22 gene mutations were consanguineous. In the studies by Lefèvre et al. and Lugassy et al., high parental consanguinity rates in ARCI patients were also reported.[15],[18]

Mutations in eight different genes in almost 80% of ARCI patients have been identified so far. Among these genes, CYP4F22 gene mutations were detected in 8% of all ARCI patients.[19] TGM1 and NIPAL4 genes have been described as the two most common mutated genes in ARCI patients. Therefore, these two genes were analyzed in our ARCI patients in the first step. In our study population, CYP4F22 gene was responsible for the 22.7% (5/22) of ARCI patients who did not have mutations in TGM1 and NIPAL4 genes.

Homozygous c.1303C>T mutation defined in our two patients was reported by Lefèvre et al. previously.[15] Our two patients were from the Mediterranean Region of Turkey. The cases reported by LeFevre were also from the coastal Mediterranean region. Therefore, there may be a founder effect for this mutation.

In one patient, we detected homozygous c.727C>T (p. Arg243Cys) mutation which was reported previously in compound heterozygous state with a frameshift variant in an ARCI patient by Pigg et al.[20]

One of our patients was homozygous for the novel c.976C > T (p. Arg326X) mutation which causes stop codon in exon 7. The other novel homozygous mutation (c.1189C > T) affects well conserved arginine residues in ichtyn protein [Figure 3]. These two mutations were not reported previously and not detected in 100 control chromosomes. In addition, PolyPhen and SIFT analysis indicated that they were damaging mutations, which supports their causative roles.
Figure 3: Amino acid sequence of CYP4F22 in different organisms (397. Arginine Residue)

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Phenotypic features of our patients were very similar to the features of previously reported patients with CYP4F22 mutations. In the study by Lefèvre et al., patients carrying CYP4F22 mutation presented with a CIE phenotype at birth, progressing later to a more lamellar aspect of the skin, and palmoplantar hiperlinearity which is the characteristic feature of this ichthyosis form.[15] In our study, a 21-year-old patient presented with LI at the time of examination; however, CIE was described during her newborn and childhood period.

It has been reported that most of the ARCI patients are not born as collodion babies.[15] Our two patients with CYP4F22 mutations had a history of collodion baby at birth.

Ectropion, one of the most common features of ARCI, was noted in all of our patients and eclabium was observed in two patients at birth [Table 2]. As the ARCI is classified in nonsyndromic ichthyosis forms, systemic findings are not expected.[11] Our ARCI patients did not have systemic involvement either. Only one patient had defective retinal pigmentation on ophthalmological examination. Retinal involvement has not been reported in ichthyosis patients previously. Among CYP 450 superfamily members, CYP27A1 and CYP11A1 have an important role in retinal cholesterol metabolism.[21] CYP4V2 mutations have been shown in Bietti's crystalline corneoretinal dystrophy which is a form of hereditary retinal degeneration.[22] However, there has been no report about retinal expression of CYP4F22 in the literature. Further studies are needed to determine whether it is coincidental or a part of the disease.

We were able to perform histopathological examination on three of five patients with CYP4F22 mutations. One patient showed hyperkeratosis, parakeratosis, and thickened stratum corneum which were consistent with the histopathological findings seen in previously reported ARCI patients.[15] In another patient, biopsy showed acanthosis spongiosis in the epidermis and perivascular eosinophilic infiltration, which were interpreted in favor of atopic dermatitis. Atopic dermatitis has been reported to be associated with ichthyosis vulgaris and XLRI.[23],[24] Oji et al. revealed that the corneodesmosin is the important for integrity of the epidermal barrier and loss of corneodesmosin causes peeling skin syndrome leading to atopy.[25] Regarding the data reported previously, it has been considered that atopic dermatitis could be a part of ichthyosis caused by CYP4F22 mutations or perhaps, it is a coincidence in this case.

  Conclusion Top

To the best of our knowledge, this is the first study investigating the molecular etiology of ichthyosis in the Turkish population and one of the few examples of molecular genetic screening of CYP4F22 gene in ARCI patients. We have reported two novel CYP4F22 gene mutations. Further studies will expand the mutation spectrum of CYP4F22 gene mutations in the etiopathogenesis of ARCI in the Turkish population. Further molecular analysis should be planned to reveal the molecular genetic etiology of the disease in ARCI patients who did not have mutations in the genes analyzed.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by Ege University Scientific Research Projects Coordination Unit.

Conflicts of interest

There are no conflicts of interest.

  References Top

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Kerr CB, Wells R. X-Linked Ichthyosis and the Xg Groups. Lancet 1964;2:1369-70.  Back to cited text no. 4
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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