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Biomedical subjects

D J Marsh

Publications and source records attributed to D J Marsh.

At least 19 recordsLinked to original sources
PubMed2001

Male breast cancer in Cowden syndrome patients with germline PTEN mutations.

Cowden syndrome (CS) (OMIM 158350) is a multiple hamartoma syndrome associated with germline mutations in the PTEN tumour suppressor gene. While CS is characterised most commonly by non-cancerous lesions (mucocutaneous trichilemmomas, acral and palmoplantar keratoses, and papillomatous papules), it is also associated with an increased susceptibility to breast cancer (in females) and thyroid cancer, as well as non-cancerous conditions of the breast and thyroid. Here we report two cases of male breast cancer occurring in patients with classical CS phenotypes and germline PTEN mutations. The first subject was diagnosed with CS indicated primarily by mucocutaneous papillomatosis, facial trichilemmomas, and macrocephaly with frontal bossing at the age of 31 years. He developed breast cancer at 41 years and subsequently died of the disease. A PTEN mutation, c.802delG, was identified in this subject, yet none of his family members showed evidence of a CS phenotype, suggesting that this PTEN mutation may be a de novo occurrence. The second subject had a CS phenotype including multiple trichilemmomas and thyroid adenoma, developed male breast cancer at 43 years, and died of the disease at 57 years. He was a carrier of a PTEN mutation c.347-351delACAAT that cosegregated with the CS phenotype in affected family members. These two cases of male breast cancer associated with germline PTEN mutations and the CS phenotype suggest that CS may be associated with an increased risk of early onset male as well as female breast cancer.

Adult↗
PubMed2001

Hamartoma and lentiginosis syndromes: clinical and molecular aspects.

The classic hamartoma syndromes and the related conditions discussed in this chapter show varying degrees of phenotypic and genetic overlap. Knowledge of the susceptibility genes underlying their phenotypes has provided additional information for the classification of these syndromes. Germline PTEN mutations appear to cause both CS and BRR. These two syndromes are therefore likely to be different manifestations of a single disease with variable expression. It has been suggested that PTEN mutation-positive CS and BRR should be grouped as a single entity for clinical purposes and classified as the 'PTEN hamartoma-tumour syndrome' [111]. Germline PTEN mutations are unlikely to cause JPS. However, germline SMAD4 mutation, especially a well-described 4-bp deletion, can be used to confirm a clinical diagnosis of JPS. Like the hamartoma syndromes, the lentiginoses also show substantial clinical overlap; it remains to be seen whether this is reflected in the molecular pathways that are involved in the pathogenesis of these syndromes. Given that the degree and type of cancer susceptibility between the hamartoma and lentiginosis syndromes is different, clarification of these syndromes at the molecular level is predicted to allow directed cancer surveillance. The molecular story is still evolving with regards to aspects of genetic heterogeneity, signalling pathways and the manner in which these hamartoma genes function in the development of their respective syndromes. It is likely that in all of these syndromes, tumours develop against a background created by loss of the growth-suppressive function of their susceptibility gene via mechanisms including disruption of the cell cycle and the activation of anti-apoptotic pathways.

Chromosome Mapping↗
PubMed2000

Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p.

