[HTML][HTML] Study of smell and reproductive organs in a mouse model for CHARGE syndrome

JEH Bergman, EA Bosman… - European journal of …, 2010 - nature.com
JEH Bergman, EA Bosman, C van Ravenswaaij-Arts, KP Steel
European journal of human genetics, 2010nature.com
CHARGE syndrome is a multiple congenital anomaly syndrome characterised by Coloboma,
Heart defects, Atresia of choanae, Retardation of growth and/or development, Genital
hypoplasia, and Ear anomalies often associated with deafness. It is caused by heterozygous
mutations in the CHD7 gene and shows a highly variable phenotype. Anosmia and
hypogonadotropic hypogonadism occur in the majority of the CHARGE patients, but the
underlying pathogenesis is unknown. Therefore, we studied the ability to smell and aspects …
Abstract
CHARGE syndrome is a multiple congenital anomaly syndrome characterised by Coloboma, Heart defects, Atresia of choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear anomalies often associated with deafness. It is caused by heterozygous mutations in the CHD7 gene and shows a highly variable phenotype. Anosmia and hypogonadotropic hypogonadism occur in the majority of the CHARGE patients, but the underlying pathogenesis is unknown. Therefore, we studied the ability to smell and aspects of the reproductive system (reproductive performance, gonadotropin-releasing hormone (GnRH) neurons and anatomy of testes and uteri) in a mouse model for CHARGE syndrome, the whirligig mouse (Chd7 Whi/+). We showed that Chromodomain Helicase DNA-binding protein 7 (Chd7) is expressed in brain areas involved in olfaction and reproduction during embryonic development. We observed poorer performance in the smell test in adult Chd7 Whi/+ mice, secondary either to olfactory dysfunction or to balance disturbances. Olfactory bulb and reproductive organ abnormalities were observed in a proportion of Chd7 Whi/+ mice. Hypothalamic GnRH neurons were slightly reduced in Chd7 Whi/+ females and reproductive performance was slightly less in Chd7 Whi/+ mice. This study shows that the penetrance of anosmia and hypogonadotropic hypogonadism is lower in Chd7 Whi/+ mice than in CHARGE patients. Interestingly, many phenotypic features of the Chd7 mutation showed incomplete penetrance in our model mice, despite the use of inbred, genetically identical mice. This supports the theory that the extreme variability of the CHARGE phenotype in both humans and mice might be attributed to variations in the fetal microenvironment or to purely stochastic events.
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