An Updated Mutation Spectrum of the γ-Secretase Complex: Novel NCSTN Gene Mutation in an Indian Family with Hidradenitis Suppurativa and Acne Conglobata

Uppala Ratnamala; Nayan K Jain; Devendrasinh D Jhala; Pullabatla V S Prasad; Nazia Saiyed; Sreelatha Nair; Uppala Radhakrishna

doi:10.4103/ijd.ijd_995_21

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 Mar-Apr;68(2):141-147. doi: 10.4103/ijd.ijd_995_21.

Authors

Uppala Ratnamala¹, Nayan K Jain¹, Devendrasinh D Jhala², Pullabatla V S Prasad³, Nazia Saiyed⁴, Sreelatha Nair⁵, Uppala Radhakrishna⁴

Affiliations

¹ From the Department of Life Sciences, Gujarat University, Ahmedabad, Gujarat, India.
² Zoology, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India.
³ Department of Dermatology, Annamalai University, Chidambaram, Tamil Nadu, India.
⁴ Department of Obstetrics and Gynecology, Oakland University-William Beaumont School of Medicine, Royal Oak, MI, USA.
⁵ Department of Medical Genetics, Lifeline Super Speciality Hospital, Adoor, Pathanamthitta, Kerala, India.

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; NCSTN gene mutation; genetic heterogeneity; hidradenitis suppurativa.