CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Frontotemporal dementia-amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1-q12.2: genetic, clinical and neuropathological analysis.

Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1-16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1-16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1-q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.

Activity of the bile duct

It is not yet known whether the bilar tree has any function other than conduction of fluid from the canaliculi to the hilum of the liver. In various animals the common bile duct was cannulated and obstructed under anaesthesia. The cystic duct was litigated. After 30 to 60 minutes an injection of various dyes was given intravenously and after a varying period the bile duct was released. Bile was collected in small samples and analysed. Dye was present in high concentration in all the samples collected. Therefore, unless there was always rupture of the duct near the cannula the bile duct is able either to extract dye or to reabsorb water. In some experiments a second injection of radioactive dye was given and from the results are due to a rupture of the duct (AU)

Haemodynamic and spatial patterns of the hepatic vascular system

A brief review of the accepted morphology of the liver relevant to hepatic haemodynamics is given, with a critical account of the methods previously used to study the parameters of hepatic circulation and of the results of such investigations. The theoretical basis of the method to be used in the experiments on the hepatic vascular bed is given. The conditions under which this theory is valid, in a real vascular system, are carefully examined. The method of preparing an isolated perfused canine liver and of recording indicator-dilution curves is described, emphasis being placed on practical considerations. Results of experiments on the pressure-flow relationships in the liver are presented to demonstrate the viability of the presentation. The concept of hepatic vascular 'spaces' and the method of their circulation from the indicator-dilution curves are described in detail. The results of the investigation into the variation of the hepatic vascular 'spaces' with flow rates are presented and the analysis of the variations in term of a regression line, are explained. On the basis of these results a three compartment model of the hepatic vascular system is proposed and the anatomical and theoretical significance of the model is examined. Further considerations of the model suggest certain lines of investigation:- (a) Functional differences between liver regions supplied by the portal vein and hepatic artery. (b) The effect of reversal of the venous circulation through the liver. Both these aspects are investigated and analysed in terms of the proposed model. The correspondence between the model and the accepted anatomy of the liver is examined. Finally the results are considered in comparision with those obtained by other methods and possible extensions of the present work are suggested (AU)