γ-Secretase Mutation in an African American Family With Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) (acne inversa; OMIM 142690) is a chronic skin condition associated with the formation of painful, suppurative, and scarring nodules that primarily affect the axillary, inguinal, and perineal areas. Heterozygous mutations in the γ-secretase genes have been identified in the pathogenesis of autosomal dominant forms of HS in 2 British, 11 Chinese, 1 Japanese, and 3 French families.¹ Hidradenitis suppurativa affects all races, and the disease often affects African Americans. To our knowledge, there are no genetic studies of HS in the African American population. Using whole-exome sequencing, we sought to identify the etiologic gene causing HS in an African American family.

The Johns Hopkins University School of Medicine Institutional Review Board approved this study under the auspices of the Baylor-Hopkins Center for Mendelian Genomics. All participants provided written informed consent to be included in this study and for the study publication. Five individuals from 1 multigenerational family of African American origin (Figure), where HS was inherited as an autosomal dominant trait, were recruited for this study and whole venous blood specimens were collected. Four individuals were affected by HS and one was not affected. The proband, II-2, is an African American woman in her 40s with the highest Sartorius score (score of 98) in the family. The Table depicts the clinical features of the 5 individuals described here.

To capture the target regions, we used the Agilent SureSelect Human All Exon 50Mb Kit (Agilent Technologies) following vendor-provided protocols. We performed whole-exome sequencing (paired-end 100 base-pair reads) on the proband using the Illumina HiSeq2000 platform (Illumina, Inc). We aligned each read to the reference genome (NCBI human genome assembly build 36; Ensembl core database release 50_361; Ensembl is a joint project between the European Molecular Biology Laboratory–European Bioinformatics Institute and the Sanger Institute; http://www.ensembl.org/index.html) using the Burrows-Wheeler Alignment tool and identified single-nucleotide variants and small insertion and deletions using Sequence Alignment/Map tools.^2-4 Polymerase chain reaction duplicates were removed using Picard software (Broad Institute; http://broadinstitute.github.io/picard). We also performed local realignment and base call quality recalibration using the Genome Analysis Toolkit (Broad Institute; https://www.broadinstitute.org/gatk).⁵ Using the phenoDB analysis tool, we applied a filter designed to prioritize conserved, rare functional variants (missense, nonsense, splice site variants, and insertion and deletions) that were heterozygous or homozygous in the proband.

We identified a heterozygous nonsense mutation in exon 4 of NCSTN (c.C349T; p.R117X) on chromosome 1. By Sanger sequencing, we validated the variant in the proband and genotyped the other 4 family members and identified the p.R117X mutation in 3 other individuals who were affected. The 1 family member who was unaffected had a negative result for the mutation.

To our knowledge, this is the first description of an NCSTN nonsense mutation causing autosomal dominant HS in an African American family and further highlights the pathogenic role of γ-secretase mutations in inherited forms of HS. γ-Secretase is an intramembranous protein complex involved in cleaving a multitude of transmembrane proteins. To date, 17 mutations have been reported in NCSTN, 3 in PSENEN, and 1 in PSEN1, which are components of the γ-secretase complex, in inherited and sporadic forms of HS. Nicastrin, the protein product of NCSTN, is thought to be involved in γ-secretase assembly, maturation, and stabilization. The exact signaling defect caused by these mutations remains unclear. However, work in murine models suggests that aberrant Notch signaling may play a role. Notch is a transmembrane protein thought to be involved in hair follicle and sebaceous gland maintenance. The hair follicles of mice deficient in γ-secretase are phenotypically identical to those of mice deficient in Notch 1 and 2 and both types of follicles are histopathologically similar to those in humans with HS.¹

We suggest that this is the first description of an NCSTN nonsense mutation causing autosomal dominant HS in an African American family. Further work characterizing these mutations and their effect in protein signaling in the skin is needed.

Accepted for Publication: December 2, 2014.

Corresponding Author: Sean Chen, BA, Department of Dermatology, Johns Hopkins University School of Medicine, 733 N Broadway St, Baltimore, MD 21205 (seanchen22@gmail.com).

Published Online: February 18, 2015. doi:10.1001/jamadermatol.2014.5306.

Author Contributions: Mr Chen and Dr Hinds had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Chen, Mattei, You, Sobreira, Hinds.

Acquisition, analysis, or interpretation of data: Chen, Mattei, You, Sobreira, Hinds.

Drafting of the manuscript: Chen, Sobreira, You, Hinds.

Critical revision of the manuscript for important intellectual content: Chen, Mattei, You, Sobreira, Hinds.

Statistical analysis: You, Sobreira.

Administrative, technical, or material support: Chen, Mattei, You, Hinds.

Study supervision: Mattei, Hinds.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by grant 1U54HG006542 from the National Institutes of Health/National Human Genome Research Institute.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are indebted to the family members for their participation in this project. We also acknowledge the intellectual contributions from all members of the Baylor-Hopkins Center for Mendelian Genomics. We further acknowledge Corinne Boehm, MS, and Ada Hamosh, MD, MPH, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, for their mentorship and guidance. None of the contributors were compensated for their contributions.

Correction: This article was corrected on April 20, 2015, to fix an error in the text.