, Volume 8, Issue 2, pp 143–147 | Cite as

Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin–Lowry syndrome

  • Shelli R. KeslerEmail author
  • Richard J. Simensen
  • Kytja Voeller
  • Fatima Abidi
  • Roger E. Stevenson
  • Charles E. Schwartz
  • Allan L. Reiss
Short Communication


Coffin–Lowry syndrome (CLS) is a rare form of X-linked mental retardation caused by mutations of the RSK2 gene, associated with cognitive impairment and skeletal malformations. We conducted the first morphometric study of CLS brain morphology by comparing brain volumes from two CLS families with healthy controls. Individuals with CLS consistently showed markedly reduced total brain volume. Cerebellum and hippocampus volumes were particularly impacted by CLS and may be associated with specific interfamilial RSK2 mutations. We provide preliminary evidence that the magnitude of hippocampus volume deviation from that of controls may predict general cognitive outcome in CLS.


Coffin–Lowry syndrome RSK2 MRI Hippocampus X-linked mental retardation 

Supplementary material

10048_2007_80_Fig1_ESM.gif (18 kb)
Supplementary Fig. 1

Scattergram showing the correlation between corrected hippocampus volume z scores and IQ for the 7 subjects with CLS (r =  −.64, p = .06) Supplementary data (DOC 18 Kb)

10048_2007_80_Fig1_ESM.tif (306 kb)
High resolution image file (TIFF 312 kb)


