Biology subjects

Hanks, S.

Publications and source records attributed to Hanks, S..

3 recordsLinked to original sources

bioRxiv2024

A spontaneous mutation in ADIPOR1 causes retinal degeneration in mice

Adiponectin receptor 1 (ADIPOR1) is a transmembrane protein necessary for normal anatomy and physiology in the retina. In a recent study of complement factor H knockout mice (Cfh-/-), our lab discovered a flecked retina phenotype and retinal thinning by fundus imaging and optical coherence tomography (OCT), respectively. The phenotype was observed in a subset (50%) of Cfh-/- mice. The thinning observed in vivo is due to an early degeneration of rod photoreceptors. This phenotype has not been reported in published studies of Cfh-/- mice. AdipoR1 knockout mice (AdipoR1-/-) and mice deficient in Membrane Frizzled Related Protein (MFRP) exhibit this phenotype, suggesting an involvement in the emergence of the retinal degeneration observed in a subset of Cfh-/- mice. Cfh and AdipoR1 are located in close proximity on mouse Chromosome 1 (Chr1) and a complementation cross between Cfh and AdipoR1 mice with retinal degeneration produced 100% progeny with retinal degeneration. Sequencing of the Cfh-/- mice revealed a c.841 C > T mutation in AdipoR1. Furthermore, one Cfh wildtype (of Cfh+/+) and 2 heterozygous (of Cfh+/-) mice exhibited retinal degeneration and were homozygous for the point mutation. The c.841 C > T mutation results in a proline to serine conversion at position 281 (P281S) in ADIPOR1. This residue is critical for ADIPOR1 open and closed conformations in the membrane. In silico modeling of candidate ADIPOR1 ligands, 11-cis-retinaldehyde and docosahexaenoic acid (DHA), that are deficient in AdipoR1-/-, suggests that ADIPOR1 is involved in trafficking retinoids and fatty acids and their combined deficiency in the ADIPOR1 mutant retinas might explain the retinal degeneration phenotype.

neuroscience↗

bioRxiv2022

SARS-CoV-2 causes periodontal fibrosis by deregulating mitochondrial beta-oxidation

The global high prevalence of COVID-19 is a major challenge for health professionals and patients. SARS-CoV-2 virus mutate predominantly in the spike proteins, whilst the other key viral components remain stable. Previous studies have shown that the human oral cavity can potentially act as reservoir of the SARS-CoV-2 virus. COVID-19 can cause severe oral mucosa lesions and is likely to be connected with poor periodontal conditions. However, the consequence of SARS-CoV-2 viral infection on human oral health has not been systematically examined. In this research, we aimed to study the pathogenicity of SARS-CoV-2 viral components on human periodontal tissues and cells. We found that by exposing to SARS-CoV-2, especially to the viral envelope and membrane proteins, the human periodontal fibroblasts could develop fibrotic pathogenic phenotypes, including hyperproliferation that was concomitant induced together with increased apoptosis and senescence. The fibrotic degeneration was mediated by a down-regulation of mitochondrial {beta}-oxidation in the fibroblasts. Fatty acid {beta}-oxidation inhibitor, etomoxir treatment could mirror the same pathological consequence on the cells, similar to SARS- CoV-2 infection. Our results therefore provide novel mechanistic insights into how SARS- CoV-2 infection can affect human periodontal health at the cell and molecular level with potential new therapeutic targets for COVID-19 induced fibrosis.

molecular biology↗

bioRxiv2020

Chromosomal instability by mutations in a novel specificity factor of the minor spliceosome

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing with a specific impact on the chromosome segregation process, and show how defects herein can cause constitutional aneuploidy.

molecular biology↗