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Jürgen K Naggert

Publications and source records attributed to Jürgen K Naggert.

At least 19 recordsLinked to original sources
PubMed2007

Characterization of the IGF system in 15 patients with Alström syndrome.

BACKGROUND: Alström syndrome (ALMS) is a rare recessively inherited progressive disease (OMIM 203800). Among its diverse spectrum of clinical features are phenotypes associated with deficiencies of the GH/IGF-I axis, including short stature, obesity, insulin resistance, hypertriglyceridaemia and heart failure. PATIENTS AND MEASUREMENTS: To characterize the IGF system in ALMS, we evaluated a subset of 15 young adults with ALMS for hepatic, renal and thyroid function. Glycaemic and hormone measurements such as insulin, GH, FSH, LH, testosterone and 17-beta-oestradiol were clinically assessed. In addition, we measured IGF-I, IGF-II, IGF binding-protein-3 (IGFBP-3) and acid labile subunit (ALS - the subunits that constitute the main somatomedin complex in the circulation), and IGFBP-1 and IGFBP-2 (known to influence the bioavailability of the IGFs). RESULTS: A significantly lower height was observed in ALMS patients compared to age-matched controls. ALMS patients were clinically obese (by weight and body mass index (BMI) standards) and leptin levels correlated with BMI. Renal and hepatic dysfunction was implicated in some patients by increased values of blood urea nitrogen (BUN) and creatinine, and transaminases, respectively. One-third of the patients presented with fasting hyperglycaemia and 80% were hyperinsulinaemic. TSH was slightly increased in 20% of patients. Baseline FSH and LH in females were within the normal range, while half of the males had abnormally low testosterone values. Male patients with hypogonadism showed significantly lower testosterone, oestrogen and ALS levels. Baseline GH values were not found to be increased. ALS and IGFBP-1 were significantly reduced and IGFBP-2 was markedly increased in ALMS patients compared to age-matched controls. The IGFs and IGFBPs were not significantly different between males and females affected with ALMS. No significant association was observed between IGFs or IGFBPs levels and weight, height, BMI, glycaemia, hyperinsulinaemia and testosterone levels. However, we found a significant association of gamma-glutamyltransferase (GGT) with IGFBP-2. IGF-I levels were significantly associated with LH in female patients. CONCLUSIONS: In summary, the reduction of ALS and the increase of IGFBP-2 points to a growth hormone deficiency (GHD) condition in ALMS. However, further tests, including GH dynamics, are needed to determine whether, or to what degree disturbances in the GH/IGF axis contribute to the relatively short stature.

Adult↗
PubMed2006

Defective carbohydrate metabolism in mice homozygous for the tubby mutation.

Tub is a member of a small gene family, the tubby-like proteins (TULPs), with predominant expression in neurons. Mice carrying a mutation in Tub develop retinal and cochlear degeneration as well as late-onset obesity with insulin resistance. During behavioral and metabolic testing, we found that homozygous C57BL/6J-Tub(tub) mice have a lower respiratory quotient than C57BL/6J controls before the onset of obesity, indicating that tubby homozygotes fail to activate carbohydrate metabolism and instead rely on fat metabolism for energy needs. In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver. Quantitation of liver mRNA levels shows that, during the transition from light to dark period, tubby mice fail to induce glucose-6-phosphate dehydrogenase (G6pdh), the rate-limiting enzyme in the pentose phosphate pathway that normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction. Reduced G6PDH protein levels and enzymatic activity in tubby mice lead accordingly to lower levels of NADPH and reduced glutathione (GSH), respectively. mRNA levels for the lipolytic enzymes acetyl-CoA synthetase and carnitine palmitoyltransferase are increased during the dark cycle and decreased during the light period, and several citric acid cycle genes are dysregulated in tubby mice. Examination of hypothalamic gene expression showed high levels of preproorexin mRNA leading to accumulation of orexin peptide in the lateral hypothalamus. We hypothesize that abnormal hypothalamic orexin expression leads to changes in liver carbohydrate metabolism and may contribute to the moderate obesity observed in tubby mice.

Acetate-CoA Ligase↗
PubMed2006

Phenotypic characterization of polygenic type 2 diabetes in TALLYHO/JngJ mice.

