AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis

Louie, Carrie M.; Caridi, Gianluca; Lopes, Vanda S.; Brancati, Francesco; Kispert, Andreas; Lancaster, Madeline A.; Schlossman, Andrew M; Otto, Edgar A.; Leitges, Michael; Gröne, Hermann Josef; López, Irma; Gudiseva, Harini V.; O’Toole, John F.; Vallespín, Elena; Ayyagari, Radha; Ayuso, Carmen; Cremers, Frans P.M.; Hollander, Anneke I. den; Koenekoop, Robert K.; Dallapiccola, Bruno; Ghiggeri, Gian Marco; Hildebrandt, Friedhelm; Valente, Enza Maria; Williams, David S.; Gleeson, Joseph G.

doi:10.1038/ng.519

Cited by 176 publications

(206 citation statements)

References 44 publications

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“…Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene. This intriguing mechanism has been already postulated for several ciliopathies including Bardet-Biedl syndrome, NPH and even JSRD, [22][23][24][25] and could also help explain the intra-familial variability observed in some INPP5E-mutated families. To this end, the systematic genetic screening of multiple ciliopathy genes based on innovative technologies such as next-generation-sequencing is expected to give a main contribution to clarify the molecular basis underlying the clinical complexity of JSRD and other ciliopathies.…”

Section: Discussionmentioning

confidence: 58%

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

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Section: Discussionmentioning

confidence: 58%

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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“…Ahi1 mutant mice either do not develop OS or develop abnormal OS leading to subsequent photoreceptor degeneration, associated with defects in vesicular trafficking of transducin, ROM1 and opsin with a decrease in Rab8 expression. 192,193 ahi1 morphant zebrafish develop abnormally shaped eyes with coloboma and defective retinal lamination.…”

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confidence: 99%

The role of primary cilia in the development and disease of the retina

2013

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“…It has been reported that Ahi1 participates in the process of intracellular vesicle trafficking and is co-localized with microtubules and the microtubuleorganizing center (33,34). We postulated that Ahi1 could participate in 5-HT 2C R vesicles sorting to degradation after endocytosis.…”

Section: Co-localization and Interaction Between Hypothalamic Ahi1 Anmentioning

confidence: 83%

Hypothalamic Ahi1 Mediates Feeding Behavior through Interaction with 5-HT2C Receptor

Wang

Huang

et al. 2012

Journal of Biological Chemistry

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It is indicated that there are important molecules interacting with brain nervous systems to regulate feeding and energy balance by influencing the signaling pathways of these systems, but relatively few of the critical players have been identified. In the present study, we provide the evidence for the role of Abelson helper integration site 1 (Ahi1) protein as a mediator of feeding behavior through interaction with serotonin receptor 2C (5-HT 2C R), known for its critical role in feeding and appetite control. First, we demonstrated the co-localization and interaction between hypothalamic Ahi1 and 5-HT 2C R. Ahi1 promoted the degradation of 5-HT 2C R through the lysosomal pathway. Then, we investigated the effects of fasting on the expression of hypothalamic Ahi1 and 5-HT 2C R. Fasting resulted in an increased Ahi1 expression and a concomitant decreased expression of 5-HT 2C R. Knockdown of hypothalamic Ahi1 led to a concomitant increased expression of 5-HT 2C R and a decrease of food intake and body weight. Last, we found that Ahi1 could regulate the expression of neuropeptide Y and proopiomelanocortin. Taken together, our results indicate that Ahi1 mediates feeding behavior by interacting with 5-HT 2C R to modulate the serotonin signaling pathway.Obesity and its associated ailments such as diabetes have become a worldwide epidemic carrying with them a heavy toll of morbidity and mortality. Over the past decades, it has become evident that neural circuits in the central nervous system play a direct and crucial role in controlling feeding and energy homeostasis (1, 2). Disruptions in the mechanisms of central nervous system energy sensing are able to alter the standard homeostatic responses and are factors that contribute to the pathophysiology of obesity and diabetes. The brain serotonin system has long been implicated in the neural regulation of food intake and energy metabolism, as highlighted by the clinical use of serotonin releasers and reuptake inhibitors as appetite suppressant and weight loss medication (3-5). Depletion of central serotonin using selective neurotoxins has been shown to result in hyperphagia and obesity, whereas the release of serotonin and the inhibition of reuptake by D-fenfluramine potently reduce feeding and body weight (6). More recently, several lines of evidence show that serotonin receptor agonists can significantly improve glucose tolerance and reduce plasma insulin in mouse models of obesity and type 2 diabetes (7-9).Numerous serotonin receptor subtypes have been identified in which serotonin receptor 2C (5-HT 2C R) 4 is recognized specifically as a mediator of serotonin-induced appetite and glucose regulation (10 -13). During the past few years, both pharmacological and genetic evidence has indicated that neuropeptide Y (NPY) and melanocortin systems are the necessary mechanisms by which 5-HT 2C R agonists reduce appetite and improve diabetic conditions (14 -16). Although significant progress has been made in the study of serotonin-mediated regulation of energy metabolism, we ...

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AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis

Cited by 176 publications

References 44 publications

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

The role of primary cilia in the development and disease of the retina

Hypothalamic Ahi1 Mediates Feeding Behavior through Interaction with 5-HT2C Receptor

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