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Patsy M Nishina

Publications and source records attributed to Patsy M Nishina.

18 recordsLinked to original sources
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

From vivarium to bedside: lessons learned from animal models.

In this review, we focus primarily on information obtained by studying mouse models of heritable ocular diseases. These models have proven to be important in advancing our understanding of disease etiology and of pathological consequences of heritable disorders. Careful phenotypic analyses of these models have lead to hypotheses regarding the function of various molecules as well as the mechanisms underlying the observed pathologies. Specific examples of the utility of mouse models in vision research are discussed.

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

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

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

Spontaneous corneal hem- and lymphangiogenesis in mice with destrin-mutation depend on VEGFR3 signaling.

Lymphangiogenesis, the formation of new lymphatic vessels, is important for tumor metastasis and induction of immunity to peripheral antigens including organ transplants. We herein describe a novel mouse model of spontaneous, secondary lymphangiogenesis in the normally avascular cornea. corn1 mice, which suffer from a deletion in the gene encoding the cytoskeletal protein destrin, develop hemangiogenesis as well as spontaneous outgrowth of LYVE-1+++/CD31+ lymphatic vessels into the cornea starting at age 4 weeks. Corneal lymphangiogenesis is delayed in onset, is less intense, and regresses earlier compared with hemangiogenesis. Moreover, the lymphangiogenesis is preceded only by a mild recruitment of CD45+ inflammatory cells into the cornea. In contrast to mice with inflammation-induced hem- and lymphangiogenesis, corn1 mice do not develop breakdown of the blood-aqueous barrier. Finally, in this novel mouse model, a blocking anti-VEGFR3 antibody significantly inhibited not only lymph- but also hemangiogenesis. In summary, destrin deletion has differential effects on spontaneous hem- and lymphangiogenesis in the normally avascular cornea and represents a novel mouse model to study the mechanisms of lymphangiogenesis and to test the antihem- and antilymphangiogenic properties of known or new antiangiogenic agents.

Actin Depolymerizing Factors↗
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↗
PubMed2003

Progress toward understanding the genetic and biochemical mechanisms of inherited photoreceptor degenerations.

More than 80 genes associated with human photoreceptor degenerations have been identified. Attention must now turn toward defining the mechanisms that lead to photoreceptor death, which occurs years to decades after the birth of the cells. Consequently, this review focuses on topics that offer insights into such mechanisms, including the one-hit or constant risk model of photoreceptor death; topological patterns of photoreceptor degeneration; mutations in ubiquitously expressed splicing factor genes associated only with photoreceptor degeneration; disorders of the retinal pigment epithelium; modifier genes; and global gene expression analysis of the retina, which will greatly increase our understanding of the downstream events that occur in response to a mutation.

Animals↗
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↗
PubMed2002

The tubby-like proteins, a family with roles in neuronal development and function.

The identification of a mutation at the tubby (Tub) locus, which causes obesity and neurosensory degeneration, led to the discovery of the tubby-like proteins (TULPs). Tub and the genes that encode three tubby-like proteins (TULP1- TULP3) form a novel, small gene family that plays an important role in maintenance and function of neuronal cells during development and post-differentiation. Although exploration of the molecular function of these genes is still in its infancy, recent biochemical studies have provided 'entry points' into pathways whose elucidation will further our understanding of TULP action. In addition, mRNA expression and translocation of the TUB protein have been shown to be regulated by thyroid hormone and by G-protein-coupled receptor signaling, respectively. These latter findings may help to link the cellular function of TUB to known mechanisms for energy homeostasis.

Amino Acid Sequence↗
PubMed2002

Genetic modification of retinal degeneration in tubby mice.

Mice that carry the recessive mutation tub develop neurosensory defects including retinal and cochlear degeneration, as well as maturity-onset obesity associated with insulin resistance. The biological function of the gene and the mechanism by which it induces its phenotypes are still unclear. In order to elucidate the pathways through which tub functions, in the current study, QTL modifiers were identified in an F2 intercross between (C57BL/6J- tub/tub and AKR/J-+/+) F1 hybrids (AKR intercross). The thickness of the outer nuclear layer of the retina and the number of photoreceptor nuclei were assessed in F2 mice homozygous for the tub mutation. A genome-wide scan revealed a significant linkage on chromosome 11 (named motr1) and two suggestive linkages on chromosomes 2 and 8. Interestingly, the same chromosome 2 region identified for the hearing modifier of tubby, the moth1 locus, showed a peak lod score of 2.3 for protection from retinal degeneration. This result suggests that the gene responsible for the QTL on chromosome 2 might be involved in a common pathway through which retinal and cochlear degeneration are induced in tubby mice.

Adaptor Proteins, Signal Transducing↗