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The Journal of Neuroscience, March 19, 2008, 28(12):3221-3226; doi:10.1523/JNEUROSCI.5528-07.2008

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Neurobiology of Disease
Mutational Analysis Establishes a Critical Role for the N Terminus of Fragile X Mental Retardation Protein FMRP

Simon P. Reeve,^1,2 * Xinda Lin,^3 * Bahar H. Sahin,⁴ Fangfang Jiang,³ Aiyu Yao,³ Zhihua Liu,³ Hui Zhi,³ Kendal Broadie,⁵ Wei Li,³ Angela Giangrande,⁴ Bassem A. Hassan,^1,2,6 and Yong Q. Zhang³

¹Laboratory of Neurogenetics, Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology and ²Department of Human Genetics, KU Leuven School of Medicine, 3000 Leuven, Belgium, ³Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, ⁴Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Inserm/Université Louis Pasteur, 67404 Illkirch, Strasbourg, France, ⁵Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232, and ⁶Doctoral Programs in Molecular and Developmental Genetics and Neuroscience, Katholieke Universiteit Leuven Group Biomedicine, 3000 Leuven, Belgium

Correspondence should be addressed to Dr. Yong Q. Zhang, Institute of Genetics and Developmental Biology, Chinese Academy of Science, Datun Road, Chaoyang District, Beijing 100101, China. Email: yqzhang{at}genetics.ac.cn

Fragile X syndrome is the most common form of heritable mental retardation caused by the loss of function of the fragile X mental retardation protein FMRP. FMRP is a multidomain, RNA-binding protein involved in RNA transport and/or translational regulation. However, the binding specificity between FMRP and its various partners including interacting proteins and mRNA targets is essentially unknown. Previous work demonstrated that dFMRP, the Drosophila homolog of human FMRP, is structurally and functionally conserved with its mammalian counterparts. Here, we perform a forward genetic screen and isolate 26 missense mutations at 13 amino acid residues in the dFMRP coding dfmr1. Interestingly, all missense mutations identified affect highly conserved residues in the N terminal of dFMRP. Loss- and gain-of-function analyses reveal altered axonal and synaptic elaborations in mutants. Yeast two-hybrid assays and in vivo analyses of interaction with CYFIP (cytoplasmic FMR1 interacting protein) in the nervous system demonstrate that some of the mutations disrupt specific protein–protein interactions. Thus, our mutational analyses establish that the N terminus of FMRP is critical for its neuronal function.

Key words: fragile X syndrome; mental retardation; FMRP; yeast two-hybrid; Drosophila; dfmr1

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Received July 23, 2007; revised Jan. 17, 2008; accepted Feb. 3, 2008.

Correspondence should be addressed to Dr. Yong Q. Zhang, Institute of Genetics and Developmental Biology, Chinese Academy of Science, Datun Road, Chaoyang District, Beijing 100101, China. Email: yqzhang{at}genetics.ac.cn

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				O. Sofola, V. Sundram, F. Ng, Y. Kleyner, J. Morales, J. Botas, F. R. Jackson, and D. L. Nelson The Drosophila FMRP and LARK RNA-Binding Proteins Function Together to Regulate Eye Development and Circadian Behavior J. Neurosci., October 8, 2008; 28(41): 10200 - 10205. [Abstract] [Full Text] [PDF]

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