Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome. Issue 8 (7th July 2014)

• Record Type: Journal Article
• Authors: Camarena, Vladimir; Cao, Lei; Abad, Clemer; Abrams, Alexander; Toledo, Yaima; Araki, Kimi; Araki, Masatake; Walz, Katherina; Young, Juan I
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 8(2014:Aug.)
• Page Start: 1003
• Page End: 1015
• Publication Date: 2014-07-07
• Subjects: autistic disorder -- intellectual disability -- MBD5 -- mouse model; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201404044
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: 2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic‐like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl‐CpG‐binding domain protein 5 ( MBD5 ), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene‐trap mouse model. Our study indicates that the Mbd5 +/ GT mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5 +/ GT mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion‐associated behavioral and cognitive symptoms. Synopsis: 2q23.1 microdeletion syndrome is a rare genetic disease that causes serious neurological deficits. In humans, haplo‐insufficiency of MBD5 was thought to be responsible. This study provides the 1st mouse model of the syndrome and confirms the causal role of MBD5. A mouse model carrying a gene trap insertion in the Mbd5 gene was generated and characterized. This mouse model recapitulates the phenotype observed in 2q23.1 microdeletion patients that includes abnormal social behavior, cognitive impairment, motor deficit and craniofacial abnormalities. Mbd5 is highly expressed in neurons. Reduced Mbd5 expression results in a deficiency of neurite outgrowth in neuronal primary cultures. This new mouse model confirms the causal role of MBD5 in the 2q23.1 microdeletion syndrome and suggests that neuronal dysfunction is responsible for the observed phenotype. Abstract : 2q23.1 microdeletion syndrome is a rare genetic disease that causes serious neurological deficits. In humans, haplo‐insufficiency of MBD5 was thought to be responsible. This study provides the 1st mouse model of the syndrome and confirms the causal role of MBD5.