The TALLYHO/JngJ (TH) strain is a newly established, polygenic mouse model for type 2 diabetes (T2D) and obesity, and we have previously reported some key physiological features of this model after the overt onset of diabetes. In the present work, we conducted a comprehensive phenotypic characterization of TH in order to completely characterize this new and relevant model for human T2D and obesity. We monitored the development of obesity and diabetes starting at 4 weeks of age by measuring body weight, glucose tolerance, and plasma levels of insulin, glucose, and triglyceride. Additionally, histological alterations in the pancreas and glucose uptake and glucose transporter 4 (GLUT4) content in soleus muscle were also examined. Compared with age- and sex-matched C57BL/6J (B6) mice, both male and female TH mice were significantly heavier, hyperleptinemic, and hyperinsulinemic at 4 weeks of age, without glucose intolerance or hyperglycemia. TH mice maintained higher body weights throughout the study period of 16 weeks. The hyperinsulinemia in TH mice worsened with age, but to a lesser degree in females than in males. Both the male and the female TH mice had enlarged pancreatic islets. Male TH mice showed impaired glucose tolerance at 8 weeks that became more prominent at 16 weeks. Plasma glucose levels continuously increased with age in male TH mice resulting in frank diabetes, while female TH mice remained normoglycemic throughout the study. Impaired glucose tolerance and hyperglycemia in male TH mice were accompanied by impaired 2-deoxyglucose uptake in the soleus muscle at basal and insulin-stimulated states, but without any reduction in GLUT4 content. Interestingly, male TH mice exhibited a drastic elevation in plasma triglyceride levels in the pre-diabetic stage that was maintained throughout the study. These findings suggest that obesity and insulin resistance are an inherent part of the TH phenotype and glucose intolerance is evident preceding progression to overt diabetes in male TH mice.

Animals↗
PubMed2005

Type 2 diabetes mouse model TallyHo carries an obesity gene on chromosome 6 that exaggerates dietary obesity.

The TallyHo (TH) mouse strain is a polygenic model for Type 2 diabetes with obesity. Genetic analysis in backcross progeny from a cross between F1 [C57BL/6J (B6) x TH] and TH mice mapped a quantitative trait locus (QTL) named TH-associated body weight 2 (tabw2) to chromosome 6. The TH-derived allele is associated with increased body weight. As a first step to identify the molecular basis of this obesity QTL, we constructed a congenic line of mice on the B6 genetic background that carries a genomic region from TH mice containing tabw2. Congenic mice homozygous for tabw2 (B6.TH-tabw2/tabw2) fed a chow diet exhibited slightly, but significantly, higher body weight and body fat and plasma leptin levels compared with controls (B6.TH-+/+). This difference was exacerbated when the animals were maintained on a high-fat and high-sucrose (HFS) diet. The diet-induced obesity in tabw2 congenic mice is accompanied by hyperleptinemia, mild hyperinsulinemia, impaired glucose tolerance, and reduced glucose uptake in adipose tissue in response to insulin administration. Using F2 progeny fed a HFS diet from an intercross of B6.TH-tabw2/+ mice, we were able to refine the map position of the tabw2 obesity susceptibility locus to a 15-cM region (95% confidence interval) extending distally from the marker D6Mit102. In summary, tabw2 congenic mice are a new animal model for diet-induced obesity that will be valuable for the study of gene-diet interactions.

Alleles↗
PubMed2005

Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia.

Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used to dissect the genetic complexity influencing the observed phenotypes. The underlying defect in the fat mutant is a Ser202Pro change in carboxypeptidase E (CPE), an enzyme responsible for the final proteolytic processing step of prohormone intermediates. On the HRS/J (HRS) inbred strain background, mice homozygous for the fat mutation exhibit early onset hyperinsulinemia followed by postpubertal moderate obesity without hyperglycemia. In contrast, on the C57BLKS/J (BKS) genetic background, fat/fat mice become severely obese, hyperinsulinemic, and hyperglycemic. Therefore, in the Cpe(fat) genetic model, the fat mutation is necessary but not sufficient for the development of obesity, Type II diabetes, and related metabolic disorders. To dissect the susceptibility loci responsible for modifying obesity- and diabetes-associated traits, we characterized, both genetically and phenotypically, fat/fat male progeny from a large intercross between BKS. HRS-fat/fat and HRS-+/+ mice. Four major loci were mapped, including a locus for body weight (body weight 1) on chromosome 14; a locus for hyperglycemia (fat-induced diabetes 1) on chromosome 19; a locus for hyperglycemia, hyperinsulinemia, and hypercholesterolemia (fat-induced diabetes 2) on chromosome 5; and a locus for adiposity and body weight (fat-induced adiposity 1) on chromosome 11. The identification of these interacting genetic determinants for obesity and Type II diabetes may allow better definition of the obesity/diabetes-related hormone signaling pathways and ultimately may provide new insights into the pathogenesis of these complex diseases.