Pheochromocytomas are tumors of the adrenal medulla originating in the chromaffin cells derived from the neural crest. Ten % of these tumors are associated with the familial cancer syndromes multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and rarely, neurofibromatosis type 1, in which germ-line mutations have been identified in RET, VHL, and NF1, respectively. In both the sporadic and familial form of pheochromocytoma, allelic loss at 1p, 3p, 17p, and 22q has been reported, yet the molecular pathogenesis of these tumors is largely unknown. Allelic loss at chromosome 1p has also been reported in other endocrine tumors, such as medullary thyroid cancer and tumors of the parathyroid gland, as well as in tumors of neural crest origin including neuroblastoma and malignant melanoma. In this study, we performed fine structure mapping of deletions at chromosome 1p in familial and sporadic pheochromocytomas to identify discrete regions likely housing tumor suppressor genes involved in the development of these tumors. Ten microsatellite markers spanning a region of approximately 70 cM (1pter to 1p34.3) were used to screen 20 pheochromocytomas from 19 unrelated patients for loss of heterozygosity (LOH). LOH was detected at five or more loci in 8 of 13 (61%) sporadic samples and at five or more loci in four of five (80%) tumor samples from patients with multiple endocrine neoplasia type 2. No LOH at 1p was detected in pheochromocytomas from two VHL patients. Analysis of the combined sporadic and familial tumor data suggested three possible regions of common somatic loss, designated as PC1 (D1S243 to D1S244), PC2 (D1S228 to D1S507), and PC3 (D1S507 toward the centromere). We propose that chromosome 1p may be the site of at least three putative tumor suppressor loci involved in the tumorigenesis of pheochromocytomas. At least one of these loci, PC2 spanning an interval of <3.8 cM, is likely to have a broader role in the development of endocrine malignancies.

Adolescent↗
PubMed2000

A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors.

Melanocortin-4 receptor (Mc4r)-null mice exhibit late-onset obesity. To determine whether aberrant metabolism contributes to the obesity, food consumption by Mc4r-null mice was restricted to (pair-fed to) that consumed by wild-type (WT) mice. Pair-fed Mc4r-null females maintained body weights intermediate to that of WT and nonpair-fed Mc4r-null females, whereas pairfeeding normalized the body weights of Mc4r-null male mice. Fat pad and circulating leptin levels were elevated in both male and female pair-fed Mc4r-null mice compared with WT mice. Oxygen consumption of Mc4r-null mice with similar body weights as WT controls was reduced by 20%. Locomotor activity of young nonobese Mc4r-null males was significantly lower than that of WT males; however, locomotion of young nonobese females was normal. Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure. Young nonobese Mc4r-null females were unable to induce uncoupling protein 1 (UCP1) in brown adipose tissue in response to peripheral leptin administration, whereas UCP1 mRNA was increased by 60% in the WT females. These results indicate that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in melanocortin-3 receptor-null mice.

Animals↗
PubMed2000

Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis.

Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumour syndromes, and somatic PTEN alterations have been shown to participate, to a greater or lesser extent, in a wide variety of sporadic neoplasia. PTEN is a tumour suppressor and dual-specificity phosphatase which affects apoptosis via its lipid phosphatase activity in the phosphoinositol-3-kinase and AKT pathway as well as inhibiting cell spreading via the focal adhesion kinase pathway. CS and BRR share some features, such as hamartomas and lipomatosis. To determine whether other syndromes characterized by overgrowth and lipomas are part of the PTEN syndrome spectrum, we ascertained six individuals with overgrowth and lipomas but who did not meet the diagnostic criteria for CS or BRR. Five had Proteus syndrome and one, a Proteus-like syndrome. When germline DNA and DNA from at least one involved tissue per case were examined for PTEN mutations, only the Proteus-like patient was found to harbour a germline R335X mutation. Interestingly, a lipomatous mass, an epidermoid naevus and arteriovenous malformation tissue, all of which were sampled from physically distinct sites, were all found to carry a second hit R130X mutation on the allele opposite the germline R335X. Both mutations have been described in CS and BRR. We postulate that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future.

Arteriovenous Malformations↗
PubMed2000

Neuropeptide Y (NPY) potentiates phenylephrine-induced mitogen-activated protein kinase activation in primary cardiomyocytes via NPY Y5 receptors.

