Variants of the <i>orexin2</i>/<i>hcrt2</i> receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity

Thompson, Miles D.; Comings, David E.; Abu-Ghazalah, Rashid M.; Jereseh, Yousef; Lin, Leo; Wade, J. A.; Sakurai, Takeshi; Tokita, Shigeru; Yoshida, Tatsushi; Tanaka, Hirokazu; Yanagisawa, Masashi; Burnham, W. McIntyre; Moldofsky, Harvey

doi:10.1002/ajmg.b.30047

Cited by 43 publications

(36 citation statements)

References 79 publications

(87 reference statements)

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“…In humans, another idiopathic sleep disorder termed excessive daytime sleepiness has been linked by single-stranded conformational polymorphism analysis to an HCRTr2 coding variant resulting in a Pro11Thr change that impaired HCRT ligand binding-related signaling 13 . These findings suggest that alterations in HCRT ligand or its receptors can disrupt neurotransmission and may play key roles in sleep-related disorders, including narcolepsy.…”

Section: Narcolepsymentioning

confidence: 99%

Mechanistic insights into influenza vaccine-associated narcolepsy

Ahmed

Steinman

2016

Human Vaccines & Immunotherapeutics

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We previously reported an increased frequency of antibodies to hypocretin (HCRT) receptor 2 in sera obtained from narcoleptic patients who received the European AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline Biologicals, s.a.) for the global influenza A H1N1 pandemic in 2009 [A(H1N1)pdm09]. These antibodies cross-reacted with a particular fragment of influenza nucleoprotein (NP) – one of the proteins naturally contained in the virus used to make seasonal influenza vaccine and pandemic influenza vaccines. The purpose of this commentary is to provide additional insights and interpretations of the findings and share additional data not presented in the original paper to help the reader appreciate the key messages of that publication. First, a brief background to narcolepsy and vaccine-induced narcolepsy will be provided. Then, additional insights and clarification will be provided on the following topics: 1) the critical difference identified in the adjuvanted A(H1N1)pdm09 vaccines, 2) the contributing factor likely for the discordant association of narcolepsy between the AS03-adjuvanted pandemic vaccines Pandemrix and Arepanrix (GlaxoSmithKline Biologicals, s.a.), 3) the significance of detecting HCRT receptor 2 (HCRTr2) antibodies in some Finnish control subjects, 4) the approach used for the detection of HCRTr2 antibodies in vaccine-associated narcolepsy, and 5) the plausibility of the proposed mechanism involving HCRTr2 modulation in vaccine-associated narcolepsy.

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Section: Narcolepsymentioning

confidence: 99%

Mechanistic insights into influenza vaccine-associated narcolepsy

Ahmed

Steinman

2016

Human Vaccines & Immunotherapeutics

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“…Some authors found a variant of orexin genes, which have been shown to be essential for normal sleep in patients with TS+ADHD. 54 correlated with the number of comorbidities. In addition to that, psychosocial factors are also very important, as an external locus of control (LOC) is associated with an increased risk of anxiety disorders.…”

Section: Sleep Disordersmentioning

confidence: 99%

Tourette's syndrome and associated disorders: a systematic review

Ferreira

Pio-Abreu

Januário

2014

Trends Psychiatry Psychother.

