A novel frameshift mutation of the PSENEN gene discovered in a Chinese family with Dowling-Degos disease And Literature Review
Creators: name: Xinhong Ge
name: Yuanhaoqi Chen
name: Syeda Sadia Ssafa
name: Jiaqi Guo
name: Biao Yang
name: Xinmei Mao
name: Xinyou Yu
name: Nan Yu
name: Li Xia
name: Mohammad Omar Faruk
name: Zhiyun Shi
Publisher: name: ISAR Publisher
Year: 2024
Subjects: Genodermatosis, Dowling-Degos disease (DDD), Whole-exome sequencin, PSENEN, Gene mutation.

description: Background: Dowling-Degos disease(DDD MIM: 615327) is a rare autosomal dominant genodermatosis characterized by progressively reticular hyperpigmentation mainly affecting flexures. such as the neck, axilla, chelidon and areas below the breasts and groin, and has obvious heterogeneity. In the past, KRT5(OMIM 179850), POFUT1(OMIM 615327) and POGLUT1 (OMIM 615696)have been identified to be the pathogenic gene of DDD. 

Literature Review: In several researches, DDD (Dowling Degos Disease) has been linked with different genes. For example Horner et al. claim that one of many keratin 5 gene’s loss-of-function mutation is what causes DDD. Hanneken et al. also described that in most DDD patients and a small number of GGD (Gali Gali Disease) patients, mutations in the keratin 5 gene (KRT5) have been linked. Ahmed et al. claim that mutations in the POGLUT1 gene result in a disseminated, papular clinical appearance, mutations in the keratin 5 (KRT5) gene promote a reticular distribution pattern. According to Mancy and Abdullah (2022), DDD is caused by several gene mutations like POGLUT1, POFUT1 and PSENEN genes, as well as keratin 5 (KRT5). According to Papadopoulou et al., the clinical manifestation is caused by mutations in many genes. While POGLUT1 gene mutations result in a widespread, papular clinical manifestation, keratin 5 (KRT5) gene mutations prefer a reticular distribution pattern. According to Garcovich et al., Dowling Degos Disease (DDD; MIM 179850, 615327, and 615696) has also been associated with a deficient NOTCH signalling. The NOTCH signalling system, which is crucial for maintaining the stability of the hair follicle tissue and other skin appendages, is improved by the POFUT1, POGLUT1, and PSENEN gene therapies. Peter et al. stated that  POGLUT1 is a crucial modulator of Notch signalling because it binds O-linked glucose to serine residues in Notch receptors that resemble repetitions of the epidermal growth factor. It also regulates the development, maturation, and segmentation of keratinocytes and melanocytes and is crucial for maintaining the homeostasis of cutaneous cells. These and other findings indicate that mutations in POGLUT1 that result in abnormalities in Notch signalling will contribute to aberrant pigmentation and keratinocyte shape (Peter et al., 2020). Loss of Notch1 and Notch2 in mice leads to abnormal pigmentation (Wilson et al., 2017). Horner et al., (2011) also suggested that Patients with Galli-Galli Disease exhibit similar mutations, and the condition is now regarded as a subgroup of DDD. 

Dowling-Degos Disease can manifest either sporadic or autosomal dominant pattern. Several case series and individual case reports cited by Horner et al. (2011) claim that women are more likely than males to experience it. We think more information need to be revealed about Dowling Degos Disease to make it an independent and specific disease pattern as this disease has close relationship with other similar types of diseases. For instance Ahmed et al. claim that DDD can imitate ADMH (Acquired dermal macular hyperpigmentation). Presenilin Enhancer Protein 2 (PEN-2) is a subunit of the -secretase enzyme complex and is encoded by PSENEN (Peter et al., 2021). The other components of this complex include anterior pharynx deficient, presenilin, and nicastrin (Peter et al., 2021). The Notch receptors that are required for the activation of Notch signalling are cleaved intracellularly by the gamma-secretase enzyme complex (Peter et al., 2021). It has been documented that Indian individuals with HS (Hydradenitis Supurativa) and DDD also had the PSENEN gene mutation (Peter et al., 2021). According to Garcovich et al., (2020), patients with mutations in PSENEN who have both pathologies seem to confirm a potential link between two seemingly unrelated conditions. However we have found and shown in this paper a novel frameshift mutation in PSENEN gene for DDD in a Chinese family by doing whole exome sequencing. As this finding has not yet been done in relevant researches and literatures we think it can lead to further understanding of DDD in a broader spectrum. 

Methods: In this study, we performed the whole-exome sequencing analyses of a large Chinese DDD family, the results were compared against 100 healthy control patients. 

Results: No mutations in the KRT5, POFUT1, or POGLUT1 genes were found. However, whole-exome sequencing revealed a novel frameshift mutation, c.168_169delTG, in the PSENEN (OMIM 613737)in seven DDD-afflicted patients. This mutation was not present in healthy individuals of the affected family, nor was it found in any of the healthy controls outside of this family. 

Conclusions: Our findings suggest that this novel frameshift mutation, c.168_169delTG, in PSENEN is responsible for causing DDD in this family, and further enhances our understanding of the clinical features and genetic pathogenesis of DDD.