Coffin–Lowry Syndrome

Abstract

The Coffin–Lowry syndrome (CLS) is a rare but well‐defined X‐linked semidominant syndrome. Cardinal features include severe mental retardation, a characteristic facial appearance, digital tapering, short stature and progressive spinal deformity. However, the clinical presentation may be markedly variable both in severity and in the expression of uncommonly associated features. In addition, a few atypical cases of the disease have been reported. Highly heterogeneous loss of function mutations in the RPS6KA3 gene encoding the protein kinase RSK2 are responsible for CLS. About two‐thirds of the mutations arise de novo.

RSK2 is a member of the ribosomal S6 serine/threonine kinase family, which plays a key role in the Ras‐ERK signalling pathway. RSKs are activated by phosphorylation in response to growth factors and neurotransmitters. RSK2 substrates include transcription factors, in accordance with a major role in regulation of gene expression. RSK2 is involved in proliferation, apoptosis and in learning and memory processes.

Key concepts

  • Coffin–Lowry syndrome is an X‐linked semidominant syndrome characterized typically by severe psychomotor and growth retardation, facial dysmorphism, digit abnormalities and progressive skeletal deformations.

  • The estimated incidence is 1 50 000–1 100 000 and approximately 70–80% of patients are sporadic cases.

  • There is no specific treatment.

  • Highly heterogeneous loss‐of‐function mutations in the RPS6KA3 gene, encoding RSK2, are responsible for Coffin–Lowry syndrome.

  • Two‐thirds of cases arise from new mutations.

  • There is no consistent phenotype/genotype correlation.

  • RSK2 is a serine/threonine kinase that acts at the distal end of the Ras‐ERK pathway and is activated by phosphorylation in response to growth factors and neurotransmitters.

  • Mice models for CLS have been generated that exhibit delayed bone formation as well as learning and memory deficits.

Keywords: X‐linked; RPS6KA3 gene; mental retardation; Coffin–Lowry syndrome; RSK2

Figure 1.

(a–d) Facial views of four males with CLS showing typical facies at different ages. (e, f) Views of the hands in two boys with CLS showing broad, tapering digits. From Hanauer and Young .

close

References

Coffin GS, Siris E and Wegenkia LC (1966) Mental retardation with osteocartilaginous anomalies. American Journal of Disease of Children 112: 205–213.

Delaunoy JP, Dubos A, Marques Pereira P and Hanauer A (2006) Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin‐Lowry syndrome. Clinical Genetics 70: 161–166.

Dufresne SD, Bjorbaek C, El‐Haschimi K et al. (2001) Altered extracellular signal‐regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice. Molecular and Cellular Biology 21: 81–87.

Field M, Tarpey P, Boyle J et al. (2006) Mutations in the RSK2(RPS6KA3) gene cause Coffin‐Lowry syndrome and nonsyndromic X‐linked mental retardation. Clinical Genetics 70: 509–515.

Hanauer A and Young ID (2002) Coffin‐Lowry syndrome: clinical and molecular features. Journal of Medical Genetics 39: 705–713.

Hauge C and Frodin M (2006) RSK and MSK in MAP kinase signalling. Journal of Cell Science 119: 3021–3023.

Lowry B, Miller JR and Fraser FC (1971) A new dominant gene mental retardation syndrome. American Journal of Disease of Children 121: 496–500.

Madrigal I, Rodriguez‐Revenga L, Armengol L et al. (2007) X‐chromosome tiling path array detection of copy number variants in patients with chromosome X‐linked mental retardation. BMC Genomics 8: 443.

Manouvrier‐Hanu S, Amiel J, Jacquot S et al. (1999) Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin‐Lowry syndrome. Journal of Medical Genetics 36: 775–778.

Marques Pereira P, Heron D and Hanauer A (2007) The first large duplication of the RSK2 gene identified in a Coffin‐Lowry syndrome patient. Human Genetics 122: 541–543.

Martinez‐Garay I, Ballesta MJ, Oltra S et al. (2003) Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin‐Lowry syndrome. Clinical Genetics 64: 491–496.

Merienne K, Jacquot S, Pannetier S et al. (1999) A missense mutation in RPS6KA3 (RSK2) responsible for non‐specific mental retardation. Nature Genetics 22: 13–14.

Micheli V, Sestini S, Parri V et al. (2007) RSK2 enzymatic assay as a second diagnotic tool in Coffin‐Lowry syndrome. Clinica Chimica Acta 384: 35–40.

Nakamura M, Amagata T, Mori M and Momoi MY (2005) RSK2 gene mutations in Coffin‐Lowry syndrome with drop episodes. Brain Development 27: 114–117.

Poirier R, Jacquot S, Vaillend C et al. (2006) Deletion of the Coffin‐Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior. Behavioral Genetics 37: 31–50.

Putz G, Bertolucci F, Raabe T, Zars T and Heisenberg M (2004) The S6KII (rsk) gene of Drosophila melanogaster differentially affects an operant and a classical learning task. Journal of Neuroscience 24: 9745–9751.

Temtamy SA, Miller JD and Hussels‐Maumenee I (1975) The Coffin‐Lowry syndrome: an inherited faciodigital mental retardation syndrome. Journal of Pediatrics 86: 724–731.

Yang X, Matsuda K, Bialek P et al. (2004) ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin‐Lowry Syndrome. Cell 117: 387–398.

Zeniou M, Pannetier S, Fryns JP and Hanauer A (2002) Unusual splice‐site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin‐Lowry syndrome. American Journal of Human Genetics 70: 1421–1433.

Zeniou‐Meyer M, Liu Y, Béglé A et al. (2008) The Coffin‐Lowry syndrome‐associated protein RSK2 is implicated in calcium‐regulated exocytosis through the regulation of PLD1. Proceedings of the National Academy of Sciences of the USA 105: 8434–8439.

Further Reading

Harum KH, Alemi L and Johnston MV (2001) Cognitive impairment in Coffin‐Lowry syndrome correlates with reduced RSK2 activation. Neurology 56: 207–214.

Kesler SR, Simensen RJ, Voeller K et al. (2007) Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin‐Lowry syndrome. Neurogenetics 8: 143–147.

Thomas GM, Rumbaugh GR, Harrar DB and Huganir RL (2005) Ribosomal S6 kinase 2 interacts with and phosphorylates PDZ domain‐containing proteins and regulates AMPA receptor transmission. Proceedings of the National Academy of Sciences of the USA 102: 15006–15011.

Zeniou M, Ding T, Trivier E and Hanauer A (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. Human Molecular Genetics 11: 2929–2940.

Web Links

Coffin‐Lowry syndrome (CLS) MIM number: 303600. OMIM: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=303600

The Coffin‐Lowry Syndrome Foundation (USA): http://clsf.info/

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hanauer, André(Mar 2009) Coffin–Lowry Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021431]