Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype.

Organic-inorganic biohybrid films from wool-keratin/jellyfish-collagen/silica/boron via sol-gel reactions for soft tissue engineering applications.

Therapeutic angiogenesis is pivotal in creating effective tissue-engineered constructs that deliver nutrients and oxygen to surrounding cells. Hence, biomaterials that promote angiogenesis can enhance the efficacy of various medical treatments, encompassing tissue engineering, wound healing, and drug delivery systems. Considering these, we propose a rapid method for producing composite silicon-boron-wool keratin/jellyfish collagen (Si-B-WK/JFC) inorganic-organic biohybrid films using sol-gel reactions. In this approach, reactive tetraethyl orthosilicate and boric acid (pKa ⩾ 9.24) were used as silicon and boron sources, respectively, and a solid-state gel was formed through the condensation reaction of these reactive groups with the keratin/collagen mixture. Once the resulting gel was thoroughly suspended in water, the films were prepared by a casting/solvent evaporation methodology. The fabricated hybrid films were characterized structurally and mechanically. In addition, angiogenic characteristics were determined by the in ovo chick chorioallantoic membrane assay, which revealed an increased vascular network within the Si-B-WK/JFC biohybrid films. In conclusion, it is believed that Si-B-WK/JFC biohybrid films with mechanical and pro-angiogenic properties have the potential to be possessed in soft tissue engineering applications, especially wound healing.

Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa.

AIMS: Colorectal carcinoma (CRC) is a common cause of morbidity and mortality worldwide, and an emerging public health problem in sub-Saharan Africa. Several authors have described an increased frequency of mismatch repair-deficient (dMMR) CRC in sub-Saharan Africa, but these tumours remain poorly characterised molecularly. We sought to interrogate the somatic molecular genetic landscape of dMMR CRC in a cohort of young patients to better inform Lynch syndrome (LS) screening strategies and personalised medicine approaches in our setting. METHODS: 32 patients (aged <60 years) were identified with dMMR CRC. DNA was extracted from selected formalin-fixed paraffin-embedded (FFPE) tissue resection samples and subjected to amplicon-based next-generation sequencing (NGS). RESULTS: Pathogenic or likely pathogenic variants were detected in the corresponding MMR gene in 14 of 18 (78%) MLH1/PMS2-deficient tumours, 5 of 8 (63%) MSH2/MSH6-deficient tumours, 1 of 4 (25%) tumours with isolated MSH6 loss and 0 of 2 tumours with isolated PMS2 loss. Previously unreported variants were identified in MLH1 (three) and MSH2 (one). Cases with a variant allele frequency suggesting a germline mutation were identified in MLH1 (eight), MSH2 (two) and MSH6 (one). Only one MMR gene variant was detected in more than one patient (MLH1 p.Q510*). Four POLE/POLD1 exonuclease domain variants were identified, one of which was previously unreported. CONCLUSION: The spectrum of disease-causing MMR gene variants in our population necessitates NGS testing for LS screening. This study also highlights the role of somatic testing on readily available FFPE samples to generate data on the epidemiology of CRC in different settings.

Nanoliposomes as nonviral vectors in cancer gene therapy.

Nonviral vectors, such as liposomes, offer potential for targeted gene delivery in cancer therapy. Liposomes, composed of phospholipid vesicles, have demonstrated efficacy as nanocarriers for genetic tools, addressing the limitations of off-targeting and degradation commonly associated with traditional gene therapy approaches. Due to their biocompatibility, stability, and tunable physicochemical properties, they offer potential in overcoming the challenges associated with gene therapy, such as low transfection efficiency and poor stability in biological fluids. Despite these advancements, there remains a gap in understanding the optimal utilization of nanoliposomes for enhanced gene delivery in cancer treatment. This review delves into the present state of nanoliposomes as carriers for genetic tools in cancer therapy, sheds light on their potential to safeguard genetic payloads and facilitate cell internalization alongside the evolution of smart nanocarriers for targeted delivery. The challenges linked to their biocompatibility and the factors that restrict their effectiveness in gene delivery are also discussed along with exploring the potential of nanoliposomes in cancer gene therapy strategies by analyzing recent advancements and offering future directions.

Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer.

Introduction: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel. Materials and methods: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR. Results: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes. Conclusion: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.