Adiposity↗
PubMed2005

New Alström syndrome phenotypes based on the evaluation of 182 cases.

BACKGROUND: Alström syndrome is a recessively inherited genetic disorder characterized by congenital retinal dystrophy that leads to blindness, hearing impairment, childhood obesity, insulin resistance, and type 2 diabetes mellitus. We provide new details on cardiologic, hepatic, gastrointestinal, urologic, pulmonary, and neurobehavioral phenotypes in Alström syndrome and describe the histopathologic findings in 5 individuals. METHODS: We obtained data on 182 patients from clinical examinations, medical record reviews, standardized questionnaires, and personal interviews with physicians and parents. RESULTS: Dilated cardiomyopathy occurred in 60% of patients. Age at onset was either during infancy, often before vision disturbances were noted, or in adolescence or adulthood. There is a risk of recurrence of infantile cardiomyopathy. Hyperinsulinemia (92%) developed in early childhood and progressed to type 2 diabetes mellitus in 82% of those older than 16 years. Hypertriglyceridemia (54%) precipitated pancreatitis in 8 patients. Urologic dysfunction and gastrointestinal disturbances occurred in 48% and 35% of patients, respectively. Fifty-three percent of patients had persistent pulmonary symptoms. Neurologic symptoms in 20% of patients included clonic tic and absence seizures. Developmental motor or language delays were observed in 46% of patients. Fibrotic infiltrations of multiple organs, that is, kidney, heart, liver, lung, urinary bladder, gonads, and pancreas, were observed. CONCLUSIONS: The wide-ranging and complex spectrum of phenotypes reported herein broadens those previously described for Alström syndrome. These findings will aid physicians in making an early and accurate diagnosis and will help effect appropriate monitoring and treatment.

Abnormalities, Multiple↗
PubMed2005

Searching QTL by gene expression: analysis of diabesity.

BACKGROUND: Recent developments in sequence databases provide the opportunity to relate the expression pattern of genes to their genomic position, thus creating a transcriptome map. Quantitative trait loci (QTL) are phenotypically-defined chromosomal regions that contribute to allelically variant biological traits, and by overlaying QTL on the transcriptome, the search for candidate genes becomes extremely focused. RESULTS: We used our novel data mining tool, ExQuest, to select genes within known diabesity QTL showing enriched expression in primary diabesity affected tissues. We then quantified transcripts in adipose, pancreas, and liver tissue from Tally Ho mice, a multigenic model for Type II diabetes (T2D), and from diabesity-resistant C57BL/6J controls. Analysis of the resulting quantitative PCR data using the Global Pattern Recognition analytical algorithm identified a number of genes whose expression is altered, and thus are novel candidates for diabesity QTL and/or pathways associated with diabesity. CONCLUSION: Transcription-based data mining of genes in QTL-limited intervals followed by efficient quantitative PCR methods is an effective strategy for identifying genes that may contribute to complex pathophysiological processes.

Algorithms↗
PubMed2005

Ocular abnormalities in Large(myd) and Large(vls) mice, spontaneous models for muscle, eye, and brain diseases.

Here we demonstrate previously unreported ocular defects in mice homozygous for a new allele of the Large gene, veils, and for Large(myd) mice. Clinically, vitreal fibroplasia and retinal vessel tortuosity and fluorescein leakage are observed. These vascular defects may be due to the extreme disorganization of the astrocytic template on which endothelial cells migrate in the retina. Abnormal electroretinograms recorded from Large(vls) or Large(myd) mice are accompanied by disorganization of the outer plexiform layer (OPL) with a dramatic reduction in the number of synaptic complexes. In both mutants, the internal limiting membrane (ILM) is disrupted with ectopic cells in the vitreous. Interestingly, while all components of the dystrophin glycoprotein complex are present at reduced levels in the OPL, they were absent in the ILM of affected mice. Finally, hypoglycosylation of alpha-dystroglycan previously implicated in muscle and brain defects is also observed in the retina and may contribute to the ocular abnormalities.

Animals↗
PubMed2005

Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis.

