Ryan Thompson

Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction

Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal pattern of inheritance and a young age at onset, often before age 25. MODY is genetically heterogeneous, with 8 distinct MODY genes identified to date and more believed to exist. We resequenced 732 kb of genomic sequence at 8p23 in 6 MODY families unlinked to known MODY genes that showed evidence of linkage at that location. Of the 410 sequence differences that we identified, 5 had a frequency <1% in the general population and segregated with diabetes in 3 of the families, including the 2 showing the strongest support for linkage at this location. The 5 mutations were all placed within 100 kb corresponding to the BLK gene. One resulted in an Ala71Thr substitution; the other 4 were noncoding and determined decreased in vitro promoter activity in reporter gene experiments. We found that BLK—a nonreceptor tyrosine-kinase of the src family of proto-oncogenes—is expressed in β-cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating transcription factors Pdx1 and Nkx6.1. These actions are greatly attenuated by the Ala71Thr mutation. These findings point to BLK as a previously unrecognized modulator of β-cell function, the deficit of which may lead to the development of diabetes.

A Visfatin Promoter Polymorphism Is Associated with Low-Grade Inflammation and Type 2 Diabetes

Visfatin (also known as pre‐B cell colony‐enhancing factor, or PBEF) is a pro‐inflammatory adipokine expressed predominantly in visceral fat. We investigated whether polymorphisms at the visfatin/PBEF locus influence the risk of type 2 diabetes (T2D). Linkage disequilibrium analysis of 52 single nucleotide polymorphisms spanning the entire gene (34.7 kb) plus 20.5 kb of the upstream region and 25.5 kb of the downstream region revealed a single haplotype block that could be tagged by seven single nucleotide polymorphisms. These seven tags were typed in a group of T2D patients (n = 814) and a group of non‐diabetic controls (n = 320) of white origin. A significant association was observed at −948C>A, with minor allele frequencies of 0.157 in T2D cases and 0.119 in non‐diabetic controls (p = 0.021). In a non‐diabetic population (n = 630), the same −948 allele that conferred increased risk of T2D was significantly associated with higher plasma levels of fibrinogen and C‐reactive protein (p = 0.0022 and 0.0038, respectively). However, no significant associations were observed with BMI, waist circumference, serum glucose levels, or fasting insulin levels. Our findings suggest that the visfatin/PBEF gene may play a role in determining T2D susceptibility, possibly by modulating chronic, low‐grade inflammatory responses.

Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion

Geldanamycin and its derivative 17AAG [17-(Allylamino)-17-demethoxygeldanamycin, telatinib] bind selectively to the Hsp90 chaperone protein and inhibit its function. We discovered that these drugs associate with mitochondria, specifically to the mitochondrial membrane voltage-dependent anion channel (VDAC) via a hydrophobic interaction that is independent of HSP90. In vitro, 17AAG functions as a Ca2+ mitochondrial regulator similar to benzoquinone-ubiquinones like Ub0. All of these compounds increase intracellular Ca2+ and diminish the plasma membrane cationic current, inhibiting urokinase activity and cell invasion. In contrast, the HSP90 inhibitor radicicol, lacking a bezoquinone moiety, has no measurable effect on cationic current and is less effective in influencing intercellular Ca2+ concentration. We conclude that some of the effects of 17-AAG and other ansamycins are due to their effects on VDAC and that this may play a role in their clinical activity.

Case 10-2018: An 84-Year-Old Man with Painless Unilateral Testicular Swelling

A Man with Painless Unilateral Testicular Swelling An 84-year-old man presented with a 6-week history of painless right testicular swelling. He had no fever or systemic symptoms. Ultrasonography revealed marked asymmetric enlargement and hypervascularity of the right testicle. A diagnostic procedure was performed.