Neuropeptide Y (NPY) has been shown to participate in the cardiovascular response mediated by the sympathetic system. In this report, we investigate the growth factor properties of NPY on cardiac myocytes. Mitogen-activated protein kinases (MAPK) are key signaling molecules in the transduction of trophic signals. Therefore, the role of NPY in inducing MAPK activation was studied in mouse neonatal cardiomyocytes. Exposure of neonatal cardiomyocytes to either NPY, phenylephrine, or angiotensin II induces a rapid phosphorylation of the extracellular responsive kinase, the c-jun N-terminal kinase, and the p38 kinase as well as an activation of protein kinase C (PKC). Moreover, NPY potentiates phenylephrine-induced MAPK and PKC stimulation. In contrast, NPY has no synergistic effect on angiotensin II-stimulated MAPK phosphorylation or PKC activity. NPY effects are pertussis toxin-sensitive and calcium-independent and are mediated by NPY Y5 receptors. Taken together, these results suggest that NPY, via G(i) protein-coupled NPY Y5 receptors, could participate in the development of cardiac hypertrophy during chronic sympathetic stimulation by potentiating alpha-adrenergic signals.

Angiotensin II↗
PubMed2000

Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors.

Germline mutations in PTEN (MMAC1/TEP1) are found in patients with Cowden syndrome, a familial cancer syndrome which is characterized by a high risk of breast and thyroid neoplasia. Although somatic intragenic PTEN mutations have rarely been found in benign and malignant sporadic thyroid tumors, loss of heterozygosity (LOH) has been reported in up to one fourth of follicular thyroid adenomas (FAs) and carcinomas. In this study, we examined PTEN expression in 139 sporadic nonmedullary thyroid tumors (55 FA, 27 follicular thyroid carcinomas, 35 papillary thyroid carcinomas, and 22 undifferentiated thyroid carcinomas) using immunohistochemistry and correlated this to the results of LOH studies. Normal follicular thyroid cells showed a strong to moderate nuclear or nuclear membrane signal although the cytoplasmic staining was less strong. In FAs the neoplastic nuclei had less intense PTEN staining, although the cytoplasmic PTEN-staining intensity did not differ significantly from that observed in normal follicular cells. In thyroid carcinomas as a group, nuclear PTEN immunostaining was mostly weak in comparison with normal thyroid follicular cells and FAs. The cytoplasmic staining was more intense than the nuclear staining in 35 to 49% of carcinomas, depending on the histological type. Among 81 informative tumors assessed for LOH, there seemed to be an associative trend between decreased nuclear and cytoplasmic staining and 10q23 LOH (P = 0.003, P = 0.008, respectively). These data support a role for PTEN in the pathogenesis of follicular thyroid tumors.

Cell Nucleus↗
PubMed2000

Neurobiological responses to ethanol in mutant mice lacking neuropeptide Y or the Y5 receptor.

We have previously shown that voluntary ethanol consumption and resistance are inversely related to neuropeptide Y (NPY) levels in NPY-knockout (NPY -/-) and NPY-overexpressing mice. Here we report that NPY -/- mice on a mixed C57BL/6Jx129/SvEv background showed increased sensitivity to locomotor activation caused by intraperitoneal (ip) injection of 1.5 g/kg of ethanol, and were resistant to sedation caused by a 3.5-g/kg dose of ethanol. In contrast, NPY -/- mice on an inbred 129/SvEv background consumed the same amount of ethanol as wild-type (WT) controls at 3%, 6%, and 10% ethanol, but consumed significantly more of a 20% solution. They exhibited normal locomotor activation following a 1.5-g/kg injection of ethanol, and displayed normal sedation in response to 2.5 and 3.0 g/kg of ethanol, suggesting a genetic background effect. Y5 receptor knockout (Y5 -/-) mice on an inbred 129/SvEv background showed normal ethanol-induced locomotor activity and normal voluntary ethanol consumption, but displayed increased sleep time caused by 2.5 and 3.0 g/kg injection of ethanol. These data extend previous results by showing that NPY -/- mice of a mixed C57BL/6Jx129/SvEv background have increased sensitivity to the locomotor activation effect caused by a low dose of ethanol, and that expression of ethanol-related phenotypes are dependent on the genetic background of NPY -/- mice.

Alcohol Drinking↗
PubMed2000

Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.

We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.

Animals↗
PubMed2000

Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.

Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.

Adipose Tissue↗
PubMed2000

Detection of apical Na(+)/H(+) exchanger activity inhibition in proximal tubules induced by acute hypertension.

