Medical University of Graz

About: Medical University of Graz is a education organization based out in Graz, Steiermark, Austria. It is known for research contribution in the topics: Population & Medicine. The organization has 5684 authors who have published 12349 publications receiving 417282 citations.

Seven‐point checklist of dermoscopy revisited

Abstract: Summary Background Most dermoscopic algorithms to diagnose melanoma were established more than 10 years ago and have been tested primarily on clear-cut melanomas and excised melanocytic naevi. Objectives To assess the diagnostic performance of pattern analysis and seven-point checklist on lesions that reflect the current clinical setting, compared with a revised seven-point checklist with a lower threshold for excision. Methods Eight experienced dermatologists viewed dermoscopic images of 100 excised melanomas, 100 excised naevi and 100 monitored naevi. Each lesion was evaluated by pattern analysis and scored as naevus, melanoma or lesion to be excised. Images were then evaluated using the seven-point criteria, with both standard and revised thresholds for excision. Results Pooled data using the pattern analysis algorithm showed that 82% of melanomas and 87·5% of monitored naevi were correctly scored as lesion to be excised and benign naevus, respectively. Using the standard and revised thresholds for the seven-point checklist, excision was recommended for 77·9% and 87·8% of the lesions in the melanoma set, respectively. The standard threshold produced ‘no excision’ recommendations for 85·6% of the monitored naevi, compared with 74·5% using the revised threshold. Pattern analysis, standard seven-point and revised seven-point algorithms resulted in recommendations of ‘excision’ for 63·6%, 60·3% and 72·0% of the excised naevi, respectively. Conclusions The diagnostic approach to naevi and melanoma should be adapted to the current clinical setting, in which patients may present with early-stage melanomas and multiple atypical naevi. To increase sensitivity, a revised seven-point checklist with a lower threshold for excision should be used.

Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease

Abstract: Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4∗), c.652C>T (p.Arg218∗), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218∗) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.