A spontaneous single-base mutation in the leptin receptor of type 1 diabetes-prone NOD/LtJ mice (designated as Lepr(db-5J)) produced a glycine640valine transversion in the extracellular domain. All mutant mice became obese and hyperinsulinemic at weaning, with 70-80% developing early-onset hyperglycemia. However, these obese diabetic mice continued to gain weight without insulin therapy. Spontaneous diabetes remission was observed in all obese females and a subset of obese males. Insulitis was largely limited to islet perimeters, with intraislet insulitis infrequently observed. In 17 obese males (age 39 weeks), we observed phenotypic heterogeneity, including full remission from hyperglycemia (24%), intermediate hyperglycemia with elevated body weight (41%), and severe hyperglycemia and weight loss (35%). The remitting normoglycemic and intermediate hyperglycemic phenotypes were associated with extensive beta-cell hyperplasia. Unlike the extensive intraislet insulitis present in diabetic lean NOD/Lt mice, the severe obese diabetic phenotype was associated with islet atrophy without extensive intraislet insulitis. These results indicated that the manipulation of the leptin/leptin receptor axis may provide a novel means of downregulating autoimmunity in type 1 diabetes and confirmed a role for leptin as a mediator in the development of this disease in NOD mice.

Amino Acid Sequence↗
PubMed2003

CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina.

Mutations within the CRB1 gene have been shown to cause human retinal diseases including retinitis pigmentosa and Leber congenital amaurosis. We have recently identified a mouse model, retinal degeneration 8 (rd8) with a single base deletion in the Crb1 gene. This mutation is predicted to cause a frame shift and premature stop codon which truncates the transmembrane and cytoplasmic domain of CRB1. Like in Drosophila crumbs (crb) mutants, staining for adherens junction proteins known to localize to the external limiting membrane, the equivalent of the zonula adherens in the mammalian retina, is discontinuous and fragmented. Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. The Crb1rd8 mouse model will facilitate the analysis of Crb1 function in the neural retina and the identification of interacting factors as candidate retinal disease genes.

Alternative Splicing↗
PubMed2003

Aberrant actin cytoskeleton leads to accelerated proliferation of corneal epithelial cells in mice deficient for destrin (actin depolymerizing factor).

Corneal disease is the most common cause of bilateral blindness in the world. Visual loss in this condition is often due to changes in morphology and function of the corneal epithelial surface. Corneal disease-1 (corn1) and corn1(2J) are spontaneous mouse mutants that develop irregular thickening of the corneal epithelium, similar to that observed in human corneal surface disease. These autosomal-recessive mutations cause an increase in the rate of proliferation of the corneal epithelial cells. Here, we report that the phenotypes in both mutants are caused by mutations within the destrin gene (also known as actin-depolymerizing factor). By positional cloning, we identified a deletion encompassing the entire coding sequence of the destrin gene in corn1 mice, and a point mutation (Pro106Ser) in the coding sequence of destrin in corn1(2J) mice. In situ analysis showed that destrin is highly expressed in the corneal epithelium. Consistent with the cellular roles for destrin, an essential regulator of actin filament turnover that acts by severing and enhancing depolymerization of actin filament, we observed that the corn1 mutations increased the content of filamentous actin in corneal epithelial cells. Our results suggest an in vivo connection between remodeling of the actin cytoskeleton and the control of cell proliferation, and a new pathway through which an aberrant actin cytoskeleton can cause epithelial hyperproliferation.

Actin Depolymerizing Factors↗
PubMed2003

Mouse genetic approaches to access pathways important in retinal function.

The laboratory mouse is a premier research tool for understanding human biology and disease. With the availability of the first complete draft sequences of the mouse genome and ongoing large scale screens for new mouse mutations to serve as novel models, the usefulness of the mouse will only increase. The vision research field, in particular, which has identified many human diseases for which no models are yet available, will benefit from the newly developed tools in mouse molecular genetics.

Animals↗
PubMed2003

New leptin receptor mutations in mice: Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy).

Three new spontaneous recessive mouse mutations in the leptin receptor gene (Lepr), Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy), originated in the CBA/J (CBA), B10.D2-H8(b)(57N)/Sn (B10) and NU/J strains, respectively. Lepr(db-rtnd) and Lepr(db-dmpg) were maintained on C57BL/6J (B6), resulting in congenic lines of B6.CBA-Lepr(db-rtnd) and B6.B10-Lepr(db-dmpg). Lepr(db-rtnd) was also maintained on CBA post F1 generation of a cross between the B6 and the CBA, generating the congenic line CBA.B6CBA-Lepr(db-rtnd). Lepr(db-rlpy) was maintained as a coisogenic strain. The aims of this study were to determine the molecular bases for these new Lepr mutations and to characterize the new mutant stocks, with respect to obesity and diabetes. Mutations were analyzed by Southern blot analysis, reverse transcriptase-polymerase chain reaction and sequencing. Body weights and plasma glucose and insulin levels were measured, and the histology of the pancreas was carried out. Lepr(db-rtnd) contained one G deletion in exon 4 of Lepr, introducing a frameshift and premature termination. Lepr(db-dmpg) had a deletion in the extracellular domain of LEPR: Lepr(db-rlpy) exhibited a large DNA deletion, leading to a complete lack of LEPR: All three mutations led to morbid obesity and diabetes. It is noteworthy that Lepr(db-rtnd) caused milder hyperglycemia accompanied by higher plasma and pancreatic insulin contents on B6 compared to that on CBA backgrounds. In summary, we discovered three new mutations of Lepr, providing new mouse models for obesity and diabetes. Furthermore, our mutant stocks will be useful in elucidating the effects of the genetic background on the Lepr mutations and in testing the specificity of antibodies to LEPR.