We previously showed that acute arterial hypertension induces an inhibition of fluid and NaCl reabsorption in proximal tubules of Sprague-Dawley rats, which is associated with a rapid reversible internalization of apical Na(+)/H(+) exchanger in brush border. To determine whether there is a corresponding inhibition of apical Na(+)/H(+) exchanger activity in proximal tubules to account for the reduced tubular reabsorption, an instrument capable of measuring intracellular pH (pH(i)) ratiometrically and repeatedly on the surface of kidney with high temporal resolution is required. We report the design and validation of such a fluorimetric system based on two ultraviolet nitrogen-pulsed lasers and a photomultiplier. pH(i) of proximal tubules in situ was measured with pH-sensitive fluorescence dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein at 5 Hz. Using the initial rate of change of pH(i) (dpH(i)/dt) during luminal Na(+) removal as an index of apical Na(+)/H(+) exchanger activity, the exchanger activity was found to be reduced by 52 +/- 11% (n = 14, P < 0.05) compared with the baseline after 20 min of induced acute hypertension. The inhibition of Na(+)/H(+) exchange activity was alleviated when the blood pressure was returned to prehypertensive level. These observations indicate that acute changes in arterial pressure can reversibly inhibit apical Na(+)/H(+) exchanger activity, which might contribute to pressure natriuresis in proximal tubule.

Acute Disease↗
PubMed1999

Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues.

Central administration of neuropeptide Y (NPY) potently induces feeding and its abundance in the hypothalamus increases when energy stores fall. Consequently, NPY is considered to be a physiological effector of feeding behavior. Surprisingly, NPY-deficient (NPY-/-) mice feed and grow normally with ad libitum access to food and manifest a normal hyperphagic response after fasting, suggesting that other feeding effectors may compensate for the lack of NPY. Agouti-related protein (AgRP), a melanocortin receptor antagonist, can also stimulate feeding behavior when administered centrally and is coexpressed in a majority of hypothalmamic NPY-ergic neurons, making AgRP a candidate compensatory factor. To test this possibility, we evaluated AgRP mRNA and protein expression, as well as responsiveness to centrally administered AgRP in NPY-/- mice. These studies demonstrate that hypothalamic AgRP mRNA and immunoreactivity are upregulated with fasting and that these increases are not affected by NPY deficiency. Interestingly, NPY-/- mice are hypersensitive to central administration of AgRP(83-132), yet exhibit a normal response to centrally administered MTII, a melanocortin receptor agonist. These data suggest that if AgRP compensates for the lack of NPY in NPY-/- mice, it is not at the level of AgRP synthesis and may instead involve alterations in the postsynaptic signaling efficacy of AgRP. Moreover, the effects of AgRP are not limited to its actions at the melanocortin-4 receptor (MC4R), because MC4R-deficient (MC4R-/-) mice manifest a significant response to centrally administered AgRP. These data imply that AgRP has additional targets in the hypothalamus.

Agouti-Related Protein↗
PubMed1999

Role of the Y5 neuropeptide Y receptor in limbic seizures.

Neuropeptide Y (NPY) is an inhibitory neuromodulator expressed abundantly in the central nervous system that is suspected of being an endogenous antiepileptic agent that can control propagation of limbic seizures. Electrophysiological and pharmacological data suggest that these actions of NPY are mediated by G protein-coupled NPY Y2 and NPY Y5 receptors. To determine whether the NPY Y5 receptor (Y5R) is required for normal control of limbic seizures, we examined hippocampal function and responsiveness to kainic acid-induced seizures in Y5R-deficient (Y5R-/-) mice. We report that Y5R-/- mice do not exhibit spontaneous seizure-like activity; however, they are more sensitive to kainic acid-induced seizures. Electrophysiological examination of hippocampal slices from mutant mice revealed normal function, but the antiepileptic effects of exogenously applied NPY were absent. These data demonstrate that Y5R has an important role in mediating NPY's inhibitory actions in the mouse hippocampus and suggest a role for Y5R in the control of limbic seizures.

