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