Portal de Periódicos da CAPES

Expanding the spectrum of γ ‐secretase gene mutation‐associated phenotypes: two novel mutations segregating with familial hidradenitis suppurativa (acne inversa) and acne conglobata

2015; Wiley; Volume: 25; Issue: 4 Linguagem: Inglês

10.1111/exd.12911

1600-0625

Uppala Ratnamala, Devendrasinh Jhala, Nayan K. Jain, Nazia Saiyed, Meda Raveendrababu, Mandava V. Rao, Timir Y. Mehta, Faiza Mohamed Al-Ali, Kavi Raval, Sreelatha Nair, Nair K. Chandramohan, Murali R. Kuracha, Swapan K. Nath, Uppala Radhakrishna,

Colorectal and Anal Carcinomas

Hidradenitis suppurativa (HS) and acne conglobata (AC) are well-described chronic inflammatory diseases of cutaneous follicular occlusion 1, 2. HS is characterized by painful comedo-like lesions in the apocrine sweat or sebaceous glands 3, 4, while AC is characterized by interconnecting abscesses on the trunk, buttocks, upper arms, thighs and face 5. Although multiple treatment modalities are used for HS and AC, there is no known cure or consistently effectual treatment 6-8. Both HS and AC aggravate over time and persist for years, often resulting in pronounced disfigurement, severe distress and diminished quality of life (S9–11). The γ-secretase-Notch signalling pathway has a role in mammalian embryonic development and wound healing in the adult (S12,13). Mutations lead to epidermal and follicular abnormalities in mouse skin that are histopathologically similar to those in human HS (S14). Notch regulates cell fate during differentiation of epidermis and hair and is associated with cyst formation (S15). γ-Secretase catalyses cleavage of many transmembrane proteins, including Notch. γ-Secretase is a multisubunit protease complex containing presenilin (catalytic subunit) (PSEN1 and PSEN2), (NCSTN), anterior pharynx-defective 1 (APH1A and APH1B) and PSENEN (PEN-2). Mutations in γ-secretase proteins may affect the stability of the complex resulting in altered Notch signalling, affecting glandular differentiation resulting in subsequent blockage, rupture and infection: a process which strongly resembles the pathogenesis of familial HS. We report the identification of two novel NCSTN gene mutations, a frameshift (p.Cys230Profsx31) and nonsense (p.Leu600X) from two unrelated large families, who have a typical HS phenotype in one (S16) (Figure S1) and AC in the other (S17) (Figure S2). The study was approved by the local ethics committee, and all subjects gave informed consent. The present mutation search adds two novel mutations in the NCSTN transcription regulator in HS and the dominantly inherited phenotype Acne conglobata. To date, 22 variations of NCSTN gene including six at splice sites have been identified (S18–28) including two reported here, accounting for almost 85% of Asian and European HS families (Table 1). The frameshift mutation c.687insCC (p.Cys230ProfsX31) in family UR-252 caused complete alteration of the amino acid sequence of the protein. In the family with AC, we observed a nonsense mutation (p.Leu600X) within exon 16 of NCSTN (see Data S1 and Table S1 for methods). To our knowledge, this is the first report of NCSTN mutation in AC. These results add a new phenotype to the phenotypic spectrum caused by γ-secretase gene mutations, which also include early-onset familial Alzheimer's disease, HS, breast cancers, dilated cardiomyopathy, frontotemporal dementia and PASH syndrome (S29–33). In both pedigrees, unaffecteds, unrelated spouses, and 100 controls from the same geographic origin did not show these two pathogenic variants. We conclude that the novel mutations in NCSTN, which segregated with phenotypic HS and AC, were causative in these families. Direct sequence analysis of γ-secretase complex genes excluded mutation in three other Indian pedigrees with HS. Similarly, for a number of families and/or cases, the genetic causes are not yet identified as known gene mutations were already excluded, suggesting that HS is most likely a heterogeneous disease and additional genes may contribute to the phenotype (S34). Other functionally comparable or co-expressed gene involvement was also identified in our bioinformatics network analyses, reinforcing the complexity of interacting genes involved in HS and AC pathogenesis (Fig. 1). The absence of pathogenic variants in the coding regions of these genes suggests that a mutation may lie in a regulatory region of one of the candidate genes, in another novel gene, or in a functional element (conserved or not). It is also probable that other Notch signalling components may contribute to the phenotypes, and those epigenetic processes may play a role in HS and AC development by controlling the expression/function of specific genes. Four NCSTN gene functional domains have been characterized. All identified HS mutations are in the extracellular domain signifying that these mutations may cause protein truncation, loss of function or the ability to bind other γ-secretase components and therefore disruption of complex formation and proteolytic activity (S35). Because of the small number of reported cases, further evaluation of additional allelic phenotypes should be performed to firmly establish the prognostic value of different γ-secretase complex mutations. This will also help us to understand the functional characterization of the gene, which often requires the discovery of the full spectrum of its associated phenotypes. We thank all members of families for their cooperation and participation in the study. The study was supported in part by Green Cross Blood Bank, Ahmedabad, India. UR (Radhakrishna) designed the study, analysed the data and drafted the manuscript; UR (Ratnamala) and NMS generated the experimental data; DJ, NKJ, MR, MVR, MRK and SKN contributed to study design and generated experimental data; TYM, FMA, KR, SN and NKC performed clinical evaluation of patients and provided patient samples and clinical data; all authors read and critically revised the manuscript and approved the final version. The authors have declared no conflicting interests. Figure S1. A. Pedigree UR-252 with Hidradenitis suppurativa (HS) from the Western part of India was previously reported by Al-Ali (S16). The pedigree comprises 211 individuals, including 36 affecteds, manifested by abscesses, fistulas and scarring in apocrine gland-bearing skin. Affected individuals are shown with black symbols and normal individuals with clear symbols. Samples included in the analysis are numbered under their symbol in the pedigree. Individuals with a slash across their symbol are deceased. Individuals with a slash across their symbol with question mark were deceased and data were unavailable. Half-filled symbol (V-90) is positive for mutation, but disease is not manifested.B. Gluteal region of affected subject with inflamed and noninflamed follicular comedones and with postinflammatory pigmentation. C. Postinflammatory hyperpigmentation HS scars. D. Comparison of a normal and mutant partial chromatograph of DNA from family UR-252. The insertion of 2-nt (CC) at nucleotide position 687 of human NCSTN is shown. E. The truncated protein is predicted to terminate at codon 261 after the addition of 31 novel amino acids within exon 6 of NCSTN. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.