title: Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia.
abstract: Really interesting new gene (RING) finger protein 170 (RNF170) is an E3 ubiquitin ligase known to mediate ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate receptors (ITPR1). It has recently been demonstrated that a point mutation of RNF170 gene is linked with autosomal-dominant sensory ataxia (ADSA), which is characterized by an age-dependent increase of walking abnormalities, a rare genetic disorder reported in only two families. Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established. Here, we generated mice lacking Rnf170 (Rnf170(-/-)) to evaluate the effect of its loss of function in vivo. Remarkably, Rnf170(-/-) mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires. As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception. Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice. These results suggest that the loss of Rnf170 gene function mediates ADSA-associated phenotypes and this gives insights on the cure of patients with ADSA and other age-dependent walking abnormalities.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 335 Gwahak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea, Graduate School of Medical Science and Engineering.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.
authors.forename: Seong Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Severans Biomedical Research Center Institute.
authors.forename: Kook Hwan
authors.initials: KH
authors.lastname: Kim
authors.affiliation: KAIST Institute for BioCentury, KAIST, Daejeon 305-701, Republic of Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Chae
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
authors.forename: Chanki
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 335 Gwahak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea.
authors.forename: Jeongjin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
authors.forename: Hee-Sup
authors.initials: HS
authors.lastname: Shin
authors.affiliation: Severans Biomedical Research Center Institute, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro Seodaemun-gu, Seoul 120-752, Republic of Korea and daesoo@kaist.ac.kr mslee0923@yuhs.ac.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 335 Gwahak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea, daesoo@kaist.ac.kr mslee0923@yuhs.ac.
authors.forename: Daesoo
authors.initials: D
authors.lastname: Kim
mesh_terms: D000367:Age Factors; D000818:Animals; D001259:Ataxia / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D005684:Gait / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*
chemical_list: C000600305:RNF170 protein, mouse; D044767:Ubiquitin-Protein Ligases