Abstract 

Background: Hidradenitis suppurativa (HS) is a complex, chronic inflammatory skin disorder whose pathophysiology is poorly understood. Genetic studies have shown that HS is predisposed by mutations in the γ-secretase gene, but only a proportion of familial and partial sporadic cases have been shown to possess such mutations. HS has high genetic heterogeneity and is thought to be triggered by a combination of genetics and environmental factors. Aims: The study aimed to investigate the genetic causes of HS in a large cohort of patients and to update the mutation spectrum of γ-secretase complex genes. Methods: We conducted mutational screening of 95 sporadic HS cases and one large family with both HS and acne conglobata (AC) to identify mutations in the coding and splice junction region of γ-secretase complex genes (nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN), and aph-1 homolog B, gamma-secretase subunit (APH1B)). Results: Our study identified a nucleotide substitution of 1876C>T in the NCSTN gene, which caused a stop codon (p.Arg626X) in the affected members of a large family with HS and AC. No pathogenic variants were detected in 95 sporadic cases of HS, indicating there is possible genetic heterogeneity. Conclusion: We report a new family with a nonsense mutation in the NCSTN gene that supports the role of the γ-secretase complex genes in HS with AC. The updated γ-secretase mutation spectrum for HS now includes 78 mutations.

Keywords: Chronic skin disorders, genetic heterogeneity, hidradenitis suppurativa, NCSTN gene mutation

How to cite this article:
Ratnamala U, Jain NK, Jhala DD, S. Prasad PV, Saiyed N, Nair S, Radhakrishna U. An updated mutation spectrum of the γ-secretase complex: Novel NCSTN gene mutation in an Indian family with hidradenitis suppurativa and acne conglobata. Indian J Dermatol 2023;68:141-7
How to cite this URL:
Ratnamala U, Jain NK, Jhala DD, S. Prasad PV, Saiyed N, Nair S, Radhakrishna U. An updated mutation spectrum of the γ-secretase complex: Novel NCSTN gene mutation in an Indian family with hidradenitis suppurativa and acne conglobata. Indian J Dermatol [serial online] 2023 [cited 2023 Apr 28];68:141-7. Available from: https://www.e-ijd.org/text.asp?2023/68/2/141/375226    Introduction 

Hidradenitis suppurativa (HS) is a chronic, suppurative cutaneous disease that usually affects individuals between puberty and middle age. HS prevalence is estimated between 0.03 and 4% globally,[1] but it is unknown in the Indian population. The condition is more common in women than men (3:1 ratio), and some studies have suggested a higher incidence in African Americans than Caucasians.[2],[3] Most commonly, HS occurs in the armpits, groin, between the buttocks, and under the breasts. Healing of affected areas is typically associated with progressive scarring (fibrosis). It is a progressive disease, with symptoms that include painful inflammatory nodules, sterile abscesses, sinus tracts, chronic seepage, and scarring. Patients with HS develop severe comorbidities and have an increased risk of mortality.[4] Currently, no diagnostic tests or cures exist for HS[5] with surgery being the only form of treatment.[6] HS is frequently misdiagnosed or not recognized, resulting in delayed diagnosis, often only discovered at an advanced stage of the disease. Delays in diagnosis and treatment have profoundly negative effects on health, economics, and social well-being. HS causes a significant negative impact on the quality of life due to the burden of purulent discharge, odor, and pain.[7]

The pathogenesis of HS is not fully understood, but putatively involves both genetic and environmental factors. Obesity and smoking exacerbate the symptoms of the disease.[8],[9] One-third of HS patients report a family history, though, most cases are sporadic.[10] Many families and cases of HS have an unexplained etiology, and pathogenic mutations of the γ-secretase genes have not been characterized.[11],[12] Recently, several pathogenic mutations in patients with familial or sporadic HS have been found in four genes comprising the γ-secretase complex: nicastrin (NCSTN), presenilin 1 (PSEN1), presenilin enhancer 2 (PSENEN) and APH1B. In this study, we report novel heterozygous nonsense mutations of the NCSTN gene in a large Indian family with HS and acne conglobata (AC). Moreover, the mutational spectrum found in HS around the world is presented along with a specific geographic distribution for some mutations.

