Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.

BACKGROUND: Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in WDR73 (OMIM: 616144). However, not all patients harbour demonstrable WDR73 deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology. METHODS: Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function. RESULTS: In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in nucleoporin, 107-KD (NUP107). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells. CONCLUSION: Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation.

Morphine reward in dopamine-deficient mice.

Dopamine has been widely implicated as a mediator of many of the behavioural responses to drugs of abuse. To test the hypothesis that dopamine is an essential mediator of various opiate-induced responses, we administered morphine to mice unable to synthesize dopamine. We found that dopamine-deficient mice are unable to mount a normal locomotor response to morphine, but a small dopamine-independent increase in locomotion remains. Dopamine-deficient mice have a rightward shift in the dose-response curve to morphine on the tail-flick test (a pain sensitivity assay), suggesting either a decreased sensitivity to the analgesic effects of morphine and/or basal hyperalgesia. In contrast, dopamine-deficient mice display a robust conditioned place preference for morphine when given either caffeine or l-dihydroxyphenylalanine (a dopamine precursor that restores dopamine throughout the brain) during the testing phases. Together, these data demonstrate that dopamine is a crucial component of morphine-induced locomotion, dopamine may contribute to morphine analgesia, but that dopamine is not required for morphine-induced reward as measured by conditioned place preference.

Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin.

Rodents learn to associate the rewarding effects of drugs with the environment in which they are encountered and, subsequently, will display a conditioned place preference (CPP) for that environment. Cocaine-induced CPP is generally thought to be mediated through inhibition of the dopamine transporter and the consequent increase in extracellular dopamine. However, here we report that dopamine-deficient (DD) mice formed a CPP for cocaine that was not blocked by a dopamine D1-receptor antagonist. Fluoxetine, a serotonin transporter (SERT) inhibitor, produced CPP in DD, but not control mice, suggesting that serotonin mediates cocaine CPP in DD mice. Inhibition of dopamine neuron firing by pretreatment with quinpirole, a dopamine D2-receptor agonist, blocked both cocaine- and fluoxetine-induced CPP in DD mice. These findings are consistent with the hypothesis that, in the absence of dopamine, cocaine-mediated SERT blockade activates dopamine neurons, which then release some other neurotransmitter that contributes to cocaine reward in DD mice.

Genetic disruption of dopamine production results in pituitary adenomas and severe prolactinemia.

BACKGROUND: Dopamine release from tuberoinfundibular dopamine neurons into the median eminence activates dopamine-D2 receptors in the pituitary gland where it inhibits lactotroph function. METHODS: We have previously described genetic dopamine-deficient mouse models which lack the ability to synthesize dopamine. Because these animals require daily treatment with 3,4-L-dihydroxyphenylalanine (L-dopa) to survive, it has not been possible to examine the consequences of chronic loss of dopamine on pituitary physiology. We use viral-mediated gene transfer to selectively restore dopamine to the dorsal striatum of dopamine-deficient mice which allows the mice to survive without L-dopa. RESULTS: We find that mice chronically lacking tuberoinfundibular dopamine secrete large amounts of prolactin due to the development of severely enlarged pituitaries composed principally of hyperplastic hypertrophic lactotrophs and multifocal prolactinomas. In addition, these mice have elevated serum growth hormone levels and aged males develop hypertrophy of the seminal vesicles. CONCLUSION: Our observations are consistent with the hypothesis that hypothalamic dopamine is a critical inhibitor of lactotroph proliferation and suggest additional roles for dopamine in the regulation of pituitary function.

Local dopamine production in the dorsal striatum restores goal-directed behavior in dopamine-deficient mice.

To determine whether dopamine signaling in the dorsal striatum is sufficient for performance of goal-directed behaviors, local dopamine production was restored in the dorsal striatum of dopamine-deficient (DD) mice through viral-mediated gene therapy. Virally rescued DD (vrDD) mice were tested for learning of an appetitive T-maze task designed to measure goal-directed behavior. The results indicate that in contrast with the performance of DD mice that have dysregulated dopamine signaling, vrDD mice were able to perform the T-maze task and reverse their behavior as well as sham-operated control mice. The authors conclude that finely tuned dopaminergic signaling within the dorsal striatum is sufficient for performance of goal-directed behavior.

Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding.

Dopamine signaling is an important component of many goal-directed behaviors, such as feeding. Acute disruption of dopamine signaling using pharmacological agents tends to inhibit normal feeding behaviors in rodents. Likewise, genetically engineered dopamine-deficient (DD) mice are unable to initiate sufficient feeding and will starve by approximately 3 weeks of age if untreated. Adequate feeding by DD mice can be achieved by daily administration of L-3,4-dihydroxyphenylalanine (L-dopa), a precursor of dopamine, which can be taken up by dopaminergic neurons, converted to dopamine, and released in a regulated manner. In contrast, adequate feeding cannot be restored with apomorphine (APO), a mixed agonist that activates D1 and D2 receptors. Viral restoration of dopamine production in neurons that project to the dorsal striatum also restores feeding in DD mice. Administration of amphetamine (AMPH) or nomifensine (NOM), drugs which increase synaptic dopamine concentration, inhibits food intake in virally rescued DD mice (vrDD) as in control animals. These results indicate that the dysregulation of dopamine signaling in the dorsal striatum is sufficient to induce hypophagia and suggest that regulated release of dopamine in that brain region is essential for normal feeding and, probably, many other goal-directed behaviors.