Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

doi:10.3390/genes14030717

. 2023 Mar 15;14(3):717.

doi: 10.3390/genes14030717.

Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Alrun Hotz^{1

2

3}, Julia Kopp¹, Emmanuelle Bourrat⁴, Vinzenz Oji^{3

5}, Kira Süßmuth⁵, Katalin Komlosi^{1

2

3}, Bakar Bouadjar⁶, Iliana Tantcheva-Poór⁷, Maritta Hellström Pigg⁸, Regina C Betz⁹, Kathrin Giehl^{3

10}, Fiona Schedel⁵, Lisa Weibel¹¹, Solveig Schulz¹², Dora V Stölzl¹³, Gianluca Tadini^{3

14}, Emine Demiral¹⁵, Karin Berggard¹⁶, Andreas D Zimmer¹, Svenja Alter^{1

2

3}, Judith Fischer^{1

2

3}

Affiliations

¹ Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
² Center for Cornification Disorders, Freiburg Center for Rare Diseases, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
³ European Reference Networks (ERN Skin), 75015 Paris, France.
⁴ Department of Dermatology, Reference Center for Rare Skin Diseases MAGEC, Saint Louis Hospital AP-HP, 75015 Paris, France.
⁵ Department of Dermatology and Venereology, Muenster University Medical Center, 48149 Muenster, Germany.
⁶ Department of Dermatology, CHU of Bab-El-Oued Algiers, Algiers 16008, Algeria.
⁷ Department of Dermatology and Venereology, Faculty of Medicine and University Hospital, University of Cologne, 50937 Cologne, Germany.
⁸ Clinical Genetics, Karolinska University Hospital, 171 64 Solna, Sweden.
⁹ Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, 53127 Bonn, Germany.
¹⁰ Department of Dermatology, Venerology und Allergology, University Hospital of Munich, 80337 Munich, Germany.
¹¹ Pediatric Skin Center, Dermatology Department, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
¹² Synlab Medical Practice for Human Genetics Jena, 07747 Jena, Germany.
¹³ Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
¹⁴ Pediatric Dermatology Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
¹⁵ Department of Medical Genetics, Inonu University School of Medicine, 44280 Malatya, Turkey.
¹⁶ Department of Dermatology and Venereology, Skåne University Hospital, 221 85 Lund, Sweden.

PMID: 36980989
PMCID: PMC10048568
DOI: 10.3390/genes14030717

Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Alrun Hotz et al. Genes (Basel). 2023.

. 2023 Mar 15;14(3):717.

doi: 10.3390/genes14030717.

Authors

Affiliations

¹ Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
² Center for Cornification Disorders, Freiburg Center for Rare Diseases, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
³ European Reference Networks (ERN Skin), 75015 Paris, France.
⁴ Department of Dermatology, Reference Center for Rare Skin Diseases MAGEC, Saint Louis Hospital AP-HP, 75015 Paris, France.
⁵ Department of Dermatology and Venereology, Muenster University Medical Center, 48149 Muenster, Germany.
⁶ Department of Dermatology, CHU of Bab-El-Oued Algiers, Algiers 16008, Algeria.
⁷ Department of Dermatology and Venereology, Faculty of Medicine and University Hospital, University of Cologne, 50937 Cologne, Germany.
⁸ Clinical Genetics, Karolinska University Hospital, 171 64 Solna, Sweden.
⁹ Institute of Human Genetics, University of Bonn, Medical Faculty & University Hospital Bonn, 53127 Bonn, Germany.
¹⁰ Department of Dermatology, Venerology und Allergology, University Hospital of Munich, 80337 Munich, Germany.
¹¹ Pediatric Skin Center, Dermatology Department, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
¹² Synlab Medical Practice for Human Genetics Jena, 07747 Jena, Germany.
¹³ Center for Inflammatory Skin Diseases, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
¹⁴ Pediatric Dermatology Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, University of Milan, 20122 Milan, Italy.
¹⁵ Department of Medical Genetics, Inonu University School of Medicine, 44280 Malatya, Turkey.
¹⁶ Department of Dermatology and Venereology, Skåne University Hospital, 221 85 Lund, Sweden.

PMID: 36980989
PMCID: PMC10048568
DOI: 10.3390/genes14030717

Abstract

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

Keywords: ABCA12; ARCI; congenital ichthyosiform erythroderma; harlequin ichthyosis; lamellar ichthyosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
(A) Distribution of all mutations in the *ABCA12* gene in our cohort of 62 patients. A total of 34 novel mutations are shown in bold and 28 previously published mutations are shown in non-bold. Red: Transmembrane domain 1 and 2 in the ABCA12 protein. Green: ATP-binding cassettes 1 and 2 in the ABCA12 protein. The transmembrane domains range from amino acids 1063 to 1271 and 1987 to 2208; the ATP binding cassettes range from amino acids 1346 to 1577 and 2254 to 2489, including the AAA domains amino acids 1370 to 1554 and 2282 to 2467 (InterPro 92.0 [22], SMART 9.0 [23]). (B) Spectrum of mutations in *ABCA12*. In the cohort of 64 patients, 62 mutations were found: 35.5% are missense mutations, 27.5% truncating deletions/duplications, 22.5% nonsense mutations, and 14.5% splice site mutations. (C) Percentage distribution of phenotypes in our cohort. Patients with HI and CIE are diagnosed with greater frequency and LI is less common. The grouping of others consists of patients with unknown phenotypes or with phenotypes which cannot be clearly assigned. (D) Combinations of mutation classes in patients with HI, CIE, or LI in our cohort. Truncating mutations on both alleles or the combination of a truncating mutation on one allele with a splice site mutation on the other allele always led to HI in our cohort, whereas missense mutations on both alleles mainly led to CIE or LI.

