RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome

Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.     

Key functions for gap junctions in skin and hearing

Cx (connexin) proteins are components of gap junctions which are aqueous pores that allow intercellular exchange of ions and small molecules. Mutations in Cx genes are linked to a range of human disorders. In the present review we discuss mutations in β-Cx genes encoding Cx26, Cx30, Cx30.3 and Cx31 which lead to skin disease and deafness. Functional studies with Cx proteins have given insights into disease-associated mechanisms and non-gap junctional roles for Cx proteins.     

Novel clinical in vivo roles for indigo carmine: high-magnification chromoscopic colonoscopy

Since the adenoma-carcinoma sequence was first proposed by Morson in the 1970s, it has become widely accepted that detection and subsequent removal of polypoid adenomas from the colon reduces the incidence of colorectal cancer. These adenomas are relatively easy to detect by conventional colonoscopy; however, large population studies have shown that despite resection of polypoid adenomas, interval colorectal cancers still occurred. Recent advances in technology have given today's endoscopists access to high-resolution and high-magnification scopes, which has facilitated detection of flat and depressed colorectal lesions. Current data suggest that such morphologically distinct lesions may account for up to 30% of all colorectal adenomas. Furthermore, flat and depressed lesions of the large bowel may confer greater malignant potential compared to polypoid adenomas. The majority of flat lesions show only subtle changes by conventional colonoscopy, but the use of stains, such as indigocarmine, in addition to magnification colonoscopy can enhance their detection significantly. In this paper, we discuss the rationale for detecting flat colorectal lesions. We explore the use of high-magnification colonoscopy and chromoendoscopy, with particular reference to the application of indigocarmine, in this patient group. We also discuss the novel therapeutic techniques now available for these lesions.     

Apolipoprotein C3 SstI polymorphism and triglyceride levels in Asian Indians

Background  

A close association between Sst I polymorphism in the 3' untranslated region of the apolipoproteinC3 (APOC3 ) gene and levels of plasma triglycerides (TG) had been reported by different investigators. Hypertriglyceridemia(HTG) is a known risk factor for coronary artery disease (CAD) in the context of Asian Indians. We conducted a study on the relationship between APOC3 SstI polymorphism (S1S1, S1S2 and S2S2 genotypes) and plasma TG levels in a group of 139 male healthy volunteers from Northern India.     

Wnt-16a, a novel Wnt-16 isoform, which shows differential expression in adult human tissues

The WNT genes encode a large family of secreted glycoprotein signalling molecules important from the earliest stages of development through to the adult. We have identified a novel isoform of the recently described WNT family member, Wnt16, following analysis of chromosome 7q31 genomic sequence. We find differential organisation of Wnt16 with the generation of two mRNA isoforms, Wnt16a and Wnt16b. These isoforms differ in the composition of their 5'-UTR and first exons and show evidence of differential expression. In normal human tissues, Wnt16a is expressed at significant levels only in the pancreas, whereas Wnt16b is expressed more ubiquitously with highest levels in adult kidney, placenta, brain, heart, and spleen. Wnt16 is one of a growing number of WNT genes showing evidence of distinct isoforms. We present evidence to suggest that these isoforms may be regulated from alternative promoters and discuss the potential functional differentiation afforded by these WNT isoforms. This may reveal subtle new mechanisms of regulation of WNT expression and function.     

Loss-of-Function Mutations in CAST Cause Peeling Skin,Leukonychia, Acral Punctate Keratoses,Cheilitis, and Knuckle Pads

Calpastatin is an endogenous specific inhibitor of calpain, a calcium-dependent cysteine protease. Here we show that loss-of-function mutations in calpastatin (CAST) are the genetic causes of an autosomal-recessive condition characterized by generalized peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads, which we propose to be given the acronym PLACK syndrome. In affected individuals with PLACK syndrome from three families of different ethnicities, we identified homozygous mutations (c.607dup, c.424A>T, and c.1750delG) in CAST, all of which were predicted to encode truncated proteins (p.Ile203Asnfs^∗8, p.Lys142^∗, and p.Val584Trpfs^∗37). Immunohistochemistry shows that staining of calpastatin is reduced in skin from affected individuals. Transmission electron microscopy revealed widening of intercellular spaces with chromatin condensation and margination in the upper stratum spinosum in lesional skin, suggesting impaired intercellular adhesion as well as keratinocyte apoptosis. A significant increase of apoptotic keratinocytes was also observed in TUNEL assays. In vitro studies utilizing siRNA-mediated CAST knockdown revealed a role for calpastatin in keratinocyte adhesion. In summary, we describe PLACK syndrome, as a clinical entity of defective epidermal adhesion, caused by loss-of-function mutations in CAST.     

Melatonin,immune function and aging

Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness. Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state.