A novel duplication of PRMD13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in drosophila eye reproduces the human phenotype.

In this study, we report a novel duplication causing North Carolina macular dystrophy (NCMD) identified applying whole genome sequencing performed on eight affected members of two presumed unrelated families mapping to the MCDR1 locus. In our families, the NCMD phenotype was associated with a 98.4 kb tandem duplication encompassing the entire CCNC and PRDM13 genes and a common DNase 1 hypersensitivity site. To study the impact of PRDM13 or CCNC dysregulation, we used the Drosophila eye development as a model. Knock-down and overexpression of CycC and CG13296, Drosophila orthologues of CCNC and PRDM13, respectively, were induced separately during eye development. In flies, eye development was not affected, while knocking down either CycC or CG13296 mutant models. Overexpression of CycC also had no effect. Strikingly, overexpression of CG13296 in Drosophila leads to a severe loss of the imaginal eye-antennal disc. This study demonstrated for the first time in an animal model that overexpression of PRDM13 alone causes a severe abnormal retinal development. It is noteworthy that mutations associated with this autosomal dominant foveal developmental disorder are frequently duplications always including an entire copy of PRDM13, or variants in one DNase 1 hypersensitivity site at this locus.

Genomic profile of colon cancer metastases.

BACKGROUND: In colon cancer, the occurrence of metastases is associated with microsatellite stability. As metastatic cells derive from a clonal expansion of primary tumor cells, specific genomic alterations are expected in addition to the common genomic profile. PATIENTS AND METHODS: Genome-wide allelotyping was performed on 75 liver metastases samples from sporadic colon cancer. RESULTS: No microsatellite instability was observed. Allelic loss on 5q in metastases was significantly different from that of non metastatic primary tumors (16/58 vs. 43/75, p=0.0008). Four additional chromosomes, 4, 7, 8 and 19, were more frequently lost in liver metastases, but statistical significance was reached only for 19q (14/63 versus 2/68 in primary tumors; p=0.033 after Dunn-Sidak adjustment). CONCLUSION: This study confirms that liver metastasis is rather restricted to patients with microsatellite stable colon cancer and these retain the 5q arm with high frequency. In addition, it suggests that loss of 19q may be critical for one of the steps involved in the development of liver metastases.

Demographic characteristics and quality of life of patients with unexplained complaints: a descriptive study in general practice.

OBJECTIVE: About 13% of GPs' consultations involve unexplained complaints (UCs). These complaints can progress to chronic conditions like medically unexplained symptoms, chronic functional symptoms or somatoform disorders. Little is known about the demographic characteristics and quality of life of patients with early stage UCs. Our study objective was to describe these characteristics. Additionally we compared them with other patient groups to serve as a frame of reference. METHODS: Descriptive study in general practices. Patients with early stage UCs who had not had elaborate diagnostic investigations were included. Demographic characteristics were compared to a Dutch general practice population. Quality of life scores were measured with the RAND-36 and compared to another Dutch general practice population and to depressed patients. RESULTS: Data of 466 patients were available for analysis. Mean age was 44 years and 74% were females, mostly higher educated. Of the patients, 63% presented with unexplained fatigue. On average, quality of life was poor (mean RAND-36 domain scores 37-73), also in comparison with other groups. CONCLUSION: General practice patients presenting with UCs have a remarkably poor quality of life. Future research should explore how early identification of patients at risk of developing chronicity can take place. Awareness of potential poor quality of life may influence GPs' medical decision making.