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Smith–Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways

Published online by Cambridge University Press:  19 April 2011

Sarah H. Elsea*
Affiliation:
Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Stephen R. Williams
Affiliation:
Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
*
*Corresponding author: Sarah H. Elsea, Department of Pediatrics, 1101 E. Marshall Street, 12-018 Sanger Hall, VCU School of Medicine, Richmond, VA 23298, USA. E-mail: selsea@vcu.edu

Abstract

Smith–Magenis syndrome (SMS) is a complex neurobehavioural disorder characterised by intellectual disability, self-injurious behaviours, sleep disturbance, obesity, and craniofacial and skeletal anomalies. Diagnostic strategies are focused towards identification of a 17p11.2 microdeletion encompassing the gene RAI1 (retinoic acid induced 1) or a mutation of RAI1. Molecular evidence shows that most SMS features are due to RAI1 haploinsufficiency, whereas variability and severity are modified by other genes in the 17p11.2 region for 17p11.2 deletion cases. The functional role of RAI1 is not completely understood, but it is probably a transcription factor acting in several different biological pathways that are dysregulated in SMS. Functional studies based on the hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes have shown that RAI1 gene dosage is crucial for normal regulation of circadian rhythm, lipid metabolism and neurotransmitter function. Here, we review the clinical and molecular features of SMS and explore more recent studies supporting possible therapeutic strategies for behavioural management.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011