**Figure 2**
(A–D) Harlequin ichthyosis in patient 36. (A) Generalized dry and red scaly skin on the back, (B) palmoplantar hyperkeratosis, (C) joint contractures at fingers and thickened fingernails, and (D) face with red, scaly skin, ectropion, and hypoplastic ears. (E) Harlequin ichthyosis in patient 26 at the day of birth. Large thick plates separated by deep cracks. Ectropion, eclabion, hypoplastic nose and ears. (F–H) Lamellar ichthyosis in patient 48. (F) Palmoplantar hyperkeratosis, (G) ichthyotic skin on the neck, and (H) skin with large dark scales and contractures of fingers. (I–L) Congenital ichthyosiform erythroderma in patient 26. (I) Thickened skin with white scales in a newborn, (J) erythroderma of the palms, (K) generalized erythroderma with fine white scales, and (L) palmoplantar hyperkeratosis.

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References

1. Rajpopat S., Moss C., Mellerio J., Vahlquist A., Gånemo A., Hellstrom-Pigg M., Ilchyshyn A., Burrows N., Lestringant G., Taylor A., et al. Harlequin ichthyosis: A review of clinical and molecular findings in 45 cases. Arch. Dermatol. 2011;147:681–686. doi: 10.1001/archdermatol.2011.9. - DOI - PubMed
1. Vahlquist A., Fischer J., Törmä H. Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment. Am. J. Clin. Dermatol. 2018;19:51–66. doi: 10.1007/s40257-017-0313-x. - DOI - PMC - PubMed
1. Paller A.S., Renert-Yuval Y., Suprun M., Esaki H., Oliva M., Huynh T.N., Ungar B., Norma Kunjravia N., Friedland R., Peng X., et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J. Allergy Clin. Immunol. 2017;139:152–165. doi: 10.1016/j.jaci.2016.07.019. - DOI - PMC - PubMed
1. Albela H., Leong K.F. Secukinumab in the treatment of a child with congenital ichthyosiform erythroderma with ABCA12 mutation. Int. J. Dermatol. 2023;62:e27–e29. doi: 10.1111/ijd.16378. - DOI - PubMed
1. Enjalbert F., Dewan P., Caley M.P., Jones E.M., Morse M.A., Kelsell D.P., Enright A.J., O’Toole E.A. 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets. J. Clin. Investig. 2020;130:4798–4810. doi: 10.1172/JCI132987. - DOI - PMC - PubMed

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[1] Rajpopat S., Moss C., Mellerio J., Vahlquist A., Gånemo A., Hellstrom-Pigg M., Ilchyshyn A., Burrows N., Lestringant G., Taylor A., et al. Harlequin ichthyosis: A review of clinical and molecular findings in 45 cases. Arch. Dermatol. 2011;147:681–686. doi: 10.1001/archdermatol.2011.9. - DOI - PubMed

[2] Rajpopat S., Moss C., Mellerio J., Vahlquist A., Gånemo A., Hellstrom-Pigg M., Ilchyshyn A., Burrows N., Lestringant G., Taylor A., et al. Harlequin ichthyosis: A review of clinical and molecular findings in 45 cases. Arch. Dermatol. 2011;147:681–686. doi: 10.1001/archdermatol.2011.9. - DOI - PubMed

[3] Vahlquist A., Fischer J., Törmä H. Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment. Am. J. Clin. Dermatol. 2018;19:51–66. doi: 10.1007/s40257-017-0313-x. - DOI - PMC - PubMed

[4] Vahlquist A., Fischer J., Törmä H. Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment. Am. J. Clin. Dermatol. 2018;19:51–66. doi: 10.1007/s40257-017-0313-x. - DOI - PMC - PubMed

[5] Paller A.S., Renert-Yuval Y., Suprun M., Esaki H., Oliva M., Huynh T.N., Ungar B., Norma Kunjravia N., Friedland R., Peng X., et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J. Allergy Clin. Immunol. 2017;139:152–165. doi: 10.1016/j.jaci.2016.07.019. - DOI - PMC - PubMed

[6] Paller A.S., Renert-Yuval Y., Suprun M., Esaki H., Oliva M., Huynh T.N., Ungar B., Norma Kunjravia N., Friedland R., Peng X., et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J. Allergy Clin. Immunol. 2017;139:152–165. doi: 10.1016/j.jaci.2016.07.019. - DOI - PMC - PubMed

[7] Albela H., Leong K.F. Secukinumab in the treatment of a child with congenital ichthyosiform erythroderma with ABCA12 mutation. Int. J. Dermatol. 2023;62:e27–e29. doi: 10.1111/ijd.16378. - DOI - PubMed

[8] Albela H., Leong K.F. Secukinumab in the treatment of a child with congenital ichthyosiform erythroderma with ABCA12 mutation. Int. J. Dermatol. 2023;62:e27–e29. doi: 10.1111/ijd.16378. - DOI - PubMed

[9] Enjalbert F., Dewan P., Caley M.P., Jones E.M., Morse M.A., Kelsell D.P., Enright A.J., O’Toole E.A. 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets. J. Clin. Investig. 2020;130:4798–4810. doi: 10.1172/JCI132987. - DOI - PMC - PubMed

[10] Enjalbert F., Dewan P., Caley M.P., Jones E.M., Morse M.A., Kelsell D.P., Enright A.J., O’Toole E.A. 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets. J. Clin. Investig. 2020;130:4798–4810. doi: 10.1172/JCI132987. - DOI - PMC - PubMed

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Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Affiliations

Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Authors

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Abstract

Conflict of interest statement

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