Animals↗
PubMed1999

Long-chain L 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency does not appear to be the primary cause of lipid myopathy in patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS).

In order to test the hypothesis that long-chain L 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is associated with the lipid myopathy and muscle carnitine deficiency observed in Bannayan-Riley-Ruvalcaba syndrome (BRRS), we studied the enzyme activity in cultured skin fibroblasts from three generations of a family with a clear dominant inheritance of BRRS. Enzyme activities were normal while the germline PTEN missense mutation P246L segregated with BRRS in this family. No PTEN mutations were identified in the original patient with BRRS and LCHAD deficiency. These data suggest that the previously reported case of LCHAD and BRRS either represents the coincidental concurrence of two rare genetic events or that a gene other than PTEN is related to LCHAD and BRRS.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation.

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C > T; S836S) occurred at a significantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P = 0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P = 0.01). These findings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.

Carcinoma, Medullary↗
PubMed1999

Time-dependent alteration of insulin-like growth factor gene expression during nerve regeneration in regions of muscle enriched with neuromuscular junctions.

Insulin-like growth factors (IGFs) increase the rate of motor axon elongation, prevent motoneuron death, and may support the reestablishment of synapses following nerve injury. In situ hybridization was used in the present study to examine the temporal and spatial distribution of IGF gene expression in soleus muscle following sciatic nerve crush in rats. In intact muscle, IGF-II gene expression was generally low, and localized to interstitial cells, possibly fibroblast and Schwann cells. These cells were found in the middle of muscle which is enriched in neuromuscular junctions. IGF-II gene expression, 4-6 days postcrush, was increased in interstitial cells. Thereafter, IGF-II gene expression was also increased in muscle cells or cells closely associated with muscle fibers, such as satellite cells. IGF-II gene expression was increased to a much greater extent in the midregion of muscle enriched in end-plates than in the two ends of muscle, but returned towards normal following the reestablishment of functional synapses. On the other hand, IGF-I gene expression was only slightly increased following nerve crush, and this increase was associated with interstitial, but not muscle cells. These results show that the IGF-I and IGF-II genes are regulated by independent signals and may play separate roles during nerve regeneration. For example, a regional increase in IGF-II gene expression may support preferential nerve terminal sprouting in the middle of muscle enriched in neuromuscular junctions, thereby increasing the probability for the reestablishment of synapses.

Animals↗
PubMed1999

Insulin-like growth factor-II increases and IGF is required for postnatal rat spinal motoneuron survival following sciatic nerve axotomy.

The prolonged disconnection of nerve from muscle results in the death of motoneurons and permanent paralysis. Because clinical nerve injuries generally involve postbirth motoneurons, there is interest in uncovering factors that may support their survival. A rich history of research dating back to the time of Santiago Ramon y Cajal and Viktor Hamburger supports the inference that there are soluble neurotrophic factors associated with nerve and muscle. However, the endogenous factors normally required for motoneuron survival following nerve injury have eluded identification. Two interrelated hypotheses were tested: (1) administration of insulin-like growth factor-II (IGF-II) can support the survival of postbirth motoneurons, and (2) endogenous IGFs are essential for motoneuron survival following nerve injury. We report that IGF-II locally administered close to the proximal nerve stump prevented the death of motoneurons (estimated by relative numbers of neuronal profiles) which ordinarily follows sciatic nerve transection in neonatal rats. By contrast, anti-IGF antiserum, as well as IGF binding proteins-4 and -6, significantly increased (P < 0.01) motoneuron death. This report shows that IGF-II can support survival, and contains the novel observation that endogenous IGF activity in or near nerves is required for motoneuron survival. Other studies have determined that IGF gene and protein expression are increased in nerve and muscle following sciatic nerve crush, and that IGFs are required for nerve regeneration. Taken together, these data show that IGFs are nerve- and muscle-derived soluble factors that support motoneuron survival as well as nerve regeneration.

Animals↗