Claudin-1, A Double-Edged Sword in Cancer.

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target.

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship.

The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.

Lafora progressive myoclonus epilepsy: disease course homogeneity in a genetic isolate.

Lafora epilepsy is characterized by starch formation in brain and skin and is diagnosed by skin biopsy or mutation detection. It has variable ages of onset (6-19 years) and death (18-32 years) even with the same mutation, likely due to extramutational factors. The authors identified 14 Lafora epilepsy patients in the genetic isolate of tribal Oman. The authors show that in this homogeneous environment and gene pool, the same mutation, EPM2B-c.468-469delAG, results in highly uniform ages of onset (14 years) and death (21 years). Biopsy, on the other hand, was not homogeneous (positive in 4/5 patients) and is, therefore, less sensitive than mutation testing.

Clinical and genetic study of spinal muscular atrophies in Oman.

This article presents a retrospective study and a prospective study on spinal muscular atrophy in Oman. For the retrospective study, data were collected from neurophysiology records, from both inpatient and outpatient files. The prospective study was conducted on children as they presented to the hospital and was funded by Sultan Qaboos University. The patients of spinal muscular atrophy were classified into types I, II, and III based on their clinical features as per the International Spinal Muscular Atrophy Consortium classification. The incidence of spinal muscular atrophy was about 1 per 6000 live births. Spinal muscular atrophy type I formed 65% of the cases. Survival motor neuron deletion was seen in 70% of cases of all types of spinal muscular atrophy. The deletion was 83% in spinal muscular atrophy type I. A further study to look into the nondeletional cases is in progress.

Novel spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis in ethnic Omani patients.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive immune disorder, characterized by fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, markedly elevated levels of inflammatory cytokines, and impaired cytotoxic activity of lymphocytes. FHL is often fatal in early infancy. Histologic features include organ infiltration by activated macrophages and lymphocytes. Four genetic loci (FHL1, 2, 3, and 4) have been identified, of which FHL2 involves mutations in the perforin gene and is present in 20-50% of patients with FHL. We herein report the first comprehensive molecular analysis of 16 unrelated cases of FHL in ethnic Omanis. Using direct DNA sequencing analysis in 11 families, seven different mutations were identified in the coding region of the perforin gene, of which five were novel. Perforin gene defects do not seem to be involved in one-third of the cases of FHL in ethnic Omanis.

Myofibrillogenesis regulator 1 gene (MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia.

Two recurrent missense mutations (c.20C>T: A7V; c.26C>T: A9V) in the gene encoding the myofibrillogenesis regulator 1 (MR-1) have been shown to cause autosomal dominant paroxysmal nonkinesigenic dyskinesia (PNKD) in 13 families of primarily European ancestry. Here we report an Omani PNKD family with seven affected family members and autosomal dominant inheritance. Our linkage analysis provided consistent positional evidence that the MR-1 gene could be the responsible disease gene. Sequence analysis identified a MR-1 missense mutation (c.20C>T; A7V) in the affected family members, whereas it was not present in five unaffected family members and 129 population controls. Taking into account that previous haplotype analyses did not reveal evidence for common founders among several PNKD families, our present findings strengthen three implications: (1) autosomal dominant PNKD seems to be a homogenous disorder, for which the MR-1 gene is the major disease gene; (2) mainly two recurrent MR-1 missense mutations (57% V7, 43% V9) account for the genetic variance of familial PNKD; (3) it supports current evidence that some of the recurrent MR-1 mutations may have arisen independently by de novo mutation at functionally convergent key sites of the brain-specific MR-1L isoform.

Identification of prognosis markers in pediatric high-risk acute lymphoblastic leukemia.

Gene expression profiling may improve the understanding of the biology behind relapse in pediatric acute lymphoblastic leukemia. Using suppression subtractive hybridization (SSH), cDNA concatenated sequencing (CCS), and reverse transcriptase real-time quantitative polymerase chain reaction (RT-RQ-PCR) on high-risk patient samples with nondeterminant chromosomal translocation, the authors identified 3 genes that were significantly overexpressed in the nonrelapsed patients: the calcium/calmodulin-dependent serine protein kinase (CASK), subunit 2 of the cofactor required for SP1 transcriptional activation (CRSP2), and granzyme K (GZMK). The level of expression of these biomarkers may help identify patients with potentially good prognosis within a group otherwise at high risk of relapse.

Trinucleotide repeat analysis of spinocerebellar ataxia patients in Oman.

OBJECTIVE: To explore the profile of cytosine/adenine/guanine (CAG) repeat expansion in Omani spinocerebellar ataxia (SCA) patients. METHODS: Ten SCA patients attending the Sultan Qaboos University Hospital Neurologic clinics, Al-Khoud, Oman in the 3 years starting from January 2000 were recruited for this study. Genomic DNA was extracted from peripheral blood samples and CAG repeat expansion analysis was carried out by polymerase chain reaction and sequencing, when required. RESULTS: The CAG triplet repeats leading to polyglutamine expansion and neurodegeneration are seen in spinocerebellar ataxias 1, 2, 3, 6, 7 and 17. By using primers for SCA 1, 2, 3 and 7, we found the repeats were in the normal range and triplet repeats do not seem to be a common cause for ataxia in Oman. CONCLUSION: Spinocerebellar ataxia in Oman has the normal range of CAG repeats for the commonly found SCA1, SCA2, SCA3 and SCA7.

An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression.

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive disease of early childhood manifested by hypercytokinemia and organ infiltration of macrophages and activated lymphocytes, and it is characterized by a fulminant clinical course. The molecular mechanism underlying this disease appears to be a deregulation of apoptosis of activated T cells and macrophages. Approximately 20-40% of patients with familial hemophagocytic lymphohistiocytosis reported worldwide had a perforin gene mutation. We report herein a novel perforin variant in the homozygous state in an Omani boy who was diagnosed 44 days after birth. Sequence analysis of the perforin gene coding region revealed a 12-base pair deletion (codon 284-287) resulting in the deletion of four amino acids in the membrane attack complex domain of the protein. This deletion maintains the reading frame of the perforin mRNA. Both parents were heterozygotes for this molecular defect. Flow-cytometric analysis revealed intracellular perforin expression at the lower end of the normal range in the cytotoxic T cells (CD3+/CD8+) and (CD3+/CD56+) and in around 50% of the natural killer cells (CD3-/CD56+). This is an additional example of a perforin variant which is associated with a significant level of cellular perforin expression and thus confirms that drastic reduction in its expression is not a constant feature in familial hemophagocytic lymphohistiocytosis type 2.