A Frameshift Mutation in <b><i>PEN-2</i></b> Causes Familial Comedones Syndrome

Abstract

Background: Familial comedones without dyskeratosis are a rare autosomal dominant skin disorder, characterized by the occurrence of comedones that are distributed all over the body with specific features. We have previously reported two Thai families with familial comedones with expanded phenotypic spectrum. However, its genetic defect and pathogenesis remain unknown. Objective: To explore the molecular defect causing familial comedones. Methods: Whole-genome linkage analysis and whole-exome sequencing in family I were performed. Results: We identified a heterozygous one-base pair insertion, c.84_85insT (p. L28FfsX93) in PEN-2, located within the linked region on chromosome 19. PCR-Sanger sequencing confirmed the identified mutation. The mutation segregated with the disease phenotype in family I and was fully penetrant. This similar mutation was also present in the unrelated affected individual from family II. Quantitative PCR revealed increased mRNA expression of PEN-2 in leukocytes of affected individuals. Conclusion: We for the first time identify PEN-2 as the causative gene of familial comedones.

Novel Mutations in PSENEN Gene in Two Chinese Acne Inversa Families Manifested as Familial Multiple Comedones and Dowling-Degos Disease

“…According to the reported mutations summarized recently by Ratnamala et al ,[20] the study on familial comedones by Panmontha et al ,[21] and the results of the present study, 30 families with 29 different mutations of the γ-secretase genes have been reported to date in AI, including 22 mutations in NCSTN , 6 mutations in PSENEN , and 1 mutation in PSEN1 . Interestingly, all the four missense mutations reported in AI previously (p.V75I, p.D185N, p.P211R, and p.Q216P) are located within the ectodomain of NCSTN .…”

“…The DYLSF domain is necessary for the binding of PEN2 to other components in the presenilin complex and the C terminus is critical for functional γ-secretase activity. [21]…”

Comorbidities or different entities? Phenotype variability associated with PSENEN mutations

“…Even more interestingly, the heterozygous one‐base pair insertion, c.84_85insT (p.L28FfsX93) of PSENEN (or PEN‐2 ) observed in the two Thai families with familial comedones by Panmontha et al . is identical to the PSENEN mutation detected in a Thai family with DDD by Ralser et al . It could be possible that mutations at different sites in the same gene may result in distinct disease phenotypes, which have been reported for a few genes.…”

“…Based on the absence of purulent nodules in partial members, distributions of AI‐like lesions and typical histology, Panmontha et al . extended the disease spectrum to diagnose familial comedones rather than AI and identified PSENEN as the causative gene . However, neither PSENEN mutations nor AI‐like lesions were detected in other patients with familial comedones.…”

Precision medicine in Thailand

“…Patients consulted for diagnosis by NGS are from all specialties, including neurologists (Veeravigrom et al, ), dentists (Intarak, Theerapanon, Ittiwut, et al, ; Nowwarote et al, ; Porntaveetus, Nowwarote, et al, b; Porntaveetus, Osathanon, et al, ), orthopedists, endocrinologists (Sangsin, Srichomthong, Pongpanich, Suphapeetiporn, & Shotelersuk, , ), hematologists (Ittiwut et al, ; Ittiwut et al, ), dermatologists (Intarak, Theerapanon, Srijunbarl, et al, ; Panmontha et al, ; Panmontha et al, ), immunologists (Suratannon et al, ), syndromologists (Porntaveetus, Abid, et al, ; Porntaveetus, Srichomthong, Ohazama, Suphapeetiporn, & Shotelersuk, ; Porntaveetus, Theerapanon, Srichomthong, & Shotelersuk, ), biochemical geneticists (Chaiyasap et al, ; Phowthongkum, Ittiwut, & Shotelersuk, ; Porntaveetus, Srichomthong, Suphapeetiporn, & Shotelersuk, ), oncologists (Sahakitrungruang et al, ), and radiologists (Yeetong, Phewplung, Kamolvisit, Suphapeetiporn, & Shotelersuk, ). We have observed a wide range of yields depending on disease groups, recruitment criteria and, very importantly the cooperation of the clinicians and the bioinformaticians.…”