Advances in Treatments for Epidermolysis Bullosa (EB): Emphasis on Stem Cell-Based Therapy.

Epidermolysis bullosa (EB) is a rare genetic dermatosis characterized by skin fragility and blister formation. With a wide phenotypic spectrum and potential extracutaneous manifestations, EB poses significant morbidity and mortality risks. Currently classified into four main subtypes based on the level of skin cleavage, EB is caused by genetic mutations affecting proteins crucial for maintaining skin integrity. The management of EB primarily focuses on preventing complications and treating symptoms through wound care, pain management, and other supportive measures. However, recent advancements in the fields of stem cell therapy, tissue engineering, and gene therapy have shown promise as potential treatments for EB. Stem cells capable of differentiating into skin cells, have demonstrated positive outcomes in preclinical and early clinical trials by promoting wound healing and reducing inflammation. Gene therapy, on the other hand, aims to correct the underlying genetic defects responsible for EB by introducing functional copies of mutated genes or modifying existing genes to restore protein function. Particularly for severe subtypes like Recessive Dystrophic Epidermolysis Bullosa (RDEB), gene therapy holds significant potential. This review aims to evaluate the role of new therapeutic approaches in the treatment of EB. The review includes findings from studies conducted on humans. While early studies and clinical trials have shown promising results, further research and trials are necessary to establish the safety and efficacy of these innovative approaches for EB treatment.

Whole exome sequencing identifies a novel variant in the COL12A1 gene in a family with Ullrich congenital muscular dystrophy 2.

BACKGROUND: Mutations within the COL12A1 gene have been linked with the onset of congenital Ullrich muscular dystrophy 2 (UCMD2) and Bethlem myopathy. The severity of the symptoms exhibited is dependent on the mutation's type and whether it is heterozygous or homozygous. METHODS: We used whole-exome sequencing to identify disease-causing variants in a nine-year-old Iranian patient who had weakness, joint contractures, delayed motor development, and other symptoms. We confirmed the pathogenicity of the identified variant using in silico tools and verified its novelty using various databases. We also performed a co-segregation study and confirmed the presence of the variant in the patient's parents by Sanger sequencing. RESULTS: Our analysis identified a novel homozygous missense variant in the affected patient in COL12A1 (c.8828 C > T; p.Pro2943Leu). This is the second reported family with UCMD2 caused by a mutation in COL12A1. Our findings confirm that this mutation results in significantly more severe symptoms than Bethlem myopathy. CONCLUSION: Our investigation contributes to the expanding body of evidence that links mutations in COL12A1 with UCMD2. Our findings confirm that the homozygous mutation in COL12A1 caused this condition and suggest that genetic testing for this mutation may be useful for diagnosing patients with this disease.

Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, ß-, and γ-HPV infections.

HPVs are DNA viruses include approximately 450 types that are classified into 5 genera (α-, ß-, γ-, µ-, and ν-HPV). The γ- and ß-HPVs are present in low copy numbers in healthy individuals; however, in patients with an inborn error of immunity, certain species of ß-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either typical or atypical. Manifestations of typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to ß-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, to RNA extracted from normal-appearing skin and wart samples of patients with typical EV to explore the viral and human genetic determinants. In 26 patients, 9 distinct biallelic mutations were detected in TMC6, TMC8, and CIB1, 7 of which are previously unreported to our knowledge. Additionally, 20 different HPV species, including 3 α-HPVs, 16 ß-HPVs, and 1 γ-HPV, were detected, 8 of which are reported here for the first time to our knowledge in patients with EV (ß-HPV-37, -47, -80, -151, and -159; α-HPV-2 and -57; and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.

Are Dyskeratosis Congenita patients at higher risk of symptomatic COVID-19?

Dyskeratosis Congenita (DC) is a rare and heterogeneous disease. This disorder is resulted from a defect in the telomere maintenance in stem cells. Telomerase RNA component, shelterin complex, and telomerase reverse transcriptase are mutated in this disease. Many studies have previously confirmed shorter leukocyte telomere length in DC. On the other hand, the association between telomere length and Coronavirus disease 2019 (COVID-19) indicated that people with a short telomere background mostly show more severe symptoms related to COVID-19, and the mortality rate among them increases as well. Because patients with DC have an abnormally short telomere length, in the current study, we hypothesized that they are at higher risk of developing symptomatic COVID-19 that requires further clinical care.

