Homozygous variant in abolishing triokinase activities is associated with isolated immunodeficiency.

Background: Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5).

Dominant dystrophic epidermolysis bullosa is associated with glycolytically active GATA3+ T helper 2 cells which may contribute to pruritus in lesional skin.

Background: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined.

Objectives: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients.

Profibrotic Subsets of SPP1 Macrophages and POSTN Fibroblasts Contribute to Fibrotic Scarring in Acne Keloidalis.

Acne keloidalis is a primary scarring alopecia characterized by longstanding inflammation in the scalp causing keloid-like scar formation and hair loss. Histologically, acne keloidalis is characterized by mixed leukocytic infiltrates in the acute stage followed by a granulomatous reaction and extensive fibrosis in the later stages. To further explore its pathogenesis, bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics were applied to occipital scalp biopsy specimens of lesional and adjacent no-lesional skin in patients with clinically active disease.

Spatial transcriptomics in human skin research.

Spatial transcriptomics is a revolutionary technique that enables researchers to characterise tissue architecture and localisation of gene expression. A plethora of technologies that map gene expression are currently being developed, aiming to facilitate spatially resolved, high-dimensional assessment of gene transcription in the context of human skin research. Knowing which gene is expressed by which cell and in which location within skin, facilitates understanding of skin function and dysfunction in both health and disease.

A review of genotrichoses and hair pathology associated with inherited skin diseases.

Genetic hair disorders, also known as genotrichoses, are characterized by abnormalities of hair structure, growth or differentiation, giving rise to a spectrum of phenotypes such as hypertrichosis, hypotrichosis and atrichia. These disorders may present as isolated phenotypes or be part of more complex phenotypes including abnormalities in skin or other organs. Genetic discoveries for hair disorders have been recently augmented with the advent of next-generation sequencing (NGS) technologies.

Loss of RhoE Function in Dermatofibroma Promotes Disorganized Dermal Fibroblast Extracellular Matrix and Increased Integrin Activation.

Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.

Comorbidities of Keloid and Hypertrophic Scars Among Participants in UK Biobank.

Importance: Keloids and hypertrophic scars (excessive scarring) are relatively understudied disfiguring chronic skin conditions with high treatment resistance.

Objective: To evaluate established comorbidities of excessive scarring in European individuals, with comparisons across ethnic groups, and to identify novel comorbidities via a phenome-wide association study (PheWAS).

Design, Setting, And Participants: This multicenter cross-sectional population-based cohort study used UK Biobank (UKB) data and fitted logistic regression models for testing associations between excessive scarring and a variety of outcomes, including previously studied comorbidities and 1518 systematically defined disease categories.

ABE8e adenine base editor precisely and efficiently corrects a recurrent COL7A1 nonsense mutation.

Base editing introduces precise single-nucleotide edits in genomic DNA and has the potential to treat genetic diseases such as the blistering skin disease recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by mutations in the COL7A1 gene and type VII collagen (C7) deficiency. Adenine base editors (ABEs) convert A-T base pairs to G-C base pairs without requiring double-stranded DNA breaks or donor DNA templates. Here, we use ABE8e, a recently evolved ABE, to correct primary RDEB patient fibroblasts harboring the recurrent RDEB nonsense mutation c.

Single-cell transcriptomics in human skin research: available technologies, technical considerations and disease applications.

Single-cell technologies have revolutionized research in the last decade, including for skin biology. Single-cell RNA sequencing has emerged as a powerful tool allowing the dissection of human disease pathophysiology at unprecedented resolution by assessing cell-to-cell variation, facilitating identification of rare cell populations and elucidating cellular heterogeneity. In dermatology, this technology has been widely applied to inflammatory skin disorders, fibrotic skin diseases, wound healing complications and cutaneous neoplasms.

The Past and Future of Rare Skin Disease Research and Therapy.

Launch of the European Society for Dermatological Research (ESDR) in 1970 coincided with genetics also entering a new era. Arriving alongside new models of DNA structure and the discovery of restriction endonucleases, the ESDR has parallel-tracked 50 years of major developments in genomics, technological innovations, and big data. Patients with rare Mendelian genetic skin diseases have witnessed the discovery of causative genes and pathogenic variants, improved genetic counseling, and the advent of prenatal diagnosis.

The TKFC Ala185Thr variant, reported as 'null' for fructose metabolism, is fully active as triokinase.

TKFC-encoded triokinase catalyses glyceraldehyde phosphorylation in fructose metabolism and favours lipogenesis in mice. In Tkfc knockouts or knockdowns, fructose oxidation predominates over lipogenesis. The highly prevalent human variant Ala185Thr-Triokinase/FMN cyclase (TKFC) has been reported to be 'null' for fructose metabolism, since Ala185-TKFC rescues the mouse TKFC-deficient phenotype, whereas Ala185Thr-TKFC does not.

A clinician's guide to omics resources in dermatology.

With recent advances in high-throughput technologies, we are now in an era where the use of large-scale datasets of biological samples and individual diseases can be analysed using omics methodologies. These include genomics, transcriptomics, proteomics, metabolomics, lipidomics and epigenomics. Omics approaches have been developed to deliver a holistic understanding of systems biology, to identify key biomarkers, and to aid in the interpretation of molecular, biochemical and environmental interactions.

Transcriptomic profiling of recessive dystrophic epidermolysis bullosa wounded skin highlights drug repurposing opportunities to improve wound healing.

Chronic wounds present a major disease burden in people with recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering skin disorder caused by mutations in COL7A1 encoding type VII collagen, the major component of anchoring fibrils at the dermal-epidermal junction. Treatment of RDEB wounds is mostly symptomatic, and there is considerable unmet need in trying to improve and accelerate wound healing. In this study, we defined transcriptomic profiles and gene pathways in RDEB wounds and compared these to intact skin in RDEB and healthy control subjects.

Metabolic perturbations in fibrosis disease.

Metabolic changes occur in all forms of disease but their impact on fibrosis is a relatively recent area of interest. This review provides an overview of the major metabolic pathways, glycolysis, amino acid metabolism and lipid metabolism, and highlights how they influence fibrosis at a cellular and tissue level, drawing on key discoveries in dermal, renal, pulmonary and hepatic fibrosis. The emerging influence of adipose tissue-derived cytokines is discussed and brings a link between fibrosis and systemic metabolism.

H syndrome: A review of treatment options and a hypothesis of phenotypic variability.

H syndrome is a rare autosomal recessive disorder with clinical features comprising: hyperpigmentation, hypertrichosis, hearing loss, heart anomalies, low height, hypogonadism and hepatosplenomegaly. H syndrome results from loss-of-function mutations in SLC29A3 which leads to abnormal proliferation and function of histiocytes. Herein, we discuss the considerable phenotypic heterogeneity detected in a consanguineous Egyptian family comprising of four affected siblings, two of which are monozygotic twin and the possible therapeutics.

New Homozygous Missense MSMO1 Mutation in Two Siblings with SC4MOL Deficiency Presenting with Psoriasiform Dermatitis.

Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene. To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported. Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology.