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  • 1
    Publication Date: 2012-05-11
    Description: Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has a familial cause in 10% of patients. Despite significant advances in the genetics of the disease, many families remain unexplained. We performed whole-genome sequencing in five family members from a pedigree with autosomal-dominant classical ALS. A family-based elimination approach was used to identify novel coding variants segregating with the disease. This list of variants was effectively shortened by genotyping these variants in 2 additional unaffected family members and 1500 unrelated population-specific controls. A novel rare coding variant in SPAG8 on chromosome 9p13.3 segregated with the disease and was not observed in controls. Mutations in SPAG8 were not encountered in 34 other unexplained ALS pedigrees, including 1 with linkage to chromosome 9p13.2–23.3. The shared haplotype containing the SPAG8 variant in this small pedigree was 22.7 Mb and overlapped with the core 9p21 linkage locus for ALS and frontotemporal dementia. Based on differences in coverage depth of known variable tandem repeat regions between affected and non-affected family members, the shared haplotype was found to contain an expanded hexanucleotide (GGGGCC) n repeat in C9orf72 in the affected members. Our results demonstrate that rare coding variants identified by whole-genome sequencing can tag a shared haplotype containing a non-coding pathogenic mutation and that changes in coverage depth can be used to reveal tandem repeat expansions. It also confirms (GGGGCC)n repeat expansions in C9orf72 as a cause of familial ALS.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2015-04-28
    Description: The congenital disorders of glycosylation (CDG), a group of inherited diseases characterized by aberrant glycosylation, encompass a wide range of defects, including glycosyltransferases, glycosidases, nucleotide-sugar transporters as well as proteins involved in maintaining Golgi architecture, pH and vesicular trafficking. Mutations in a previously undescribed protein, TMEM165, were recently shown to cause a new form of CDG, termed TMEM165-CDG. TMEM165-CDG patients exhibit cartilage and bone dysplasia and altered glycosylation of serum glycoproteins. We utilized a morpholino knockdown strategy in zebrafish to investigate the physiologic and pathogenic functions of TMEM165. Inhibition of tmem165 expression in developing zebrafish embryos caused craniofacial abnormalities, largely attributable to fewer chondrocytes. Decreased expression of several markers of cartilage and bone development suggests that Tmem165 deficiency alters both chondrocyte and osteoblast differentiation. Glycomic analysis of tmem165 morphants also revealed altered initiation, processing and extension of N -glycans, paralleling some of the glycosylation changes noted in human patients. Collectively, these findings highlight the utility of zebrafish to elucidate pathogenic mechanisms associated with glycosylation disorders and suggest that the cartilage and bone dysplasia manifested in TMEM165-CDG patients may stem from abnormal development of chondrocytes and osteoblasts.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2014-09-30
    Description: Aims Symptoms and symptom burden have a central place in diagnosis and management of atrial fibrillation (AF). The aim of the present study is to investigate whether severity of AF symptoms impacts prognosis in permanent AF. Methods and results We studied the relation between AF symptom severity [quantified with the Toronto AF Severity Scale (AFSS)] and cardiovascular outcome in patients included in the RACE II study. The primary endpoint was a composite of cardiovascular morbidity and mortality. Secondary outcome was cardiovascular hospitalizations. Of 614 permanent AF patients in RACE II, AFSS questionnaires were available in 558 patients (91%). Mean age was 68 ± 8 years. One hundred and seventy-four patients (31%) reported a low score (score 0–3; lowest tertile), 190 patients (34%) reported a moderate score (score 4–9; middle tertile), and 194 (35%) reported a high score (score 10–35; highest tertile). Patients with the most severe symptoms were more often women, had higher N-terminal prohormone of brain natriuretic peptide concentrations, and had more previous heart failure hospitalizations. Median follow-up was 3.0 (interquartile range 2.3–3.0) years. The primary endpoint occurred most frequently in the highest tertile of the AFSS [16 (9%), 19 (10%), 36 (19%), respectively, P = 0.01], being mainly driven by heart failure hospitalizations [4 (2%), 1 (1%), 16 (8%), respectively, P 〈 0.001]. After multivariable adjustment, higher AFSS scores were associated with the primary endpoint [hazard ratio 1.38 (1.15–1.66), P = 0.001], as well as with cardiovascular hospitalizations [hazard ratio 1.33 (1.14–1.54), P 〈 0.001]. Conclusion In permanent AF, after multivariable adjustment, symptom severity is associated with cardiovascular outcome.
    Print ISSN: 1099-5129
    Electronic ISSN: 1532-2092
    Topics: Medicine
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