A nonsense variant in KRT31 is associated with autosomal-dominant monilethrix.

BACKGROUND: Monilethrix is a rare hereditary hair disorder that is characterised by a beaded hair shaft structure and increased hair fragility. Patients may also present with keratosis pilaris and nail changes. Research has identified three genes for autosomal-dominant monilethrix (KRT81, KRT83, and KRT86), and one gene for the autosomal-recessive form (DSG4). OBJECTIVES: To investigate the genetic basis of autosomal-dominant monilethrix in families with no pathogenic variants in any of the known monilethrix genes, and to understand the mechanistic basis of variant pathogenicity using a cellular model. METHODS: Nine affected individuals from four unrelated families were included in this study. A clinical diagnosis of monilethrix was assigned based on clinical examination and/or trichoscopy. Exome sequencing (ES) was performed in six individuals to identify pathogenic variants, and Sanger sequencing was used for co-segregation and haplotype analyses. Cell culture experiments (immunoblotting, immunofluorescence, and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analyses) were used to confirm variant pathogenicity, to determine expression and subcellular localisation of proteins, and to identify a possible nonsense-mediated mRNA decay. RESULTS: In six affected individuals with clinically suggested monilethrix, ES led to the identification of the nonsense variant c.1081G>T; p.(Glu361*) in KRT31, which was subsequently identified in other affected members of these families by Sanger sequencing. This variant led to the abolition of both the last three amino acids of the 2B subdomain and the complete C-terminal tail domain of keratin 31. Immunoblotting demonstrated that when co-expressed with its binding partner keratin 85, the truncated keratin 31 was still expressed, albeit less abundantly than the wild type protein. Immunofluorescence revealed that p.(Glu361*) keratin 31 had an altered cytoskeletal localisation and formed vesicular-like structures in the cell cytoplasm near the cell membrane. RT-qPCR analysis did not generate evidence for a nonsense mediated decay of the mutant transcript. CONCLUSIONS: This study is the first to identify pathogenic variants in KRT31 as a cause of autosomal-dominant monilethrix. This highlights the importance of hair keratin proteins in hair biology, and will increase the molecular diagnostic yield for rare ectodermal phenotypes of hair and nail tissues.

Identification of a Novel PLCD1 Variant in a Danish Family with Hereditary Leukonychia.

A 1-year-old girl presented with porcelain white fingernails, accidentally discovered when she was referred for an infantile hemangioma consultation. The family reported that the nails had been milky white since birth and her father had similar white finger and toenails. The father remembered that additional family members on his side of the family presented with white nails; however, he could not provide exact information about the number of other relatives affected by this nail abnormality. The girl and her father were the only available family members with white nails presented for this study (Figure 1). The girl presented with leukonychia totalis on all fingernails only, while the father had this abnormality on all finger and toenails (Figure 2). We were not aware of any association with other diseases or features in this family, except hemangioma in the girl. (SKINmed. 2023;21:44-46).

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence.

The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase-regulated nuclear-cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ran⋅GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ran⋅GTP levels and accelerated the cell cycle and DNA damage repair. As a result, normal cells overexpressing RCC1 evaded DNA damage-induced cell cycle arrest and senescence, mimicking colorectal carcinoma cells with high endogenous RCC1 levels. The RCC1-induced inhibition of senescence required Ran and exportin 1 and involved the activation of importin ß-dependent nuclear import of 53BP1, a large NCT cargo. Our results indicate that changes in the activity of the Ran⋅GTP-regulated NCT modulate the rate of the cell cycle and the efficiency of DNA repair. Through the essential role of RCC1 in regulation of cellular Ran⋅GTP levels and NCT, RCC1 expression enables the proliferation of cells that sustain DNA damage.

Clinical and histopathological changes in palatal mucosa following two treatment modalities in patients wearing maxillary complete dentures with suction cup.

AIM: The aim of the study was to determine the clinical and histopathological effect on palatal hyperplasia caused by suction cups by different methods of management used for recovery of abused tissues. MATERIALS AND METHODS: A total of 35 subjects agreed for biopsy procedure, from 50 patients who gave consent for the study. Out of the 35 subjects, 20 were randomly selected for treatment with discontinuation of denture (Group I) and 15 selected for denture relined with tissue conditioner (COE-comfort) (Group II). Punch biopsy procedure was performed on these patients to study the histopathology of the lesion before the two modalities of treatment was administered on them. RESULTS: Inflammation caused by suction cup decreased considerably by both the treatment modalities, i.e., the use of tissue conditioner as well as discontinuation of denture (tissue rest) for a period of 2 weeks. CONCLUSION: It was concluded that wearing denture day and night considerably increased the severity of inflammatory papillary hyperplasia of palate. Healing was better with tissue conditioner when compared with tissue rest.

Role of AIF in cardiac apoptosis in hypertrophic cardiomyocytes from Dahl salt-sensitive rats.

AIMS: The caspases are thought to be central mediators of the apoptotic program, but recent data indicate that apoptosis may also be mediated by caspase-independent mechanisms such as apoptosis-inducing factor (AIF). The role of AIF-induced apoptosis in heart, however, is currently not well understood. The aim of this study was to investigate the presence of and conditions for AIF-induced cardiac apoptosis in vitro. METHODS AND RESULTS: Hypertrophic cardiomyocyte (H-CM) cultures were prepared from the hearts of Dahl salt-sensitive rats fed a high salt diet. Apoptotic stimulation induced by hypoxia/reoxygenation or staurosporine (1 microM) enhanced AIF release in H-CMs compared with non-hypertrophic cardiomyocytes (N-CMs). Caspase inhibition using zVAD.fmk (25 microM) or overexpression of CrmA using recombinant adenovirus only partially protected N-CMs from apoptosis (63 +/- 0.93%) and provided no significant protection against apoptosis in hypertrophic cells (23 +/- 1.03%). On the other hand, poly-ADP-ribose polymerase inhibition using 4-AN (20 microM) during apoptotic stimulation blocked the release of AIF from mitochondria and significantly improved cell viability in hypertrophied cardiomyocytes (74 +/- 1.18%). CONCLUSION: A caspase-dependent, apoptotic pathway is important for N-CM death, whereas a caspase-independent, AIF-mediated pathway plays a critical role in H-CMs.

Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression.

PURPOSE: Ovarian cancer is the leading cause of death among all gynecological malignancies in Western countries. Although therapy for ovarian cancer has been greatly improved in the past 20 years, the overall survival for patients with advanced ovarian cancer has not changed significantly. The poor survival rates in patients with advanced ovarian cancer are due both to late diagnosis and to lack of effective drugs for the majority of patients who have a relapse and develop resistance to current chemotherapy agents used for ovarian cancer. Thus, developing and discovering effective novel drugs with different molecular structures from conventional chemotherapy agents have become an urgent clinical need. METHODS: Ovarian cancer cells were treated with lovastatin and atorvastatin. Apoptosis in these cells and tumor formation in soft agar were determined. The molecular mechanism by which statins suppress ovarian cancer cell growth was evaluated. RESULTS: Both lovastatin and atorvastatin effectively induced apoptosis in ovarian cancer cells and suppressed anchorage-independent growth of these cells in soft agar. Further investigation of the molecular mechanism has revealed that the expression of Cdc42 and Rac1, small GTPase family members, was highly induced in the cells by these statins along with the activation of Jun N-terminal kinases (JNK). In addition, Bim, a proapoptotic protein, was significantly induced by these statins. CONCLUSIONS: Our findings provide new insight into the molecular mechanism by which statins induce apoptosis in ovarian cancer cells and may lead to novel therapies for advanced ovarian cancer.