Akiyama, Masashi

Murase, Chiaki

Nomura, Toshifumi

Ogi, Tomoo

Takeichi, Takuya

Journal of Investigative Dermatology

English

Nagoya Repository

The Journal of Investigative Dermatology   Letter to the Editor   Hereditary mucoepithelial dysplasia/autosomal-dominant IFAP syndrome is a clinical spectrum due to SREBF1 variants   Chiaki Murase1,, Takuya Takeichi1, Toshifumi Nomura2, Tomoo Ogi3, and Masashi Akiyama1,*   1Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan 2Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan 3Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 466-8550, Japan   ORCIDs Chiaki Murase: https://orcid.org/0000-0001-5331-1222 Takuya Takeichi: https://orcid.org/0000-0001-5958-2875 Toshifumi Nomura: https://orcid.org/0000-0002-9954-6446 Tomoo Ogi: https://orcid.org/0000-0002-5492-9072 Masashi Akiyama: https://orcid.org/0000-0001-5863-9315   Correspondence: * Masashi Akiyama, MD, PhD, Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Telephone: +81-52-744-2314 E-mail: makiyama@med.nagoya-u.ac.jp   Short title: HMD/AD IFAP due to SREBF1 variants   Abbreviations: HMD: hereditary mucoepithelial dysplasia; SREBP1: sterol regulatory element-binding protein 1; IFAP: ichthyosis follicularis with atrichia and photophobia; S1P: site-1-protease.   Funding sources: This study was supported by funding from the Advanced Research and Development Programs for Medical Innovation (AMED-CREST) (19gm0910002h0105) of the Japan Agency for Medical Research and Development (AMED) to M.A. This work was also supported by Grant-in-Aid for Scientific Research (B) (18H02832) from the Japan Society for the Promotion of Science (JSPS) and by Health and Labor Sciences Research Grants for Research on Intractable Diseases (20FC1052) from the Ministry of Health, Labor and Welfare of Japan to M.A. This research was supported by AMED under Grant Number JP19ek0109281h0003. This study was also supported in part by JSPS KAKENHI Grant Number 20K08648.   Conflicts of interest: None declared   Word, table and figure counts: 988 words, 1 table, 0 figures   To the Editor: We read with great interest the recent report by Morice-Picard et al. (2020) on how mutations in SREBF1 (OMIM: 184756) are associated with hereditary mucoepithelial dysplasia (HMD) (OMIM: 158310). SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which is involved in promoting the transcription of lipogenes that are associated with cholesterol and fatty acid biosynthesis (Zhang et al., 2017).    Morice-Picard et al. (2020) performed causative mutation search in seven patients from four independent families with HMD, and they concluded that the alteration of amino acid residue Arg557 by theheterozygous missense mutation c.1669C>T (p.Arg557Cys) or c.1670G>A (p.Arg557His) in SREBF1 (NM_001005291.2) causes HMD, based on the results of seven patients from four independent families (Morice-Picard et al., 2020).    Here we report a Japanese woman (the proband) and her daughter who had clinical features of autosomal-dominant ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome.   Ethics committee approval was obtained by Nagoya University Graduate School of Medicine and all research was performed in accordance with the Declaration of Helsinki principles. Written informed consent was obtained from the participants. Sanger sequencing of genomic DNA from each patient found no mutations in MBTPS2 (MIM: 300294), suggesting a genetic etiology distinct from that in typical X-linked IFAP syndrome (OMIM: 308205) in this pedigree. Next, we performed the whole-exome sequencing of genomic DNA from each patient. This sequencing found the heterozygous missense mutation c.1669C>T (p.Arg557Cys) in SREBF1 (NM_001005291.2) in both patients. Neither parent of the proband was affected, and the mutation p.Arg557Cys in SREBF1 in the present family is considered to be a de novomutation. Interestingly, the SREBF1 mutation in the present family is identical to that reported in HMD patients by Morice-Picard et al. (2020).    