Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
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PMID:Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome. 2358 Feb 1

Postural orthostatic tachycardia syndrome (POTS), estimated to affect 500,000 people in the United States alone, is a growing source of impairment and disability. Symptoms often consist of physical, cognitive, and psychological impairment. The symptoms are driven by fluctuations in cerebral blood flow. Cerebral perfusion is tightly controlled and linked to brain function as changes in posture can result in quick hemovascular regulation by the autonomic nervous system. Any delay in hemoregulation and cerebral blood flow can result in neurological symptoms. POTS is associated with chronic autonomic dysregulation, and people with POTS suffer differing degrees of cerebral hypoperfusion causing variability in symptoms. This article reviews the cases of two siblings (22 years old and 19 years old) who both suffer from POTS. They suffered physical symptoms along with difficulty organizing thoughts, sustaining attention, thinking quickly, multitasking, and recalling recent information, as well as depression and anxiety. These sisters have Full-Scale IQs (FSIQ) above average, yet they received academic accommodations and have ongoing cognitive dysfunction that prevents them from furthering their true potential. These cases illustrate the need for neuropsychologists and other treating providers to understand POTS, the related pathophysiology, and how cognitively debilitating POTS can be, even in the context of intact and high FSIQ scores.
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PMID:The Neuropsychological Profile of Postural Orthostatic Tachycardia Syndrome: Sibling Case Study. 3056 46