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Objective: To compile data on Tourette's syndrome (TS), tics and associated disorders. Methods: A systematic review of the literature was conducted using the 5S levels of organization of healthcare research evidence (systems, summaries, synopses, syntheses, studies), based on the model described by Haynes. The search keywords were Tourette, tics and comorbidity, which were cross-referenced. Studies provided by publishers and articles being processed on July 31, 2013, were also included. Results: Of all studies retrieved during the search, 64 were selected because they analyzed the epidemiology, clinical features and etiopathogenesis of TS and its comorbidities. TS is classified as a hyperkinetic movement disorder, and at least 90% of the patients have neuropsychiatric comorbidities, of which attention deficit hyperactivity and obsessive-compulsive disorders are the most common. The syndrome is clinically heterogeneous and has been associated with a dysfunction of cortico-striatal-thalamic-cortical circuits involving various neurotransmitters. Although its genetic etiology has been widely studied, other factors may be important to understand this syndrome and its associated disorders. Conclusions: TS is a neurodevelopmental disorder that results from the impact of stress factors on a vulnerable biological substrate during the critical periods of neurodevelopment. The study of TS and its comorbidities may contribute, at different levels, to the understanding of several neuropsychiatric disorders of clinical and therapeutic relevance. Keywords: Attention deficit disorder with hyperactivity, comorbidity, obsessive-compulsive disorder, tics, Tourette's syndrome. ResumoObjetivo: Compilar o conhecimento existente sobre a síndrome de Tourette (ST), tiques e patologias associadas. Metodologia: Foi realizada uma revisão sistemática da literatura usando os níveis 5S (sistemas, sumários, sinopses, sínteses e estudos) de organização de evidência de pesquisa em saúde, com base no modelo proposto por Haynes. Os termos de busca foram Tourette, tiques e comorbidades, completados por pesquisa por referência cruzada. Os artigos fornecidos pelos editores e aqueles a serem processados para publicação em 31 de julho de 2013 também foram incluídos. Resultados: De todos os artigos encontrados durante a pesquisa, 64 foram selecionados porque analisavam a epidemiologia, as características clínicas e a etiopatogenia da ST. A ST define-se como um distúrbio hipercinético do movimento, e pelo menos 90% dos pacientes apresentam comorbidades neuropsiquiátricas, das quais as mais comuns são a perturbação de déficit de atenção com hiperatividade e a perturbação obsessivo--compulsiva. Esta síndrome é clinicamente heterogênea e tem sido relacionada com a disfunção dos circuitos córtico-estriado--tálamo-corticais envolvendo vários neurotransmissores. Apesar de sua etiologia genética ter sido amplamente estudada, outros fatores podem ser importantes para entender esta síndrome e as perturbações relacionadas. Conclusões: A ST resulta de uma p...

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“…Samples were denatured at 951C for 5 min and chilled to 41C for 5 min before loading. The entire volume of buffer and PCR product, 18 ml, was loaded into separate wells of Novex 4-20% tris-boric acid-EDTA (TBE) gels [40,41] and run at 151C using 80 V for 19 h to resolve the PCR fragments. The DNA was visualized using the Novex SilverXpress Staining Kit (Uppsala, Sweden).…”

Section: Sequence Variant Detection In the Cyslt 1 Receptor Genementioning

confidence: 99%

“…LTD 4 -induced calcium mobilization in cells expressing G300S variants and I206S variants was compared with CysLT 1 wild-type. Maximum fluorescence levels were measured in a Molecular Devices Fluorometric Imaging Plate Reader [47] as reported previously [26,41].…”

Section: Culture and Transfection Of Cellsmentioning

confidence: 99%

A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate

Thompson¹,

Capra

Takasaki

et al. 2007

Pharmacogenetics and Genomics

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Atopy is a well-defined immune phenotype that is reported to be a risk factor for asthma. Among the many loci that contribute to a genetic predisposition to asthma, the cysteinyl leukotriene receptor genes and their variants have been important subjects of study because they are functionally and pharmacologically implicated in the atopy phenotype affecting many asthma subjects. Moreover, the product of cysteinyl-leukotriene 1 receptor gene (CysLT1), located at Xq13.2, is targeted by LT receptor antagonists. In our earlier association study, the M201V variant of the cysteinyl-leukotriene 2 receptor gene (CysLT2), located at 13q14, was implicated in atopic asthma. Here we report the screening of the coding region of the CysLT1, gene in the highly asthmatic Tristan da Cunha population. In this population, we discovered a CysLT1 G300S variant that is carried with a significantly higher frequency in atopics and asthmatics from the Tristan da Cunha population. Furthermore, we report the asthma independent association of the CysLT1 G300S variant with atopy. Subsequently, we compared the changes conferred by each SNP on CysLT function. The CysLT1 300S receptor interacts with LTD4 with significantly greater potency. For the 300S variant, a statistically significant decrease in the effector concentration for half-maximum response (EC50) for intracellular Ca flux and total InsP generation is observed. Other aspects of the receptor function and activity, such as desensitization, pharmacologic profile in response to montelukast, and cellular localization, are unchanged. These in vitro analyses provide evidence that the 300S CysLT1 variant, found more commonly in atopics in the Tristan da Cunha population, encodes a functionally more sensitive variant.

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Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity

Cited by 43 publications

References 79 publications

Mechanistic insights into influenza vaccine-associated narcolepsy

Mechanistic insights into influenza vaccine-associated narcolepsy

Tourette's syndrome and associated disorders: a systematic review

A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate

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