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A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype

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Abstract

The MECP2 gene on Xq28 encodes a transcriptional repressor, which binds to and modulates expression of active genes. Mutations in MECP2 cause classic or preserved speech variant Rett syndrome and intellectual disability in females and early demise or marked neurodevelopmental handicap in males. The consequences of a hypomorphic Mecp2 allele were recently investigated in a mouse model, which developed obesity, motor, social, learning, and behavioral deficits, predicting a human neurobehavioral syndrome. Here, we describe mutation analysis of a nondysmorphic female proband and her father who presented with primarily neuropsychiatric manifestations and obesity with relative sparing of intelligence, language, growth, and gross motor skills. We identified and characterized a novel missense mutation (c.454C>G; p.P152A) in the critical methyl-binding domain of MeCP2 that disrupts MeCP2 functional activity. We show that a gradient of impairment is present when the p.P152A mutation is compared with an allelic p.P152R mutation, which causes classic Rett syndrome and another Rett syndrome-causing mutation, such that protein–heterochromatin binding observed by immunofluorescence and immunoblotting is wild-type > P152A > P152R > T158 M, consistent with the severity of the observed phenotype. Our findings provide evidence for very mild phenotypes in humans associated with partial reduction of MeCP2 function arising from subtle variation in MECP2.

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Acknowledgments

We would like to thank Jennifer Gentile and Susan Waisbren for neuropsychological testing and Yiping Shen for his help with MECP2 controls. Abidemi Adegbola was supported by an NIH (NIGMS) grant (grant number T32 GM007748). Michael Gonzales was supported by an NIH (NIMH) grant (grant number T32MH073124). Janine Lasalle was supported by NIH (NICHD) grants (grants numbers R01HD041462 and R01HD048799).

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Authors and Affiliations

  1. Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Abidemi A. Adegbola & Andrew Chess

  2. Harvard Medical School, Boston, MA, USA

    Abidemi A. Adegbola, Andrew Chess & Gerald F. Cox

  3. Division of Genetics, Department of Medicine, Children’s Hospital Boston, Boston, MA, USA

    Abidemi A. Adegbola & Gerald F. Cox

  4. Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, Davis, CA, USA

    Michael L. Gonzales & Janine M. LaSalle

  5. Department of Clinical Research, Genzyme Corporation, Cambridge, MA, USA

    Gerald F. Cox

  6. Harvard-Partners Center for Genetics and Genomics, 77 Avenue Louis Pasteur, NRB 250, Boston, MA, 02115, USA

    Abidemi A. Adegbola

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  1. Abidemi A. Adegbola
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  2. Michael L. Gonzales
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  3. Andrew Chess
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  4. Janine M. LaSalle
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  5. Gerald F. Cox
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Correspondence to Abidemi A. Adegbola.

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A. A. Adegbola and M. L. Gonzales contributed equally to this study.

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Adegbola, A.A., Gonzales, M.L., Chess, A. et al. A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype. Hum Genet 124, 615–623 (2009). https://doi.org/10.1007/s00439-008-0585-6

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