Mutations in MBTPS2 underlie X-linked IFAP syndrome (Oeffner et al., 2009). Skewed X-inactivation contributes to the variable phenotypes in female cases of X-linked IFAP syndrome (Murase et al., 2020). In contrast, female patients with SREBF1 mutations show the severe phenotypes seen in the present patients.   The triad of IFAP syndrome includes follicular ichthyosis, atrichia, and photophobia of varying severities (Oeffner et al., 2009). The two female patients in the present Japanese pedigree showed the full triad ofIFAP syndrome and presented with severe phenotypes of that syndrome (Sato-Matsumura et al., 2000). Briefly, the proband and her daughter had almost all the classical and some of the minor symptoms, including severe photophobia, extensive non-inflammatory follicular hyperkeratosis, non-scarring total alopecia, psoriasiform hyperkeratosis of the extremities, recurrent cheilitis, and nail deformity (Sato-Matsumura et al., 2000). From these clinical features, the present patients were diagnosed with IFAP.   Recently, Wang et al. (2020) described 11 pedigrees with autosomal-dominant IFAP syndrome that carried three mutations in SREBF1: c.1579C>T, p.Arg527Cys (nine pedigrees),c.1582_1584del, p.Asn528del (one pedigree), and c.1589T>C, p.Leu530Pro (one pedigree). The three detected SREBF1 mutations caused the substitution or deletion of residues 527, 528, or 530, which are crucial for S1P cleavage in SREBP1 (Wang et al., 2020). Wang et al. (2020) concluded that c.1579C>T in SREBF1 is a recurrent hotspot mutation underlying autosomal-dominant IFAP syndrome. The different reference sequences of SREBF1—NM_001005291.2 and NM_004176.3—were adopted for the mutation search by Morice-Picard et al. (2020) and Wang et al. (2020), respectively, and in fact, c.1579C>T in the report by Wang et al.(2020) is identical to c.1669C>T in the report by Morice-Picard et al. (2020). The mutation identified in the present patients is also identical to the recurrent hotspot mutation in SREBF1 detected in the HMD patients and the autosomal-dominant IFAP syndrome cases (Wang et al., 2020).   The present patients did not show erythema on the oral, nasal or vaginal mucosae, which are substantial in HMD (Scheman et al., 1989). However, the proband had vulvitis and a dark red, hyperkeratotic, papillomatous plaque on her vulva (Sato-Matsumura et al., 2000). The perineal lesions of the mother seemed to be consistently provoked by pregnancy, and the vulvitis subsided spontaneously within four weeks after her deliveries. Her vulvar lesions resembled the perineal lesion that is characteristic of HMD.   HMD and IFAP syndrome share many clinical symptoms: photophobia, keratosis pilaris, non-scarring alopecia, psoriasiform plaques, and angular cheilitis (Hernández-Martín et al., 2012). Table 1 summarizes acomparison of characteristic clinical features from previous reports on HMD and autosomal-dominant IFAP syndrome patients. Notably, there are many differences between patients with HMD and those with autosomal-dominant IFAP syndrome, although there are some similarities between these two phenotypes. Notably, the present patients had psoriasiform perineal intertrigo, which was seen in six of the seven HMD patients due to the alteration of the amino acid residue Arg557 in SREBP1 (Morice-Picard et al., 2020). The heterozygous missense mutation c.1669C>T (p.Arg557Cys) in SREBF1 (NM_001005291.2)might have led to the overlapping symptoms and the HMD, and autosomal-dominant IFAP might be on a spectrum of clinical phenotypes.   It was revealed that SREBP1 variants cause impairments to site-1-protease (S1P) cleavage that inhibit nuclear translocation of the transcriptionally activated form of SREBP1 in vitro (Wang et al., 2020). Moreover, RNA sequencing of scalp skin from autosomal-dominant IFAP syndrome patients shows significant reductions in transcript levels of keratin genes and low-density lipoprotein receptor, which are known to be expressed in the outer root sheath of hair follicles (Wang et al., 2020). These findings indicate that SREBP1 signaling is necessary for hair growth, skin barrier function, epidermal differentiation, and ocular function.   