Recalcitrant Cutaneous Warts in a Family with Inherited ICOS Deficiency.

Recalcitrant warts, caused by human papillomaviruses (HPVs), can be a cutaneous manifestation of inborn error of immunity. This study investigated the clinical manifestations, immunodeficiency, single-gene susceptibility, and HPV repertoire in a consanguineous family with severe sinopulmonary infections and recalcitrant warts. Clinical and immunologic evaluations, including FACS and lymphocyte transformation test, provided evidence for immunodeficiency. Combined whole-exome sequencing and genome-wide homozygosity mapping were utilized to disclose candidate sequence variants. Whole-transcriptome sequencing was used to concomitantly investigate the HPV genotypes and the consequences of detected sequence variants in the host. The proband, a male aged 41 years, was found to be homozygous for the c.6delG, p.Lys2Asnfs∗17 variant in ICOS, encoding the inducible T-cell costimulator. This variant was located inside the 5 megabase of runs of homozygosity on 2q33.2. RNA sequencing confirmed the deleteriousness of the ICOS variant in three skin biopsies revealing significant downregulation of ICOS and its ligand, ICOSLG. Reads unaligned to the human genome were applied to 926 different viruses, and α-HPV57, ß-HPV107, ß-HPV14, and ß-HPV17 were detected. Collectively, we describe a previously unrecognized inborn error of T-cell immunity to HPVs, indicating that autosomal recessive ICOS deficiency can underlie recalcitrant warts, emphasizing the immunologic underpinnings of recalcitrant warts at the nexus of human and viral genomic variation.

Molecular insight of dyskeratosis congenita: Defects in telomere length homeostasis.

BACKGROUND: Dyskeratosis congenita (DC) is a rare disease and is a heterogenous disorder, with its inheritance patterns as autosomal dominant, autosomal recessive, and X-linked recessive. This disorder occurs due to faulty maintenance of telomeres in stem cells. This congenital condition is diagnosed with three symptoms: oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. However, because it has a wide range of symptoms, it may have phenotypes similar to other diseases. For this reason, it is necessary to use methods of measuring the Telomere Length (TL) and determining the shortness of the telomere in these patients so that it can be distinguished from other diseases. Today, the Next Generation Sequencing technique accurately detects mutations in the target genes. AIM: This work aims to review and summarize how each of the DC genes is involved in TL, and how to diagnose and differentiate the disease using clinical signs and methods to measure TL. It also offers treatments for DC patients, such as Hematopoietic Stem Cell Transplantation and Androgen therapy. RELEVANCE FOR PATIENTS: In DC patients, the genes involved in telomere homeostasis are mutated. Because these patients may have an overlapping phenotype with other diseases, it is best to perform whole-exome sequencing after genetics counseling to find the relevant mutation. As DC is a multi-systemic disease, we need to monitor patients frequently through annual lung function tests, ultrasounds, gynecological examinations, and skin examinations.

Molecular and biochemical mechanisms of human iris color: A comprehensive review.

Eye color is determined as a polymorphism and polygenic trait. Brown is the most common eye color in the world, accounting for about 79%, blue eye color for about 8-10%, hazel for 5%, and green for 2%. Rare-colored eyes include gray and red/violet. Different factors are involved in determining eye color. The two most important factors are the iris pigment and the way light is scattered from the iris. Gene expression determines the iris pigmentation and how much melanin is present in the eye, which is the number of melanin subunits that identify eye color. The genes involved in the pigmentation of single-nucleotide polymorphism (SNP) have a significant role; and even some genes are included only in the eye color through SNP. MicroRNAs also affect melanocyte synthesis, which is usually affected by the downregulation of essential genes involved in pigmentation. In this study, we assess the biochemical pathways of melanin synthesis, and the role of each gene in this pathway also has been examined in the signaling pathway that stimulates melanin synthesis.