Down-regulation of PERK enhances resistance to ionizing radiation

Although, ionizing radiation (IR) has been implicated to cause stress in endoplasmic reticulum (ER), how ER stress signaling and major ER stress sensors modulate cellular response to IR is unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER transmembrane protein which initiates unfolded protein response (UPR) or ER stress signaling when ER homeostasis is disturbed. Here, we report that down-regulation of PERK resulted in increased clonogenic survival, enhanced DNA repair and reduced apoptosis in irradiated cancer cells. Our study demonstrated that PERK has a role in sensitizing cancer cells to IR. 

Nestor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation

Background: Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Nestor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure.

Results: Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope.

Conclusions: Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.

Presentation of lacrimo-auriculodento- digital (LADD) syndrome in a young female patient

BACKGROUND: Lacrimo-auriculo-dento-digital (LADD) syndrome (OMIM #149730) is an autosomal-dominant congenital disorder that can be caused by heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 (FGFR2) and 3 (FGFR3), and has been found in association with a mutation in the FGF10 gene, which encodes an Fgfr ligand. Clinical signs vary, but the condition is characterised by involvement of the lacrimal and salivary systems, cup-shaped ears, hearing loss and dental abnormalities. Additional features may include involvement of the hands and feet with other body systems particularly the kidneys.

CASE REPORT: Previous literature on the subject has been reviewed and this case is the first presentation of LADD syndrome in the Republic of Ireland, as a sporadic case in a 12-year-old girl who exhibited a range of dental and digital anomalies.

TREATMENT: Her general medical practitioner managed her medical care whilst her oral care necessitated a multidisciplinary approach involving restorative and orthodontic elements.

FOLLOW-UP: The initial restorative phase of treatment has successfully improved the appearance of the patient's anterior teeth using direct resin composite build-ups.