   Materials and Methods 

HS case selection. The study included 95 sporadic HS subjects, who were examined by two independent board-certified dermatologists (RR and TM), at VS Hospital in Ahmedabad, India, using the visual-aided questionnaire for self-assessment of HS.[13] Disease severity was determined using the Hurley score,[14] Hidradenitis Suppurativa Severity Score System (IHS4),[15] and autoinflammatory disease damage index (ADDI).[16] The average age of sporadic participants in the HS study included in this analysis was 34 years (48 men and 47 women). All cases had a disease history of over 5 years. None of the patients were reported to have a syndromic condition; however, a few had diabetes or hypertension as comorbidities. A detailed clinical database of all affected individuals is collected in the study. This study was approved by the institutional review board of William Beaumont Hospital, Royal Oak, MI, USA.

HS family AC. A three-generation HS family from India with AC containing four affected and three unaffected members was described previously by Prasad et al.[17] Affected members present with multiple painful swellings over the face, chest, and axillae, as well as large nodules in the gluteal area. Biopsies of the lesions revealed multiple epidermal inclusion cysts and perifolliculitis with neutrophilic and histiocytic infiltrates [Figure 1].

Figure 1: (a) Clinical photographs of two affected individuals (III-1 and III-2) from a family with HS and acne conglobata. (b) Partial pedigree of the same family. Affected individuals are shown with blackened symbols, and clear symbols denote unaffected. (c) Comparison of translation products of the normal and mutated NCSTN allele. The truncated protein terminates at codon 626. (d) Partial nucleotide sequence of normal and (e) HS and acne conglobata-affected individual. Sequence analysis of affected and unaffected members revealed a nonsense mutation in affected members, p.1876C>T in exon 16 of the NCSTN gene, that resulted in a premature stop codon substitution of Arg at codon 626 (p. Arg626X)

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Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood using a Gentra Puregene Blood DNA Extraction Kit (Qiagen, Valencia, CA) according to the manufacturer's protocol. The γ-secretase complex genes were sequenced from each HS family member and 95 cases of sporadic HS using the Sanger sequencing technique. DNA was polymerase chain reaction (PCR)-amplified for regions covering the entire coding sequence and splice junctions of all γ-secretase complex genes. All purified PCR products were bidirectionally sequenced using the dideoxy (Sanger) method with appropriate oligonucleotides for all patients (Applied Biosystems, Life Technologies). Also, we have sequenced a minimum of 100 ancestry-matched control samples for identified gene variant. Detailed methodology, PCR oligos, and conditions were reported earlier.[18]

The study was approved by the Institutional Review Board of Beaumont Health System, Royal Oak, MI, USA (HIC#: 2015-172) on May 21, 2015.

   Results 

Sequencing analysis revealed a novel heterozygous 1876C>T mutation in exon 16 of the NCSTN gene in affected individuals of the HS family with AC. As a result of this nonsense mutation converts the CGA arginine codon at residue 626 to a TGA termination codon (p. Arg626X). The mutation was observed as heterozygous in affected members and was absent in unaffected members of the family or the 100 controls matched for age, sex, ethnicity, and geographical origin [Figure 1]. The 95 sporadic cases did not reveal pathogenic variants in either coding or noncoding regions of γ-secretase complex genes including splice sites.

   Discussion 

The identification of γ-secretase gene mutations in HS has been progressing rapidly in recent years. HS disease is characterized by significant genetic heterogeneity until 78 different pathogenic mutations have been discovered in four γ-secretase genes including 52 mutations in NCSTN, 22 in PSENEN, three in PSEN1, and only one likely pathogenic mutation in APH 1B,[11],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61] accounting for over 90% of Asian and European familial HS. Most genetic variants have been described in cases with family histories, but there are few mutations in sporadic cases. Several genetic studies have reported genetic heterogeneity in HS.[11],[26],[30],[41],[62] However, our study excluded 95 sporadic HS cases without g-secretase gene mutations, further supporting genetic heterogeneity. The identification of this NCSTN gene mutation in family with HS and AC provides further evidence that γ-secretase complex gene mutations may be predominantly involved in familial HS and only a fraction of sporadic HS cases.

