Phenotypic Characterization of Rnf216 Null Mice Reveals Sexual Dimorphism

Presentation Number: SUN 470
Date of Presentation: April 2nd, 2017

Marina Cholanian*1, Latrice Doreen Faulkner1, Yee-Ming Chan2, Kimberly H Cox1, Camelia M. Saffarini1 and Stephanie Beth Seminara1
1Massachusetts General Hospital, Boston, MA, 2Boston Children's Hospital, Boston, MA


The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia (also known as Gordon Holmes syndrome) can be caused by inactivating mutations in RNF216 (an E3 ubiquitin ligase); biallelic truncating mutations in RNF216 appear sufficient to cause disease. As Rnf216 deficient mice have yet to be described, we sought to characterize the phenotype of these animals.

Targeted deletion of exons 4 and 5 of Rnf216 was achieved by homologous recombination on a C57BL/6/129Sv background strain by EUCOMM. Rnf216 null mice are viable. Knockout adult animals display normal feeding and motor activity. Sexual assignment was unequivocal for homozygous mutants. Mutant females had lower body weight than wildtype between 21 and 31 days of age, but mutant males were not significantly different from controls.


On external examination, Rnf216-/- male mice demonstrate underdevelopment of the genitalia compared to WT littermate controls. Mutant mice have significantly decreased anogenital distance, decreased penile width and length, and reduced testicular weight. Rnf216-/- males are unable to sire litters when placed in a cage with WT females of proven fertility. On histology, the testes show atrophy, absence of lumen, and vacuolization in seminiferous tubules. Heterozygous males are indistinguishable from WT males.

In contrast to the mutant males, Rnf216-/- female mice demonstrate normal markers of sexual maturation, such as the time to vaginal opening and the time to first estrus, at comparable times to those of WT animals. Estrous cycling patterns are normal. Rnf216-/- females have a short latency to their first litter when mated with males of proven fertility and produce an average number of litters and number of pups/litter which are comparable to that of WT controls.

On motor skills testing, Rnf216-/- males are significantly impaired in their ability to remain on the rotarod compared to WT littermates at 4 and 6 months of age. However, at the same time points, female Rnf216 -/- mice do demonstrate any differences in motor performance compared to control animals.

In summary, Rnf216 deficiency results in hypogonadism and motor deficits in male, but not female, mice. As both male and female patients with loss of function mutations in RNF216 have been described, the phenotypic discordance between male and female mutant mice is unexpected and suggests that sex steroids might play a role in susceptibility to Rnf216-mediated neurodegeneration.


Disclosure: YMC: Advisory Group Member, AbbVie. Nothing to Disclose: MC, LDF, KHC, CMS, SBS