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References

References

1Shinawi, M. and Cheung, S.W. (2008) The array CGH and its clinical applications. Drug Discovery Today 13, 760-770CrossRefGoogle ScholarPubMed
2Sudmant, P.H. et al. (2010) Diversity of human copy number variation and multicopy genes. Science 330, 641-646CrossRefGoogle ScholarPubMed
3Smith, A.C. et al. (1986) Interstitial deletion of (17)(p11.2p11.2) in nine patients. American Journal of Medical Genetics 24, 393-414CrossRefGoogle Scholar
4Girirajan, S. et al. (2006) Genotype-phenotype correlation in Smith–Magenis syndrome: evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genetics in Medicine 8, 417-427CrossRefGoogle Scholar
5Slager, R.E. et al. (2003) Mutations in RAI1 associated with Smith–Magenis syndrome. Nature Genetics 33, 466-468CrossRefGoogle ScholarPubMed
6Bi, W. et al. (2005) Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith–Magenis syndrome. Human Molecular Genetics 14, 983-995CrossRefGoogle ScholarPubMed
7Carmona-Mora, P. et al. (2010) Functional and cellular characterization of human retinoic acid induced 1 (RAI1) mutations associated with Smith–Magenis syndrome. BMC Molecular Biology 11, 63CrossRefGoogle ScholarPubMed
8Zhang, F. et al. (2010) Identification of uncommon recurrent Potocki–Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS. American Journal of Human Genetics 86, 462-470CrossRefGoogle ScholarPubMed
9Turner, D.J. et al. (2008) Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nature Genetics 40, 90-95CrossRefGoogle ScholarPubMed
10Lee, J.A., Carvalho, C.M. and Lupski, J.R. (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235-1247CrossRefGoogle ScholarPubMed
11Yatsenko, S.A. et al. (2005) Trisomy 17p10-p12 due to mosaic supernumerary marker chromosome: delineation of molecular breakpoints and clinical phenotype, and comparison to other proximal 17p segmental duplications. American Journal of Medical Genetics A 138, 175-180CrossRefGoogle Scholar
12Elsea, S.H. and Girirajan, S. (2008) Smith–Magenis syndrome. European Journal of Human Genetics 16, 412-421CrossRefGoogle ScholarPubMed
13Zori, R.T. et al. (1993) Clinical, cytogenetic, and molecular evidence for an infant with Smith–Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion. American Journal of Medical Genetics 47, 504-511CrossRefGoogle ScholarPubMed
14Williams, S.R. et al. (2009) Array comparative genomic hybridisation of 52 subjects with a Smith–Magenis-like phenotype: identification of dosage sensitive loci also associated with schizophrenia, autism, and developmental delay. Journal of Medical Genetics 47, 223-229CrossRefGoogle ScholarPubMed
15Allanson, J.E., Greenberg, F. and Smith, A.C. (1999) The face of Smith–Magenis syndrome: a subjective and objective study. Journal of Medical Genetics 36, 394-397CrossRefGoogle ScholarPubMed
16Tomona, N. et al. (2006) Craniofacial and dental phenotype of Smith–Magenis syndrome. American Journal of Medical Genetics A 140, 2556-2561CrossRefGoogle ScholarPubMed
17Edelman, E. et al. (2007) Gender, genotype, and phenotype differences in Smith–Magenis syndrome: a meta-analysis of 105 cases. Clinical Genetics 71, 540-550CrossRefGoogle ScholarPubMed
18Truong, H.T. et al. (2010) Frameshift mutation hotspot identified in Smith–Magenis syndrome: case report and review of literature. BMC Medical Genetics 11, 142CrossRefGoogle ScholarPubMed
19Burns, B. et al. (2010) Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. Human Molecular Genetics 19, 4026-4042CrossRefGoogle ScholarPubMed
20Gropman, A.L. et al. (2007) New developments in Smith–Magenis syndrome (del 17p11.2). Current Opinion in Neurology 20, 125-134CrossRefGoogle ScholarPubMed
21Di Cicco, M. et al. (2001) Otorhinolaringologic manifestation of Smith–Magenis syndrome. International Journal of Pediatric Otorhinolaryngology 59, 147-150CrossRefGoogle ScholarPubMed
22Greenberg, F. et al. (1996) Multi-disciplinary clinical study of Smith–Magenis syndrome (deletion 17p11.2). American Journal of Medical Genetics 62, 247-2543.0.CO;2-Q>CrossRefGoogle ScholarPubMed
23Liburd, N. et al. (2001) Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith–Magenis syndrome. Human Genetics 109, 535-541CrossRefGoogle Scholar
24Chen, R.M. et al. (1996) Ophthalmic manifestations of Smith–Magenis syndrome. Ophthalmology 103, 1084-1091CrossRefGoogle ScholarPubMed
25Finucane, B.M. et al. (1993) Eye abnormalities in the Smith–Magenis contiguous gene deletion syndrome. American Journal of Medical Genetics 45, 443-446CrossRefGoogle ScholarPubMed
26Smith, A.C., Dykens, E. and Greenberg, F. (1998) Sleep disturbance in Smith–Magenis syndrome (del 17 p11.2). American Journal of Medical Genetics 81, 186-1913.0.CO;2-D>CrossRefGoogle ScholarPubMed
27Finucane, B.M. and Jaeger, E.R. (1997) Smith–Magenis syndrome. Ophthalmology 104, 732-733CrossRefGoogle ScholarPubMed
28Gropman, A.L., Duncan, W.C. and Smith, A.C. (2006) Neurologic and developmental features of the Smith–Magenis syndrome (del 17p11.2). Pediatric Neurology 34, 337-350CrossRefGoogle ScholarPubMed
29Potocki, L. et al. (2003) Variability in clinical phenotype despite common chromosomal deletion in Smith–Magenis syndrome [del(17)(p11.2p11.2)]. Genetics in Medicine 5, 430-434CrossRefGoogle Scholar
30Potocki, L. et al. (2000) Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome. Journal of Medical Genetics 37, 428-433CrossRefGoogle ScholarPubMed
31De Leersnyder, H. et al. (2006) Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome. Molecular and Cellular Endocrinology 252, 88-91CrossRefGoogle Scholar
32De Leersnyder, H. et al. (2001) Inversion of the circadian rhythm of melatonin in the Smith–Magenis syndrome. Journal of Pediatrics 139, 111-116CrossRefGoogle ScholarPubMed
33Boudreau, E.A. et al. (2009) Review of disrupted sleep patterns in Smith–Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. American Journal of Medical Genetics A 149A, 1382-1391CrossRefGoogle Scholar
34Park, S.S. et al. (2002) Structure and evolution of the Smith–Magenis syndrome repeat gene clusters, SMS-REPs. Genome Research 12, 729-738CrossRefGoogle ScholarPubMed
35Chen, K.S. et al. (1997) Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nature Genetics 17, 154-163CrossRefGoogle ScholarPubMed
36Shaw, C.J. and Lupski, J.R. (2005) Non-recurrent 17p11.2 deletions are generated by homologous and non-homologous mechanisms. Human Genetics 116, 1-7CrossRefGoogle ScholarPubMed
