Original article Mutation analysis of methyl-CpG binding protein family genes in autistic patients Hong Li a , Takanori Yamagata a , Masato Mori a , Akihiro Yasuhara b , Mariko Y. Momoi a, * a Department of Pediatrics, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Tochigi 329-0498, Japan b Department of Pediatrics, Kansai Medical University Kohri Hospital, 8-45 Kourihonndouri, Neyagawa, Osaka 572-8551, Japan Received 6 July 2004; accepted 10 August 2004 Abstract Methyl-CpG binding protein 2 gene (MECP2), the gene implicated in Rett syndrome, was also reported to be involved in mental retardation and autism. MECP2, MBD1,MBD2,MBD3,and MBD4 comprise a nuclear protein family sharing the methyl-CpG bindin domain (MBD) and are related to transcriptional repression. In 65 Japanese autistic patients, all the exons of each gene we mutations by DHPLC, and the results were confirmed by direct sequencing. An R269C mutation that resulted in the additio a cysteine rich region was found in the MBD1 gene in one patient. This mutation was also detected in the patient’s father with some phenotypes of autism and his normal sister, but not in 151 controls. Two repeat length polymorphisms, (GGGGCC)2 to 3 a were detected in MBD2, and several polymorphisms were detected in each gene. Although our findings could not confirm this family are responsible for the etiology in the majority of autistic patients, the R269C mutation in the MBD1 gene may The potential association of the high-polymorphic gene variants with autism needs to be studied further. Furthermore, the are useful for linkage analysis. q 2004 Published by Elsevier B.V. Keywords: Autism; Methyl-CpG binding protein genes; MECP2; MBD1 1. Introduction Autism (MIM 209850) is a neurodevelopmental disorder that affectsat leastfive in 10,000individuals.It is characterizedby impairmentsin reciprocal social interactionand communication, and restrictedand stereotyped patterns of interests and activities. Thus far, only the mutations of the neuroligin 3 and 4 genes have been detected in a few patients with autism [1]. Methyl-CpG binding protein 2 ( MECP2) gene mutation was reportedas the cause of Rett syndrome,a neurodevelopmental disorder associated with some autistic phenotypes [2], and in X-linked mentalretardation. Additionally, a mutation in MECP2, IVS2C2delTAAG, was reported in one case of infantile autism [3]. MeCP2 selectivelybinds to methylatedDNA and represses transcription, leading to gene inactivation, and is reported to correlate with neuronal maturation. The methyl-CpG binding protein family consists of five members, MECP2 and MBD1-4, sharing a common methyl- CpG binding domain (MBD), and they were mapped to Xq28, 18q21.1, 18q21.3, 19p13, and 3q21, respectively [4 All MBDs except MBD4, relating to DNA mismatch-repair, form complexes with histone deacetylase and are involved in recruiting histone deacetylases to methyl-CpG enriched regions in the genome to repress transcription [5]. A study on the expression of MBD genes showed that MBD1-3, all have a broad expression in multiple murine tissues includi the brain [6].Additionally, some patients with an 18q deletion, including the 18q21 deletion, where MBD1 and 2 were localized, had autism or atypical Rettsyndrome [7]. From the above data, it is suggested that the MBD family genes can be candidate genes for autistic disorders. Thus, we screened these genes for disease-causative mutations autistic patients. 0387-7604/$ - see front matter doi:10.1016/j.braindev.2004.08.003 Brain & Development 27 (2005) 321–325 www.elsevier.com/locate/braindev * Corresponding author. Tel.: C81 285 58 7366; fax: C81 285 44 6123. E-mail address: mymomoi@jichi.ac.jp (M.Y. Momoi).