Amino Acid Sequence↗
PubMed2002

Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6.

The autosomal recessive mouse mutation retinal degeneration 6 (rd6) causes small, white retinal spots and progressive photoreceptor degeneration similar to that observed in human flecked retinal diseases. Using a positional cloning approach, we determined that rd6 mice carry a splice donor mutation in the mouse homolog of the human membrane-type frizzled-related protein (Mfrp) gene that results in the skipping of exon 4. We found that mRNA of Mfrp is predominantly expressed in the eye, and at a lower level in the brain. To determine where in the eye Mfrp is expressed, in situ hybridization was done and showed that Mfrp is expressed specifically in the retinal pigment epithelium (RPE) and ciliary epithelium of the eye. The deduced amino acid sequence of MFRP contains a region with similarities to the cysteine-rich domain (CRD) of frizzled, a gene originally found in Drosophila that controls tissue polarity. The CRD is essential for Wnt binding and signaling. Wnt signaling has been shown to be involved in the control of gene expression, cell adhesion, planar polarity, proliferation and apoptosis. We also observed the localization of Wnt family proteins in the apical membrane of the RPE. Our results provide genetic evidence for an involvement of the Mfrp gene expressed by RPE in the degeneration of photoreceptors.

Amino Acid Sequence↗
PubMed2002

Genetic modifiers of vision and hearing.

The identification of 'disease genes' and the mutations within them has greatly enhanced our understanding of normal function in the eye and ear. At the same time, it has become clear that these single-gene mutations must reside in a permissive genetic background for a disease phenotype to manifest. Segregating background genes can also modify the age of onset, rate of progression or severity of these diseases. These background genes that interact with the disease mutation and that are responsible for the specific phenotypes observed are commonly called genetic modifiers. Identification of these modifier genes may define the biological pathways that lead from the primary genetic defect to the aberrant phenotype. Once the identities of modifier genes that suppress vision or hearing loss become known, the door opens to new potential therapeutic targets, since these modifier genes may be more amenable to treatment than the primary mutant gene.

Animals↗
PubMed2002

Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome.

Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alström syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alström syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alström syndrome and the common diseases that characterize it.

Amino Acid Sequence↗
PubMed2002

Microtubule-associated protein 1A is a modifier of tubby hearing (moth1).

Once a mutation in the gene tub was identified as the cause of obesity, retinal degeneration and hearing loss in tubby mice, it became increasingly evident that the members of the tub gene family (tulps) influence maintenance and function of the neuronal cell lineage. Suggested molecular functions of tubby-like proteins include roles in vesicular trafficking, mediation of insulin signaling and gene transcription. The mechanisms through which tub functions in neurons, however, have yet to be elucidated. Here we report the positional cloning of an auditory quantitative trait locus (QTL), the modifier of tubby hearing 1 gene (moth1), whose wildtype alleles from strains AKR/J, CAST/Ei and 129P2/OlaHsd protect tubby mice from hearing loss. Through a transgenic rescue experiment, we verified that sequence polymorphisms in the neuron-specific microtubule-associated protein 1a gene (Mtap1a) observed in the susceptible strain C57BL/6J (B6) are crucial for the hearing-loss phenotype. We also show that these polymorphisms change the binding efficiency of MTAP1A to postsynaptic density molecule 95 (PSD95), a core component in the cytoarchitecture of synapses. This indicates that at least some of the observed polymorphisms are functionally important and that the hearing loss in C57BL/6J-tub/tub (B6-tub/tub) mice may be caused by impaired protein interactions involving MTAP1A. We therefore propose that tub may be associated with synaptic function in neuronal cells.

Adaptor Proteins, Signal Transducing↗