37Shaw, C.J., Withers, M.A. and Lupski, J.R. (2004) Uncommon deletions of the Smith–Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates. American Journal of Human Genetics 75, 75-81CrossRefGoogle ScholarPubMed
38Stankiewicz, P. et al. (2003) Genome architecture catalyzes nonrecurrent chromosomal rearrangements. American Journal of Human Genetics 72, 1101-1116CrossRefGoogle ScholarPubMed
39Potocki, L. et al. (2000) Molecular mechanism for duplication 17p11.2- the homologous recombination reciprocal of the Smith–Magenis microdeletion. Nature Genetics 24, 84-87CrossRefGoogle ScholarPubMed
40Bi, W. et al. (2003) Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. American Journal of Human Genetics 73, 1302-1315CrossRefGoogle ScholarPubMed
41Shaw, C.J., Bi, W. and Lupski, J.R. (2002) Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2. American Journal of Human Genetics 71, 1072-1081CrossRefGoogle ScholarPubMed
42Bi, W. et al. (2006) RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith–Magenis syndrome. American Journal of Medical Genetics A 140, 2454-2463CrossRefGoogle ScholarPubMed
43Girirajan, S. et al. (2005) RAI1 variations in Smith–Magenis syndrome patients without 17p11.2 deletions. Journal of Medical Genetics 42, 820-828CrossRefGoogle ScholarPubMed
44Bi, W. et al. (2004) Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith–Magenis syndrome. Human Genetics 115, 515-524CrossRefGoogle ScholarPubMed
45Treadwell-Deering, D.E., Powell, M.P. and Potocki, L. (2010) Cognitive and behavioral characterization of the Potocki–Lupski syndrome (duplication 17p11.2). Journal of Developmental and Behavioral Pediatrics 31, 137-143CrossRefGoogle ScholarPubMed
46Potocki, L. et al. (2007) Characterization of Potocki–Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. American Journal of Human Genetics 80, 633-649CrossRefGoogle Scholar
47Soler-Alfonso, C. et al. (2010) Potocki–Lupski syndrome: a microduplication syndrome associated with oropharyngeal dysphagia and failure to thrive. Journal of Pediatrics. Dec 16; [Epub ahead of print]Google ScholarPubMed
48Waterston, R.H. et al. (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520-562Google ScholarPubMed
49Walz, K. et al. (2003) Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. Molecular and Cellular Biology 23, 3646-3655CrossRefGoogle Scholar
50Girirajan, S. and Elsea, S.H. (2009) Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice. Mammalian Genome 20, 247-255CrossRefGoogle ScholarPubMed
51Ricard, G. et al. (2010) Phenotypic consequences of copy number variation: insights from Smith–Magenis and Potocki–Lupski syndrome mouse models. PLoS Biology 8, e1000543CrossRefGoogle ScholarPubMed
52Bi, W. et al. (2007) Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes. Human Molecular Genetics 16, 1802-1813CrossRefGoogle ScholarPubMed
53Walz, K. et al. (2004) Behavioral characterization of mouse models for Smith–Magenis syndrome and dup(17)(p11.2p11.2). Human Molecular Genetics 13, 367-378CrossRefGoogle Scholar
54Walz, K. et al. (2006) Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). Journal of Clinical Investigation 116, 3035-3041CrossRefGoogle Scholar
55Girirajan, S. et al. (2008) How much is too much? Phenotypic consequences of Rai1 overexpression in mice. European Journal of Human Genetics 16, 941-954CrossRefGoogle ScholarPubMed
56Molina, J. et al. (2008) Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki–Lupski syndrome. Human Molecular Genetics 17, 2486-2495CrossRefGoogle Scholar
57Capili, A.D. et al. (2001) Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains. EMBO Journal 20, 165-177CrossRefGoogle Scholar
58Imai, Y. et al. (1995) Cloning of a retinoic acid-induced gene, GT1, in the embryonal carcinoma cell line P19: neuron-specific expression in the mouse brain. Brain Research. Molecular Brain Research 31, 1-9CrossRefGoogle ScholarPubMed
59Bienz, M. (2006) The PHD finger, a nuclear protein-interaction domain. Trends in Biochemical Sciences 31, 35-40CrossRefGoogle ScholarPubMed
60Girirajan, S. et al. (2009) A functional network module for Smith–Magenis syndrome. Clinical Genetics 75, 364-374CrossRefGoogle ScholarPubMed
61Turek, F.W. et al. (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043-1045CrossRefGoogle ScholarPubMed
62Angelucci, F., Brene, S. and Mathe, A.A. (2005) BDNF in schizophrenia, depression and corresponding animal models. Molecular Psychiatry 10, 345-352CrossRefGoogle ScholarPubMed
63Duncan, L.E. et al. (2009) Variation in brain-derived neurotrophic factor (BDNF) gene is associated with symptoms of depression. Journal of Affective Disorders 115, 215-219CrossRefGoogle ScholarPubMed
64Wendland, J.R. et al. (2007) A large case-control study of common functional SLC6A4 and BDNF variants in obsessive-compulsive disorder. Neuropsychopharmacology 32, 2543-2551CrossRefGoogle ScholarPubMed
65Kramar, E.A. et al. (2010) BDNF upregulation rescues synaptic plasticity in middle-aged ovariectomized rats. Neurobiology of Aging. Jul 29; [Epub ahead of print]Google ScholarPubMed
66Lauterborn, J.C. et al. (2009) Ampakines cause sustained increases in brain-derived neurotrophic factor signaling at excitatory synapses without changes in AMPA receptor subunit expression. Neuroscience 159, 283-295CrossRefGoogle ScholarPubMed
67Ogier, M. et al. (2007) Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome. Journal of Neuroscience 27, 10912-10917CrossRefGoogle Scholar
68Simmons, D.A. et al. (2009) Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice. Proceedings of the National Academy of Sciences of the United States of America 106, 4906-4911CrossRefGoogle ScholarPubMed
69Williams, S.R. et al. (2010) Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. American Journal of Human Genetics 87, 219-228CrossRefGoogle ScholarPubMed
70Laje, G. et al. (2010) Pharmacological treatment of disruptive behavior in Smith-Magenis syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 154C, 463-468CrossRefGoogle ScholarPubMed
71Di Lorenzo, L. et al. (2003) Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry. International Journal of Obesity and Related Metabolic Disorders 27, 1353-1358CrossRefGoogle Scholar
72Vollmers, C. et al. (2009) Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression. Proceedings of the National Academy of Sciences of the United States of America 106, 21453-21458CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

The NCBI Bookshelf entry for SMS provides a comprehensive review, including medical management recommendations: