Human Genetics

, Volume 124, Issue 6, pp 615–623

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

  • Abidemi A. Adegbola
  • Michael L. Gonzales
  • Andrew Chess
  • Janine M. LaSalle
  • Gerald F. Cox
Original Investigation

DOI: 10.1007/s00439-008-0585-6

Cite this article as:
Adegbola, A.A., Gonzales, M.L., Chess, A. et al. Hum Genet (2009) 124: 615. doi:10.1007/s00439-008-0585-6

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.

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Abidemi A. Adegbola
    • 1
    • 2
    • 3
    • 6
  • Michael L. Gonzales
    • 4
  • Andrew Chess
    • 1
    • 2
  • Janine M. LaSalle
    • 4
  • Gerald F. Cox
    • 2
    • 3
    • 5
  1. 1.Center for Human Genetic Research, Department of MedicineMassachusetts General HospitalBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA
  3. 3.Division of Genetics, Department of MedicineChildren’s Hospital BostonBostonUSA
  4. 4.Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of MedicineUniversity of CaliforniaDavisUSA
  5. 5.Department of Clinical ResearchGenzyme CorporationCambridgeUSA
  6. 6.Harvard-Partners Center for Genetics and GenomicsBostonUSA