Our γ-secretase gene mutation screening suggests that there are additional genes or other molecular mechanisms that contribute to the HS phenotype. Several different mechanisms may explain the disease's etiology. The absence of pathogenic polymorphic variants in the coding regions of γ-secretase genes indicates that the mutation may lie in a regulatory region of one of these γ-secretase genes. While the mutation may be a duplication or a deletion within the γ-secretase complex genomic region, this has not yet been reported. Earlier, four genetic loci at 6q25.1-25.2, 19p12-p13.11, 13q14.11, and 4q21.1, associated with the risk of HS, have been identified using family-based linkage and association studies. However, the genes involved in pathogenesis at these loci are yet to be identified.[63],[64] Epigenetic variation may also play a role in HS, our recent ongoing epigenome-wide methylation pilot studies have demonstrated profound methylation differences in multiple cytosine and guanine separated by a phosphate (CpG) sites in various genes in HS subjects previously excluded from γ-secretase complex gene mutations (unpublished). Recent studies identified microRNA, cytochrome, and cytokine gene methylation dysregulations associated with HS.[65],[66],[67],[68]

Other associated rare syndromes and diseases. This study also suggests that distinct mutations in the NCSTN may cause different diseases and syndromes. The rare syndromes and diseases that have been associated with HS mutations include pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome, Crohn's disease, Dowling–Degos disease, and AC [Table 1]. Our study provides evidence that HS is a heterogeneous disease as the γ-secretase genes NCSTN, PSEN1, PSENEN, and APH1B are involved in the pathogenesis of only some familial and/or sporadic HS cases. The identification of γ-secretase gene variants in most familial and limited cases of sporadic disease indicates that these genes may be of greater importance in familial disease than previously believed. Investigations of additional familial and sporadic cases are required to establish the contributions of γ-secretase alleles in HS and to identify additional genes underlying this debilitating disease. Epigenome-wide studies also should be considered in HS individuals excluded from γ-secretase complex gene mutations. Consideration of epigenetic factors as molecular controls of HS phenotype opens up new theoretical and experimental possibilities.

Limitations of the study: It is important to note a few limitations. The study sample consisted only of people of Indian ancestry and targeted sequencing of genes of the γ-secretase complex (NCSTN, PSEN1, PSENEN, and APH1B) genomic regions that harbor variants associated with HS. The sequenced regions were coding and regulatory, not introns. Despite this limitation, we have detected a novel pathogenic mutation in a large family with HS and AC. To identify novel variants/genes associated with HS, whole-genome sequencing of both familial and sporadic cases is needed.

In summary, this study presents a novel truncating mutation in the NCSTN gene in the Indian HS family with AC confirming that γ-secretase genes may play a role in familial HS pathophysiology and other related rare syndromes and diseases. Furthermore, we present here a review study of the mutational spectrum of HS. The spectrum of γ-secretase mutations shows that 67% of mutations are identified in the NCSTN gene coding region followed by 28% in PSENEN. Mutations reported so far include missense mutations, nonsense mutations, stop codon mutations, small deletions, duplications, small insertions, and one splice site mutation. No copy number variations were reported for HS patients. Future studies with larger samples are needed to replicate these findings and also for establishing genotype/phenotype correlations in HS patients.

Acknowledgment

We thank the patients for their cooperation in the study. We thank the late Mr. Vix Kennedy of the HS-USA forum for his support and encouragement for the study. We would like to thank the late Lt Col Dr. Nikhil Moorchung for his technical assistance during his Indian Council of Medical Research (ICMR)-sponsored visiting scientist program at Beaumont Health, MI, USA.

Abbreviations

HS = hidradenitis suppurativa, HS-PASH = hidradenitis suppurativa with pyoderma gangrenosum, HS-Crohn's = hidradenitis suppurativa with Crohn's disease, HS-AC = hidradenitis suppurativa with acne conglobate, HS-DD = hidradenitis suppurativa with Dowling–Degos disease, HS-KTS = hidradenitis suppurativa with Klippel–Trenaunay syndrome, PMID = PubMed.

Authors contribution

U.R (Ratnamala) U.R (Radhakrishna), N.K.J, D.J, P.V.S.P, N.S, and S.N designed the research studies; U.R and S.N. experimented and analyzed the data. All authors contributed to writing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

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    68.Radhakrishna U, Ratnamala U, Jhala DD, Uppala LV, Vedangi A, Patel M, et al. Hidradenitis suppurativa presents a methylome dysregulation capable to explain the pro-inflammatory microenvironment. Are these DNA methylations potential therapeutic targets? in Production. 2023.  
    
  [Figure 1]
 
 
  [Table 1]