SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

Goodarzi, Mark O.; Lehman, Donna M.; Taylor, Kent D.; Guo, Xiuqing; Cui, Jinrui; Quiñones, Manuel J.; Clee, Susanne M.; Yandell, Brian S.; Blangero, John; Hsueh, Willa A.; Attie, Alan D.; Stern, Michael P.; Rotter, Jerome I.

doi:10.2337/db06-1677

Cited by 92 publications

(67 citation statements)

References 41 publications

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“…As an example, one gene identified by this analysis, SORCS1, has recently been identified as one of many genes where variants contribute to diabetes risk and glycemic control in humans, further demonstrating the utility of this model for understanding human disease. 19,24 A second potential limitation is that this is a mouse model dependent on both strain (BTBR) and leptin deficiency. Overt leptin deficiency is not a characteristic of human diabetes, although the obesity commonly encountered in patients with type 2 diabetes is associated with leptin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…The relatively rapid onset allows opportunities for testing therapeutic strategies aimed at halting or ameliorating DN in a much shorter time span, especially important in the context of working with a model organism that under the best of circumstances has a lifespan of approximately 2 years. 11,18,19 Fourth, there is increasing recognition of an inflammatory component in human and experimental DN, usually characterized by an influx of monocytes/macrophages. Progression of DN in the BTBR ob/ob mouse is also characterized by an influx of monocytes/macrophages.…”

Section: Discussionmentioning

confidence: 99%

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BTBR Ob/Ob Mutant Mice Model Progressive Diabetic Nephropathy

Hudkins

Pichaiwong

Wietecha

et al. 2010

Journal of the American Society of Nephrology

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There remains a need for robust mouse models of diabetic nephropathy (DN) that mimic key features of advanced human DN. The recently developed mouse strain BTBR with the ob/ob leptin-deficiency mutation develops severe type 2 diabetes, hypercholesterolemia, elevated triglycerides, and insulin resistance, but the renal phenotype has not been characterized. Here, we show that these obese, diabetic mice rapidly develop morphologic renal lesions characteristic of both early and advanced human DN. BTBR ob/ob mice developed progressive proteinuria beginning at 4 weeks. Glomerular hypertrophy and accumulation of mesangial matrix, characteristic of early DN, were present by 8 weeks, and glomerular lesions similar to those of advanced human DN were present by 20 weeks. By 22 weeks, we observed an approximately 20% increase in basement membrane thickness and a Ͼ50% increase in mesangial matrix. Diffuse mesangial sclerosis (focally approaching nodular glomerulosclerosis), focal arteriolar hyalinosis, mesangiolysis, and focal mild interstitial fibrosis were present. Loss of podocytes was present early and persisted. In summary, BTBR ob/ob mice develop a constellation of abnormalities that closely resemble advanced human DN more rapidly than most other murine models, making this strain particularly attractive for testing therapeutic interventions. Diabetic nephropathy (DN) is the largest single cause of ESRD in the United States, accounting for nearly half of the patients who enter the dialysis patient population each year and currently accounting for 45% of prevalent kidney failure in the United States. 1-4 Although both type 1 and type 2 diabetes lead to DN, the current epidemic of DN is due to type 2 diabetes; however, understanding the mechanisms that produce the constellation of clinical and pathologic alterations that define DN in humans remains very incomplete, in part because clinical DN is a slowly progressive disease, and relevant animal models that produce this constellation of pathologic and clinical abnormalities have important limitations. Mice rendered hyperglycemic by administration of streptozotocin (STZ) or through genetic predisposition such as the db/db mouse can develop some features of DN, most notably glomerular mesangial expansion, but do so only over prolonged periods and do not progress to ESRD. [5][6][7][8][9] Most murine models to date have failed to develop reliably marked mesangial expansion or the

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BTBR Ob/Ob Mutant Mice Model Progressive Diabetic Nephropathy

Hudkins

Pichaiwong

Wietecha

et al. 2010

Journal of the American Society of Nephrology

Self Cite

205

284

View full text Add to dashboard Cite

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“…The syntenic regions in rats 55 and humans 56 are also associated with fasting insulin levels and insulin secretion. Similarly to the situation in mice, association in humans is strongest in overweight women.…”

