Project

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Deciphering the genetic bases of congenital oculomotor diseases

Applicant Di Gioia Silvio Alessandro
Number 155081
Funding scheme Early Postdoc.Mobility
Research institution Department of Neurology Children's Hospital Boston
Institution of higher education Institution abroad - IACH
Main discipline Genetics
Start/End 01.07.2014 - 31.12.2015
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All Disciplines (2)

Discipline
Genetics
Neurophysiology and Brain Research

Keywords (9)

Ophtalmology; Genetics; Neurology; Axonal guidance; Functional analysis; Congenital cranial dysinnervation disorders; Strabismus; Genotype-phenotype correlation; Next-generation sequencing

Lay Summary (Italian)

Lead
I disordini congeniti dell’innervazione cranica (noti come CCDD) compredono un gran numero di malattie legate a difetti nello sviluppo dell’innervazione dei muscoli extraoculari e sono clinicamente caratterizzati da strabismo, associato o meno a ptosi palpebrale. Per molte forme di CCDD e’ stata identificata la causa genetica, mentre per molti altri casi resta ancora oscura quale sia la mutatazione che possa spiegare l’insorgenza del disturbo. Lo scopo di questo progetto e’ quindi quello di identificare i geni-malattia per alcune specifiche forme irrisolte di CCDD: la ptosi congenita ed alcune forme di fibrosi congenita dei muscoli extraoculari (CFEOM).
Lay summary

Soggetto e obiettivi

La ptosi palpebrale e’ generalmente un sintomo accessorio delle CCDD dovuto ad una limitata o assente funzionalita’ del muscolo levator palpebrae.  In alcuni casi sono  state identificate famiglie in cui la ptosi e’ l’unico sintomo osservabile, in tal caso si parla di ptosi congenita isolata. Per questa forma di CCDD sono stati identificati diversi loci genetici, ma finora nessun gene e’ stato associato alla malattia. Per quanto riguarda la CFEOM invece, sono stati identificate finora 3 differenti forme (CFEOM1, CFEOM2 e CFEOM3), ognuna caratterizzata da mutazioni in diversi geni coinvolti nel pathway del controllo dell’allungamento dell’assone e nella sua migrazione verso il muscolo da innervare. Alcune famiglie pero’, nonostante presentino chiari sintomi CFEOM sono risultati negativi per mutazioni nei vari geni noti suggerendo la presenza di ulteriori geni causa malattia ancora da identificare.  Scopo del progetto  sara’ quindi quello di analizzare l’intero corredo genetico di queste famiglie con ptosi e con CFEOM attraverso le moderne tecniche di sequenziamento totale dell’esoma e cercare di identificare il/i gene/i malattia. Una volta identificato il gene si procedera’ a caratterizzare la sua funzione del gene grazie alla creazione di modelli murini.

Contesto socio-scientifico

L’identificazione dei geni causa CCDD ha un enorme impatto sia sulla diagnosi che sulla clinica. Infatti sebbene questi disturbi siano curabili chirurgicamente ad un livello puramente estetico, e’ purtroppo impossibile recuperare la funzione muscolare con la chirurgia.  L’identificazione di nuovi geni permettera’ quindi l’ideazione di nuovi farmaci che possano portare in un futuro al completo recupero della funzione muscolare. Inoltre lo studio funzionale permettera’ di  svelare nuovi aspetti della funzione nervosa e comprendere meglio lo sviluppo dei nervi cranici.

Direct link to Lay Summary Last update: 20.07.2015

Responsible applicant and co-applicants

Publications

Publication
A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome
Di Gioia Silvio Alessandro, Connors Samantha, Matsunami Norisada, Cannavino Jessica, Rose Matthew F., Gilette Nicole M., Artoni Pietro, de Macena Sobreira Nara Lygia, Chan Wai-Man, Webb Bryn D., Robson Caroline D., Cheng Long, Van Ryzin Carol, Ramirez-Martinez Andres, Mohassel Payam, Leppert Mark, Scholand Mary Beth, Grunseich Christopher, Ferreira Carlos R., Hartman Tyler, Hayes Ian M., Morgan Tim, Markie David M., Fagiolini Michela, et al. (2017), A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome, in Nature Communications, 8, 16077-16077.
Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects
Park Jong G., Tischfield Max A., Nugent Alicia A., Cheng Long, Di Gioia Silvio Alessandro, Chan Wai-Man, Maconachie Gail, Bosley Thomas M., Summers C. Gail, Hunter David G., Robson Caroline D., Gottlob Irene, Engle Elizabeth C. (2016), Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects, in The American Journal of Human Genetics, 98(6), 1220-1227.

Collaboration

Group / person Country
Types of collaboration
Stephen P. Robertson group/ University of Otago, Dunedin New Zealand (Oceania)
- Publication
Ethylin Jabs group/Mount Sinai United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
John Carey Group/ University of Utah United States of America (North America)
- Publication
Francis Collins group/National Health Institue United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
American Society of Human Genetics Poster Isolated hereditary congenital ptosis can be caused by defects of the craniofacial development 18.10.2016 Vancouver, Canada Di Gioia Silvio Alessandro;
Speaker at Weekly Genetic department talk Individual talk Molecular genetics of cranial dysinnervation disorders 17.12.2015 Department of Medical Genetics, University of Lausanne, Switzerland Di Gioia Silvio Alessandro;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions SNSF fellows gathering: a night of science and networking International 2016

Associated projects

Number Title Start Funding scheme
164677 Deciphering the genetic bases of congenital cranial dysinnervation disorders 01.01.2016 Advanced Postdoc.Mobility

Abstract

The congenital cranial dysinnervation disorders (CCDDs) are a class of diseases caused by abnormal development of nerves innervating cranial musculature. Those altering development of ocular cranial nerves lead to impairment of ocular motility and eyelid dysfunction (ptosis). These disorders include, among others, Duane retraction syndrome (DRS), congenital fibrosis of the extraocular muscles (CFEOM), and horizontal gaze palsy. In some cases the syndromes can be associated with other neurological and/or systemic developmental defects. The Engle lab has characterized the clinical features and genetic causes of multiple forms of these disorders and, through functional studies and animal modeling, have found the genes to play roles in motor neuron identity and axon growth and guidance. The project will have three aims. The first aim is to identify and expand the spectrum of CCDDs by deciphering genetic data of a large number of families having CFEOM or congenital isolated ptosis (CIP). To perform this task we will use the most recent next generation sequencing technologies by systematically screening a total of 24 families affected with CIP and unsolved CFEOM. For variant filtering we will also take advantage of the Broad Institute sequencing data analysis facility, in addition to a proprietary filtering pipeline. The identified causative gene will be used to screen the larger cohort of isolated CCDDs cases counting more than 1500 probands. The second aim of this project is to establish a correct genotype-phenotype correlation for new CFEOM and CIP genes. This task will be achieved by extensive review of clinical data of the affected individuals, and through collaboration with ophthalmologists of Boston Children’s Hospital. The clinical data will be integrated with genetic and functional data to describe a complete list of phenotypes. The third aim is to investigate the molecular function of mutant genes in normal and abnormal development both in vitro and in vivo, and determine the link between the mutated gene and CCDD phenotype. This aim will encompass both in vitro studies and the generation of mouse models carrying the mutated allele to finely dissect its phenotype.By expanding the genetics of CCDDs, this project will increase our understanding of the development of cranial nerves and their normal and aberrant innervation of extraocular muscles, and reveal new important aspects of nervous system development.
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