In conclusion, we identified a family with autosomal-dominant IFAP syndrome caused by the recurrent hotspot mutation c.1669C>T (p.Arg557Cys) in SREBF1 (NM_001005291.2). This hotspot mutation hasbeen reported in HMD families and autosomal-dominant IFAP families, independently (Morice-Picard et al., 2020, Wang et al., 2020). The present patients showed perineal lesions characteristic of HMD in addition to the typical clinical features of autosomal-dominant IFAP syndrome. The present family suggests that the mutation c.1669C>T (p.Arg557Cys) in SREBF1 (NM_001005291.2) might be a recurrent hotspot mutation for HMD and autosomal-dominant IFAP syndrome and that HMD and autosomal-dominant IFAP syndrome due to the SREBF1 mutations are diseases on the same clinical spectrum.     Data availability statement: No datasets were generated or analyzed during the current study.   Conflicts of interest: None declared   Acknowledgements This study was supported by funding from the Advanced Research and Development Programs for Medical Innovation (AMED-CREST) (19gm0910002h0105) of the Japan Agency for Medical Research and Development (AMED) to M.A. This work was also supported by Grant-in-Aid for Scientific Research (B) (18H02832) from the Japan Society for the Promotion of Science (JSPS) and by Health and Labor Sciences Research Grant for Research on Intractable Diseases (20FC1052) from the Ministry of Health, Labor and Welfare of Japan to M.A. This research was supported by AMED under Grant Number JP19ek0109281h0003 to M.A. This study was also supported in part by JSPS KAKENHI Grant Number 20K08648 to T.T.   Author contributions Conceptualization: CM, MA; Data curation: CM, TT, TN; Formal analysis: TO; Funding acquisition: TT, MA; Investigation: CM, TT ; Project Administration: CM, TT; Resources: TN; Supervision: MA; Validation: TT, MA; Visualization: CM; Writing: CM, TT, MA   References Hernández-Martín A, Colmenero I, Torrelo A. Hereditary mucoepithelial dysplasia: report of two sporadic cases. Pediatric dermatology 2012;29(3):311-5. Morice-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. The Journal of investigative dermatology 2020;140(6):1289-92.e2. Murase C, Takeichi T, Okuno Y, Ikumi K, Morita A, Akiyama M. Deep phenotyping of ichthyosis follicularis with atrichia and photophobia syndrome associated with MBTPS2 mutations. The Journal of dermatology 2020;47(3):e87-e8. Oeffner 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. American journal of human genetics 2009;84(4):459-67. Sato-Matsumura KC, Matsumura T, Kumakiri M, Hosokawa K, Nakamura H, Kobayashi H, et al. Ichthyosis follicularis with alopecia and photophobia in a mother and daughter. The British journal of dermatology 2000;142(1):157-62. Scheman AJ, Ray DJ, Witkop CJ, Jr., Dahl MV. Hereditary mucoepithelial dysplasia. Case report and review of the literature. Journal of the American Academy of Dermatology 1989;21(2 Pt 2):351-7. Wang H, Humbatova A, Liu Y, Qin W, Lee M, Cesarato N, et al. Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome. American journal of human genetics 2020. Zhang D, Tomisato W, Su L, Sun L, Choi JH, Zhang Z, et al. Skin-specific regulation of SREBP processing and lipid biosynthesis by glycerol kinase 5. Proceedings of the National Academy of Sciences of the United States of America 2017;114(26):E5197-e206.   Table 1. Comparison of clinical features seen in HMD and autosomal-dominant IFAP syndrome caused by SREBF1 variants Affected Organs Clinical features Hereditary mucoepithelialdysplasia Autosomal-dominant IFAP syndrome The present patients Eyes Photophobia Frequent  Yes Yes Keratitis Frequent  Yes Yes Cataracts Often  Usual  No Hair and Nails Hypotrichosis Yes  Yes Yes Onycho-dystrophy ND Seldom  Yes Skin Follicular keratosis Yes  Yes Yes Psoriasiform perineal intertrigo Usual  No Yes Angular cheilitis ND Seldom  Yes Mouth Red oral mucosa Yes  No No Deeply fissured tongue Yes  No No Internal organs Lung disease No No No Modified from Hernández-Martín et al. ND, not described   1    

Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants

https://nagoya.repo.nii.ac.jp/record/2001707/files/JID_accepted_version_2020-9.pdf

Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants

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