|Year : 2022 | Volume
| Issue : 3 | Page : 188-189
A novel mutation in Keratin 10 passed down in a family with familial steatocystoma multiplex
Kun-Lin Lu1, Chuang-Wei Wang2, Wen-Hung Chung3, Fang-Ying Wang4
1 Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch; College of Medicine, Chang Gung University, Taoyuan City, Taiwan
2 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
3 Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
4 College of Medicine, Chang Gung University, Taoyuan City; Department of Biomedical Engineering, College of Medicine, College of Engineering, National Taiwan University, Taipei, Taiwan
|Date of Submission||30-Sep-2021|
|Date of Decision||18-Apr-2022|
|Date of Acceptance||30-May-2022|
|Date of Web Publication||29-Sep-2022|
Dr. Fang-Ying Wang
Department of Dermatology, Chang Gung Memorial Hospitals, Linkou Branch, No. 5, Fuxing St., Guishan, Taoyuan City
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Lu KL, Wang CW, Chung WH, Wang FY. A novel mutation in Keratin 10 passed down in a family with familial steatocystoma multiplex. Dermatol Sin 2022;40:188-9
|How to cite this URL:|
Lu KL, Wang CW, Chung WH, Wang FY. A novel mutation in Keratin 10 passed down in a family with familial steatocystoma multiplex. Dermatol Sin [serial online] 2022 [cited 2022 Nov 26];40:188-9. Available from: https://www.dermsinica.org/text.asp?2022/40/3/188/357356
Wen-Hung Chung is affiliated to Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch; College of Medicine, Chang Gung University, Taoyuan City; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei and Keelung, Linkou; Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Linkou; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China, Department of Medical Research, Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan; Department of Dermatology, School of Clinical Medicine, Beijing Tsinghua Chang Gung Hospital, Tsinghua University, Beijing; School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Medical Research, Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
Familial steatocystoma multiplex is known as an inherited cutaneous disorder in which multiple small cysts containing yellowish sebum develop on body parts including the trunk, upper arms, face, and neck. Passed down in an autosomal dominant fashion, familial steatocystoma multiplex has almost exclusively been reported to be contributed by mutations within the keratin (KRT) 17 gene. Herein, we report a family with familial steatocystoma multiplex which has no identifiable mutation in KRT17 but shows an autosomal dominant inheritance of a likely pathogenic in-frame insertion in KRT10.
A 19-year-old male patient was presented with widely distributed cysts since puberty. Physical examinations of both the index case and his father showed multiple yellowish, soft, and small cysts on each of their trunk, bilateral upper limbs, face, and neck [Figure 1]a. Otherwise, their skin, nail, and hair conditions were normal, with no history of any other cutaneous disease. Skin biopsies of both cases revealed cysts each lined by a thin layer of corrugated stratified squamous epithelium with adjacent pilosebaceous structures, consistent with steatocystoma [Figure 1]b. Besides the index case and his father, his paternal grandmother was also found with the same skin condition, demonstrating an autosomal dominant trait within the kindred [Figure 1c]. Accordingly, the diagnoses of familial steatocystoma multiplex were made.
|Figure 1: (a) Multiple cysts on the trunk of the patient (shown by arrowhead), diagnosed as steatocystoma by skin biopsy. (b) The skin biopsy revealed a cyst lined by a thin layer of corrugated stratified squamous epithelium with some sebaceous glands that are contiguous with the cyst wall, consistent with steatocystoma (hematoxylin and eosin stain). (c) The family tree of the index case, suggesting an autosomal dominant inheritance trait|
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When it comes to whole-exome sequencing of the index case and his father, no shared exonic variant of KRT17 was identified based on autosomal dominant model analysis. Intriguingly, we found an in-frame insertion in the exonic V2 subdomain within the carboxyl-terminus of the KRT10 gene shared by both cases. This novel and rare variant of KRT10, p. Gly565_His566ins20, has only been reported once with uncertain clinical significance on the National Center for Biotechnology Information and has not been reported elsewhere. To the best of our knowledge, this is the first report of an inherited mutation other than KRT17 that associates with familial steatocystoma multiplex.
Mutations in cutaneous keratin genes encoding for keratin intermediate filaments lead to fragilities in keratinocytes and appendages, resulting in a variety of inherited cutaneous disorders. Similar to KRT17, KRT10 belongs to the type 1 intermediate filament protein family and is composed of an aminoterminal domain, a central rod domain, and a carboxyl-terminal domain, and has been considered one of the most relevant genes relating to familial steatocystoma multiplex. Indeed, both KRT17 and KRT10 are known to be enriched in the suprabasal cells lining the cyst of steatocystoma. In a later animal study, dysfunction of KRT10 was further shown to increase the differentiation of epidermal stem cells toward the sebocyte lineage. However, although hotspot mutations of the central rod domain in KRT10 are identified to cause autosomal dominant skin disorders such as epidermolytic ichthyosis, the clinical significance of the mutations within the carboxyl-terminal domain of it remains elusive. To evaluate the pathogenicity of the KRT10 variant consisting of the insertion of 20 amino acids into the carboxyl-terminal domain reported here, we compared its predicted protein structure with that of the wild-type KRT10 by AlphaFold2, the most powerful neural network-based model for this purpose. Empowered by the artificial intelligence program, we are able to demonstrate that the lengthy amino acid sequence inserted results in marked deformity in protein level [Figure 2]. In addition, we further adopted MutPred-Indel, a machine learning-based prediction with good predictive performance specifically designed for in-frame insertion/deletion, to look into the pathogenicity of this insertion. As expected, the result predicts the insertion to be pathogenic, since it prominently lengthens the repetitive loops within the V2 subdomain that is vital for maintaining local secondary order.
|Figure 2: The predicted protein structure of by AlphaFold2 of (a) the referential kertain 10. (b) The mutated kertain 10|
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There are limitations of this article. First, we could not obtain informed consent for skin biopsy from the patient's paternal grandmother or other family members. Second, despite the strong diagnostic utility of whole-exome sequencing, it may fail to detect noncoding variants. However, there has not been a noncoding variant in KRT17 reported being linked to steatocystoma multiplex.
In this article, we present the first familial steatocystoma multiplex cases associated with a rare, and autosomal dominantly-inherited mutation in KRT10 that is likely pathogenic, warranting more reports and further investigations into the pathogenic mechanisms of steatocystoma multiplex.
This study was approved by the ethics review boards of Chang Gung Memorial Hospital in Taiwan. (approval number: 202200283B0)
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
We would like to thank the Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan, for supporting us the whole-exome sequencing analysis in this study.
Financial support and sponsorship
This work was supported in part by grants from the Ministry of Science and Technology, Taiwan (MOST 109-2320-B-182A-008 -MY3), and Chang Gung Memorial Hospital (CMRPG3K2181, BMRPG-290011, CMRPGBL0021).
Conflicts of interest
Prof. Wen-Hung Chung, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
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[Figure 1], [Figure 2]