Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease

Background and aimsNon-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes.MethodsExome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison to healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis and molecular expression arrays.ResultsWe identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion compared to wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators and production of reactive oxygen species.ConclusionWe have identified and characterized a rare causal variant in MTTP and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinemia. Our findings provide insights into mechanisms driving progressive NAFLD

Design Strategy from the Population Perspective

The population perspective on organizational change downplays the consequences of managerial action and focuses on populations rather than on single organizations as evolving units. The population perspective is useful in suggesting broad classes of design strategies. Using this perspective, we argue that models of organizational change must accurately represent the diversity of units studied, be based on tests of alternative explanations, and explicitly incorporate organizational dynamics. Moreover, designs must take account of five empirical generalizations about organizations: individuals' intentions are not a good guide to organizational outcomes, environments are difficult to describe with typologies of a few attributes, designs are a joint product of organizational forms and environmental characteristics, population effects are as important as individual intentions, and environmental trends are increasingly short-lived. We present a simple classification of four categories of macro environments and draw inferences about the kinds of design strategies appropriate in each. We conclude with a strategy of design strategies: questions and issues to consider before beginning detailed planning.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69050/2/10.1177_014920638401000106.pd