  1. 1.
    Ahuja SR et al (2003) Coffin–Lowry syndrome. Indian J Pediatr 70(12):1001–1002PubMedGoogle Scholar
  2. 2.
    Hanauer A, Young ID (2002) Coffin–Lowry syndrome: clinical and molecular features. J Med Genet 39(10):705–713PubMedCrossRefGoogle Scholar
  3. 3.
    Simensen RJ et al (2002) Cognitive function in Coffin–Lowry syndrome. Clin Genet 61(4):299–304PubMedCrossRefGoogle Scholar
  4. 4.
    Stephenson JB et al (2005) The movement disorders of Coffin–Lowry syndrome. Brain Dev 27(2):108–113PubMedCrossRefGoogle Scholar
  5. 5.
    Touraine RL, Zeniou M, Hanauer A (2002) A syndromic form of X-linked mental retardation: the Coffin–Lowry syndrome. Eur J Pediatr 161(4):179–187PubMedCrossRefGoogle Scholar
  6. 6.
    Guimiot F et al (2004) Expression of the RSK2 gene during early human development. Gene Expr Patterns 4(1):111–114PubMedCrossRefGoogle Scholar
  7. 7.
    Zeniou M et al (2002) Expression analysis of RSK gene family members: the RSK2 gene, mutated in Coffin–Lowry syndrome, is prominently expressed in brain structures essential for cognitive function and learning. Hum Mol Genet 11(23):2929–2940PubMedCrossRefGoogle Scholar
  8. 8.
    Ozden A et al (1994) Callosal dysgenesis in a patient with Coffin–Lowry syndrome. Indian J Pediatr 61(1):101–103PubMedGoogle Scholar
  9. 9.
    Coffin GS (2003) Postmortem findings in the Coffin–Lowry syndrome. Genet Med 5(3):187–193PubMedCrossRefGoogle Scholar
  10. 10.
    Kondoh T et al (1998) New radiological finding by magnetic resonance imaging examination of the brain in Coffin–Lowry syndrome. J Hum Genet 43(1):59–61PubMedCrossRefGoogle Scholar
  11. 11.
    Thorndike R, Hagen E, Sattler J (1986) The Stanford–Binet intelligence scale, 4th edn. Riverside Publishing, Chicago, ILGoogle Scholar
  12. 12.
    Alpern G, Boll T, Shearer M (2000) Developmental profile II manual. Western Psychological Services, Los Angeles, CAGoogle Scholar
  13. 13.
    Ewers M et al (2006) Multicenter assessment of reliability of cranial MRI. Neurobiol Aging 27:1051–1059PubMedCrossRefGoogle Scholar
  14. 14.
    Kates WR et al (1999) Automated Talairach atlas-based parcellation and measurement of cerebral lobes in children. Psychiatry Res 91(1):11–30PubMedGoogle Scholar
  15. 15.
    Reiss AL et al (1998) Reliability and validity of an algorithm for fuzzy tissue segmentation of MRI. J Comput Assist Tomogr 22(3):471–479PubMedCrossRefGoogle Scholar
  16. 16.
    Kates WR et al (1997) Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res 75(1):31–48PubMedGoogle Scholar
  17. 17.
    Weeber EJ, Levenson JM, Sweatt JD (2002) Molecular genetics of human cognition. Mol Interv 2(6):376–391, 339PubMedCrossRefGoogle Scholar
  18. 18.
    Johnston MV, Alemi L, Harum KH (2003) Learning, memory, and transcription factors. Pediatr Res 53(3):369–374PubMedCrossRefGoogle Scholar
  19. 19.
    Lonze BE et al (2002) Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34(3):371–385PubMedCrossRefGoogle Scholar
  20. 20.
    Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35(4):605–623PubMedCrossRefGoogle Scholar
  21. 21.
    Lezak M (1995) Neuropsychological assessment, 3rd edn. Oxford University Press, New York, NYGoogle Scholar
  22. 22.
    Sweatt JD, Weeber EJ, Lombroso PJ (2003) Genetics of childhood disorders: LI. Learning and memory, part 4. Human cognitive disorders and the ras/ERK/CREB pathway. J Am Acad Child Adolesc Psychiatry 42(6):741–744PubMedCrossRefGoogle Scholar
  23. 23.
    Harum KH, Alemi L, Johnston MV (2001) Cognitive impairment in Coffin–Lowry syndrome correlates with reduced RSK2 activation. Neurology 56(2):207–214PubMedGoogle Scholar
  24. 24.
    Woo MS et al (2004) Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site. Mol Cell Biol 24(7):3025–3035PubMedCrossRefGoogle Scholar
  25. 25.
    Sullivan EV et al (2001) Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment. Hippocampus 11(6):754–762PubMedCrossRefGoogle Scholar
  26. 26.
    Toga AW, Thompson PM (2005) Genetics of brain structure and intelligence. Annu Rev Neurosci 28:1–23PubMedCrossRefGoogle Scholar
  27. 27.
    Countryman RA et al (2005) CREB phosphorylation and c-Fos expression in the hippocampus of rats during acquisition and recall of a socially transmitted food preference. Hippocampus 15(1):56–67PubMedCrossRefGoogle Scholar
  28. 28.
    Hao Y et al (2004) Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 24(29):6590–6599PubMedCrossRefGoogle Scholar
  29. 29.
    Hu B et al (2004) Changes in trkB-ERK1/2-CREB/Elk-1 pathways in hippocampal mossy fiber organization after traumatic brain injury. J Cereb Blood Flow Metab 24(8):934–943PubMedCrossRefGoogle Scholar
  30. 30.
    Mantamadiotis T et al (2002) Disruption of CREB function in brain leads to neurodegeneration. Nat Genet 31(1):47–54PubMedCrossRefGoogle Scholar
  31. 31.
    Ying SW et al (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 22(5):1532–1540PubMedGoogle Scholar
  32. 32.
    Geuze E, Vermetten E, Bremner JD (2005) MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. Mol Psychiatry 10(2):160–184PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Shelli R. Kesler
    • 1
    Email author
  • Richard J. Simensen
    • 2
  • Kytja Voeller
    • 2
  • Fatima Abidi
    • 2
  • Roger E. Stevenson
    • 2
  • Charles E. Schwartz
    • 2
  • Allan L. Reiss
    • 1
  1. 1.Center for Interdisciplinary Brain Sciences ResearchStanford University School of MedicineStanfordUSA
  2. 2.Greenwood Genetic CenterGreenwoodUSA

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