Anomalies oculaires chez le modèle murin C57Bl/6Toupee : implications sur la variabilité phénotypique du syndrome CHARGE et sur le rôle de FAM172A dans le développement oculaire
CHARGE syndrome is a rare genetic disease for which the acronym stands for the main characteristics initially identified to describe the syndrome: coloboma, heart problems, choanal atresia, retarded growth and development, genital anomalies and ear defects. Patients present highly variable combinations of anomalies, even between members of the same family. The main cause of this syndrome is a mutation in the CHD7 gene, but new genes whose mutation can also give rise to this syndrome, such as FAM172A, were recently identified. The Fam172a gene is mutated in the Toupee mouse model, which presents the main characteristics of CHARGE syndrome. Interestingly, while FVBToupee animals present coloboma in a strong proportion, 55% of B6ToupeeTg/Tg individuals and 16% of B6ToupeeTg/+ individuals present microphthalmia and anophthalmia.  First, detailed characterization of these ocular anomalies revealed that microphthalmia and anophthalmia are much more frequent in the right eye of B6Toupee mice, with varying degrees of severity.  Then, comparative analysis of ToupeeTg/Tg and Chd7Gt/+models in FVB and C57Bl/6 genetic backgrounds further revealed significant differences in penetrance and phenotypic presentation, suggesting that the identity of the causative gene and the genetic background both modulate phenotypic outcome of CHARGE syndrome.  Finally, characterization of FVBToupeeTg/+;Chd7Gt/+ double heterozygotes confirmed a moderate genetic interaction between Fam172a and Chd7 while investigations of Chd7Gt/+ neonatal mortality allowed to suspect feeding problems.
Fam172a Chd7 CHARGE syndrome Phenotypic variability Genetic background Neonatal mortality Coloboma Microphthalmia Anophthalmia Eye development