Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region [(CAG)n-CAG-CAG]. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36-39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.

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Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available. In this study, we characterize IA frequency and the CAG repeat distribution in fifteen populations of diverse ethnic origin. We estimate the HD new mutation rate in a series of populations using molecular IA expansion rates. The frequency of IAs was highest in Hispanic Americans and Northern Europeans, and lowest in black Africans and East Asians. The prevalence of HD correlated with the frequency of IAs by population and with the proportion of IAs found on the HD-associated A1 haplotype. The HD new mutation rate was estimated to be highest in populations with the highest frequency of IAs. In European ancestry populations, one in 5,372 individuals from the general population and 7.1% of individuals with an expanded CAG repeat in the HD range are estimated to have a molecular new mutation. Our data suggest that the new mutation rate for HD varies substantially between populations, and that IA frequency and haplotype are closely linked to observed epidemiological differences in the prevalence of HD across major ancestry groups in different countries.

Appropriate regulation of genes that coordinate pancreas progenitor proliferation and differentiation is required for pancreas development. Here, we explore the role of H3K4 methylation and the Trithorax group (TrxG) complexes in mediating gene expression during pancreas development. Disruption of TrxG complex assembly, but not catalytic activity, prevented endocrine cell differentiation in pancreas progenitor spheroids. In vivo loss of TrxG catalytic activity in PDX1 + cells increased apoptosis and the fraction of progenitors in the G1 phase of the cell cycle. Pancreas progenitors were reallocated to the acinar lineage, primarily at the expense of NEUROG3 + endocrine progenitors. Later in development, acinar and endocrine cell numbers were decreased, and increased gene expression variance and reduced terminal marker activation in acinar cells led to their incomplete differentiation. These findings demonstrate that TrxG co-activator activity is required for gene induction, whereas TrxG catalytic activity and H3K4 methylation help maintain transcriptional stability.

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Facility and ethical procedures were followed according to protocols approved by the University of British Columbia Animal Care Committee. All mice were maintained on a regular chow diet ad libitum and housed up to 5 mice per cage on a 12-hour light/dark cycle. Timed matings were used to determine embryonic stages and the morning of vaginal plug discovery was considered embryonic day 0.5 (E0.5). Previously generated Dpy30 flox/flox mice ( 22) were crossed to Neurog3-Cre driver mice ( 23) to obtain conditional deletion of Dpy30 exon 4 in endocrine progenitors. In all studies, knockout mice (Dpy30N; Neurog3-Cre; Dpy30 flox/flox ) were compared to Cre-negative littermate controls (Dpy30 flox/flox or Dpy30 flox/wt ). At noon on the day

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Background Patients with inflammatory bowel disease (IBD) post–liver transplant (LT) may have bowel inflammation requiring biologic therapy. We aimed to evaluate the safety of combination biologic and antirejection therapy in IBD patients after LT from a tertiary center case series and an updated literature review. Methods Inflammatory bowel disease patients undergoing LT between 1985 and 2018 and requiring combination biologic and antirejection therapy post-LT were identified from the London Health Sciences Transplant Registry (Ontario, Canada). Safety outcomes were extracted by medical chart review. For an updated literature review, EMBASE, Medline, and CENTRAL were searched to identify studies evaluating the safety of combination biologic and antirejection therapy in IBD patients. Results In the case series, 19 patients were identified. Most underwent LT for primary sclerosing cholangitis (PSC; 14/19, 74%) treated with anti-integrins (8/19, 42%) or tumor necrosis factor α (TNF) antagonists (6/19, 32%). Infections occurred in 11/19 (58%) patients, most commonly Clostridium difficile (4/19, 21%). Two patients required colectomy, and 1 patient required re-transplantation. In the literature review, 13 case series and 8 case reports reporting outcomes for 122 IBD patients treated with biologic and antirejection therapy post-LT were included. PSC was the indication for LT in 97/122 (80%) patients, and 91/122 (75%) patients were treated with TNF antagonists. Infections occurred in 32/122 (26%) patients, primarily Clostridium difficile (7/122, 6%). Conclusions Inflammatory bowel disease patients receiving combination biologic and antirejection therapy post-LT appeared to be at increased risk of Clostridium difficile. Compared with the general liver transplant population in the published literature, there was no increased risk of serious infection.