Section: Sorcs1 a Diabetes Risk Factor And Regulator Of Insulin Secrmentioning

confidence: 99%

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Schmidt

Willnow

2016

Atherosclerosis

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VPS10P domain receptors are a unique class of sorting receptors that direct intracellular transport of target proteins in neurons and that play central roles in neurodegenerative processes. Surprisingly, genome-wide association studies now implicate the very same receptors in cardiovascular and metabolic disturbances. In this review, we discuss current findings that uncovered some of the molecular mechanisms whereby sorting receptors, such as SORLA, sortilin, and SORCS1 control homeostasis in cardiovascular and metabolic tissues, and how they promote hypercholesterolemia, atherosclerosis, obesity, and diabetes, when being altered.3

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“…This gene codes for a Vsp10p-D receptor family member transmembrane protein, which functions to sort and traffi c proteins ( 32 ). Genetic variation in this gene has been associated with both the development of type II diabetes ( 33,34 ) and risk for development of Alzheimer disease ( 35 ). These two diseases are correlated with serum lipid levels and genetic variation in another Vsp10p-D receptor gene, Sort1 , which has been linked to serum LDL levels ( 36,37 ).…”

Section: Cluster Of Qtl On Distal Chr 19 Can Be Narrowed To a Small Nmentioning

confidence: 99%

Recalculation of 23 mouse HDL QTL datasets improves accuracy and allows for better candidate gene analysis

Ackert‐Bicknell

Paigen

Korstanje

2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org among these different subpopulations are not understood, and the genes responsible for the subpopulation differences among individuals are unknown.Several approaches, including genetic mapping studies, have been used to identify novel genes involved in the regulation of HDL levels. In mice, the technique of quantitative trait locus (QTL) mapping, which uses crosses between different inbred strains of mice, has been heavily employed over the past 15 years. These results have been summarized in several reviews ( 6, 7 ). One limitation of traditional QTL analysis is low mapping resolution, which is a result of the limited genetic recombination possible in onegeneration backcrosses [i.e., A×(A×B)] and two-generation intercrosses [i.e., (A×B)×(A×B)]. The 95% confi dence interval (CI), the interval in which the causative gene is most likely to reside, is usually very broad. For example, one large study of bone mineral density QTL found that the average CI width for traditionally mapped QTL was 32 cM ( 8 ). As it can be assumed that there are, on average, 20 genes per cM ( 9 ), the number of candidate genes per QTL can be very large, making the identifi cation of the causative gene very diffi cult. In the past few years, several methods have been developed that combine accumulated data from the different crosses, allowing for narrowing of the CI for QTL and reducing candidate gene lists ( 10 ). However, the success of these methods heavily depends on the accuracy of the QTL mapping.The current standard genetic map for the mouse is curated and maintained by the Mouse Genome Informatics (MGI) Group at The Jackson Laboratory (www.informatics. jax.org) ( 11 ). Mapping QTL requires accurate genetic map information for both the relative order of markers and the distances between them ( 12 ). Recently, Shifman and colleagues published a new genetic map based on a large population of a heterogeneous stock ( 13 ). Cox and colleagues integrated a total of 7,080 standard, simplesequence length polymorphism (SSLP) markers to this single-nucleotide polymorphism (SNP)-based map, generating a corrected mouse genetic map ( 14 ). This new map Abstract In the past 15 years, the quantitative trait locus (QTL) mapping approach has been applied to crosses between different inbred mouse strains to identify genetic loci associated with plasma HDL cholesterol levels. Although successful, a disadvantage of this method is low mapping resolution, as often several hundred candidate genes fall within the confi dence interval for each locus. Methods have been developed to narrow these loci by combining the data from the different crosses, but they rely on the accurate mapping of the QTL and the treatment of the data in a consistent manner. We collected 23 raw datasets used for the mapping of previously published HDL QTL and reanalyzed the data from each cross using a consistent method and the latest mouse genetic map. By utilizing this approach, we identifi ed novel QTL and QTL that were mapped...

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SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

Cited by 92 publications

References 41 publications

BTBR Ob/Ob Mutant Mice Model Progressive Diabetic Nephropathy

BTBR Ob/Ob Mutant Mice Model Progressive Diabetic Nephropathy

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Recalculation of 23 mouse HDL QTL datasets improves accuracy and allows for better candidate gene analysis

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