Volume 50, Issue 5 pp. 715-719

CONCISE COMMUNICATION

An intronic splice-site variant in MBTPS2 underlies ichthyosis follicularis with atrichia and photophobia syndrome

Gang Chen,

Gang Chen

orcid.org/0000-0001-8163-7916

Department of Dermatology and Venereology, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

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Mengwei Wang,

Mengwei Wang

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

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Peiguang Wang,

Peiguang Wang

Department of Dermatology and Venereology, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

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Bo Liang,

Corresponding Author

Bo Liang

[email protected]

orcid.org/0000-0003-0267-8184

Department of Dermatology and Venereology, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

Department of Clinical Laboratory, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Correspondence

Bo Liang, 218 Jixi Road, Hefei City, Anhui Province, IL 230000, China.

Email: [email protected]

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Gang Chen,

Gang Chen

orcid.org/0000-0001-8163-7916

Department of Dermatology and Venereology, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

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Mengwei Wang,

Mengwei Wang

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

Search for more papers by this author

Peiguang Wang,

Peiguang Wang

Department of Dermatology and Venereology, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

Search for more papers by this author

Bo Liang,

Corresponding Author

Bo Liang

[email protected]

orcid.org/0000-0003-0267-8184

Department of Dermatology and Venereology, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China

Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, China

Department of Clinical Laboratory, The First Affiliated Hospital, Anhui Medical University, Hefei, China

Correspondence

Bo Liang, 218 Jixi Road, Hefei City, Anhui Province, IL 230000, China.

Email: [email protected]

Search for more papers by this author

First published: 20 December 2022

https://doi.org/10.1111/1346-8138.16684

Gand Chen and Mengwei Wang contributed equally to this work.

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Abstract

Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare genodermatosis characterized by a classic triad of follicular ichthyosis, alopecia, and photophobia. We report a Chinese patient displaying features of IFAP triad along with painful palmoplantar keratoderma, recurrent infections, periorificial keratotic plaques, nail dystrophy, and pachyonychia. Whole-exome sequencing revealed an intronic variant (NM_015884.3: exon7:c.970+5G>A) in the gene MBTPS2. Sanger sequencing confirmed that the variant segerated with phenotype in the family. Sequencing of cDNAs derived from the patient indicated the variant introduced a new splice donor site, leading to partial skipping of exon 7 (r.951_970del). An in vitro mini-gene assay also revealed abnormal splicing of exon 7. This study presents a case complicated with X-linked IFAP syndrome and Olmsted syndrome, and highlights the significance of using validation assays to identify the pathogenicity of intronic variants in MBTPS2.

CONFLICT OF INTEREST

The authors have no conflicts of interest to declare.

REFERENCES

1Macleod J. Three cases of ‘ichthyosis follicularis’ associated with baldness. Br J Dermatol. 1909; 21: 165–89.
Web of Science® Google Scholar
2Irurzun I, Natale MI, Agostinelli ML, Lamberti M, Montero D, Granda C, et al. Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: two syndromes that share a common clinical spectrum. Pediatr Dermatol. 2021; 38: 568–74.
10.1111/pde.14560
PubMed Web of Science® Google Scholar
3Oeffner F, Fischer G, Happle R, König A, Betz RC, Bornholdt D, et al. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet. 2009; 84: 459–67.
10.1016/j.ajhg.2009.03.014
CAS PubMed Web of Science® Google Scholar
4Caengprasath N, Theerapanon T, Porntaveetus T, Shotelersuk V. MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders. J Transl Med. 2021; 19: 114.
10.1186/s12967-021-02779-5
CAS PubMed Web of Science® Google Scholar
5Bornholdt D, Atkinson TP, Bouadjar B, Catteau B, Cox H, de Silva D, et al. Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2. Hum Mutat. 2013; 34: 587–94.
10.1002/humu.22275
CAS PubMed Web of Science® Google Scholar
6Wang HJ, Humbatova A, Liu YX, Qin W, Lee M, Cesarato N, et al. Mutations in SREBF1, encoding sterol regulatory element binding transcription factor 1, cause autosomal-dominant IFAP syndrome. Am J Hum Genet. 2020; 107: 34–45.
10.1016/j.ajhg.2020.05.006
CAS PubMed Web of Science® Google Scholar
7Morice-Picard F, Michaud V, Lasseaux E, Rezvani HR, Plaisant C, Bessis D, et al. Hereditary mucoepithelial dysplasia results from heterozygous variants at p.Arg557 mutational hotspot in SREBF1, encoding a transcription factor involved in cholesterol homeostasis. J Invest Dermatol. 2020; 140: 1289–92.
10.1016/j.jid.2019.10.014
CAS PubMed Web of Science® Google Scholar
8Murase C, Takeichi T, Nomura T, Ogi T, Akiyama M. Hereditary mucoepithelial dysplasia and autosomal-dominant IFAP syndrome is a clinical spectrum due to SREBF1 variants. J Invest Dermatol. 2021; 141: 1596–8.
10.1016/j.jid.2020.09.035
CAS PubMed Web of Science® Google Scholar
9Rentzsch P, Schubach M, Shendure J, Kircher M. CADD-splice-improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med. 2021; 13: 12.
10.1186/s13073-021-00835-9
PubMed Web of Science® Google Scholar
10Wang HJ, Tang ZL, Lin ZM, Dai LL, Chen Q, Yang Y. Recurrent splice-site mutation in MBTPS2 underlying IFAP syndrome with Olmsted syndrome-like features in a Chinese patient. Clin Exp Dermatol. 2014; 39: 158–61.
10.1111/ced.12248
CAS PubMed Web of Science® Google Scholar
11Oeffner F, Martinez F, Schaffer J, Salhi A, Monfort S, Oltra S, et al. Intronic mutations affecting splicing of MBTPS2 cause ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome. Exp Dermatol. 2011; 20: 448–9.
10.1111/j.1600-0625.2010.01238.x
CAS Web of Science® Google Scholar
12Chen F, Wang J, Yao Z, Li M. A novel MBTPS2 start codon mutation causes a mild ichthyosis follicularis with atrichia and photophobia phenotype. Clin Exp Dermatol. 2020; 45: 505–7.
10.1111/ced.14114
CAS PubMed Web of Science® Google Scholar
13Lin ZM, Chen Q, Lee MY, Cao X, Zhang J, Ma D, et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet. 2012; 90: 558–64.
10.1016/j.ajhg.2012.02.006
CAS PubMed Web of Science® Google Scholar
14Haghighi A, Scott CA, Poon DS, Yaghoobi R, Saleh-Gohari N, Plagnol V, et al. A missense mutation in the MBTPS2 gene underlies the X-linked form of Olmsted syndrome. J Invest Dermatol. 2013; 133: 571–3.
10.1038/jid.2012.289
CAS PubMed Web of Science® Google Scholar
15Nemer G, Safi R, Kreidieh F, Usta J, Bergqvist C, Ballout F, et al. Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: the interaction of MBTPS2 and TRPV3. Arch Dermatol Res. 2017; 309: 637–43.
10.1007/s00403-017-1762-z
CAS PubMed Web of Science® Google Scholar

Volume50, Issue5

May 2023

Pages 715-719

An intronic splice-site variant in MBTPS2 underlies ichthyosis follicularis with atrichia and photophobia syndrome

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An intronic splice-site variant in MBTPS2 underlies ichthyosis follicularis with atrichia and photophobia syndrome

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CONFLICT OF INTEREST

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