Evaluation for Kienböck Disease Familial Clustering: A Population-Based Cohort Study.

PURPOSE: Kienböck disease (KD) is rare and its etiology remains unknown. As a result, the ideal treatment is also in question. Our primary purpose was to test the hypothesis that KD would demonstrate familial clustering in a large statewide population with comprehensive genealogical records, possibly suggesting a genetic etiologic contribution. Our secondary purpose was to evaluate for associations between KD and known risk factors for avascular necrosis. METHODS: Patients diagnosed with KD were identified by searching medical records from a comprehensive statewide database, the Utah Population Database. This database contains pedigrees dating back to the early 1800s, which are linked to 31 million medical records for 11 million patients from 1996 to the present. Affected individuals were then mapped to pedigrees to identify high-risk families with an increased incidence of KD relative to control pedigrees. The magnitude of familial risk of KD in related individuals was calculated using Cox regression models. Association of risk factors related to KD was analyzed using conditional logistic regression. RESULTS: We identified 394 affected individuals linked to 194 unrelated high-risk pedigrees with increased incidence of KD. The relative risk of developing KD was significantly elevated in first-degree relatives. There was a significant correlation between alcohol, glucocorticoid, and tobacco use and a history of diabetes, and the diagnosis of KD. CONCLUSIONS: Familial clustering of KD observed in the Utah Population Database cohort indicates a potential genetic contribution to the etiology of the disease. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to the onset and progression of KD. CLINICAL RELEVANCE: This study suggests that there is a potential genetic contribution to the etiology of KD and that the disease has a significant association with several risk factors.

Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.

Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.

Corticosterone responses change seasonally in free-living house sparrows (Passer domesticus).

Avian corticosterone (CORT) concentrations vary seasonally for many species, but most studies examined species from extreme environments or from only a few times of the year. It is unclear how general a phenomenon this is. We examined both baseline and stress-induced CORT from house sparrows (Passer domesticus) in two habitats-Massachusetts, similar to their ancestral habitat; and New Mexico, a semi-arid desert where the house sparrow only thrives as an obligate human commensal. We captured both males and females during four times of the year-Spring (when the male cloacal protuberance indicated birds were in breeding condition), Fall, Winter, and in the late summer when birds were undergoing a prebasic molt. Birds were heaviest and had the longest wing chord lengths in the Fall at both sites and Massachusetts birds were approximately 10% heavier than New Mexico birds. House sparrows also showed a seasonal variation in the amount of fat stores, but the seasonal pattern differed. Massachusetts birds were fatter overall and showed the most fat during Fall and Winter, whereas New Mexico birds showed the most fat in the Spring. Both baseline and stress-induced total CORT did not differ between sexes or sites, with the exceptions of baseline CORT in the Fall and stress-induced CORT in the Spring being elevated in Massachusetts males. There was a distinct seasonal pattern at both sites, however, with total CORT being highest in the Spring and Winter and lowest during Fall and molt. This seasonal pattern was mirrored in corticosterone binding globulin (CBG) capacities, and when free CORT was estimated, the seasonal pattern disappeared. Stress-induced free CORT, however, was higher in Massachusetts males and females during the Fall and Winter, suggesting a potential differential response to stress associated with commensalism.