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Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome

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Abstract

Smith-Magenis syndrome (SMS) is a mental retardation/multiple congenital anomalies disorder associated with a heterozygous ~4-Mb deletion in 17p11.2. Patients with SMS show variability in clinical phenotype despite a common deletion found in >75–80% of patients. Recently, point mutations in the retinoic acid induced 1 (RAI1) gene, which lies within the SMS critical interval, were identified in three patients with many SMS features in whom no deletion was detected. It is not clear if the entire SMS phenotype can be accounted for by RAI1 haploinsufficiency, nor has the precise function of RAI1 been delineated. We report two novel RAI1 mutations, one frameshift and one nonsense allele, in nondeletion SMS patients. Comparisons of the clinical features in these two patients, three of the previously reported RAI1 point mutation cases, and the patients with a common deletion suggest that the majority of the clinical features in SMS result from RAI1 mutation, although phenotypic variability exists even among the individuals with RAI1 point mutations. Bioinformatics analyses of RAI1 and comparative genomics between human and mouse orthologues revealed a zinc finger-like plant homeo domain (PHD) at the carboxyl terminus that is conserved in the trithorax group of chromatin-based transcription regulators. These findings suggest RAI1 is involved in transcriptional control through a multi-protein complex whose function may be altered in individuals with SMS.

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References

  • Aasland R, Gibson TJ, Stewart AF (1995) The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem Sci 20:56–59

    Article  CAS  PubMed  Google Scholar 

  • Ames GF-L (1986) Bacterial periplasmic transport systems: structure, mechanism, and evolution. Annu Rev Biochem 55:397–425

    Article  CAS  PubMed  Google Scholar 

  • Bayarsaihan D, Soto RJ, Lukens LN (1998) Cloning and characterization of a novel sequence-specific single-stranded-DNA-binding protein. Biochem J 331:447–452

    PubMed  Google Scholar 

  • Bi W, Yan J, Stankiewicz P, Park S-S, Walz K, Boerkoel CF, Potocki L, Shaffer LG, Devriendt K, Nowaczyk MJM, Inoue K, Lupski JR (2002) Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse. Genome Res 12:713–728

    Article  CAS  PubMed  Google Scholar 

  • Bi W, Park S-S, Shaw CJ, Withers MA, Patel PI, Lupski JR (2003) Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am J Hum Genet 73:1302–1315

    Article  CAS  PubMed  Google Scholar 

  • Capili AD, Schultz DC, Rauscher FJ III, Borden KLB (2001) Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains. EMBO J 20:165–177

    Article  CAS  PubMed  Google Scholar 

  • Chen K-S, Potocki L, Lupski JR (1996) The Smith-Magenis syndrome [del(17)p11.2]: Clinical review and molecular advances. MRDD Res Rev 2:122–129

    Article  Google Scholar 

  • Chen K-S, Manian P, Koeuth T, Potocki L, Zhao Q, Chinault AC, Lee CC, Lupski JR (1997) Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet 17:154–163

    CAS  PubMed  Google Scholar 

  • Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA (1992) A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet 2:113–118

    CAS  PubMed  Google Scholar 

  • Finucane BM, Konar D, Haas-Givler B, Kurtz MB, Scott CI Jr (1994) The spasmodic upper-body squeeze: a characteristic behavior in Smith-Magenis syndrome. Dev Med Child Neurol 36:78–83

    CAS  PubMed  Google Scholar 

  • Greenberg F, Guzzetta V, Montes de Oca-Luna R, Magenis RE, Smith ACM, Richter SF, Kondo I, Dobyns WB, Patel PI, Lupski JR (1991) Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet 49:1207–1218

    CAS  PubMed  Google Scholar 

  • Greenberg F, Lewis RA, Potocki L, Glaze D, Parke J, Killian J, Murphy MA, Williamson D, Brown F, Dutton R, McCluggage C, Friedman E, Sulek M, Lupski JR (1996) Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2). Am J Med Genet 62:247–254

    Article  CAS  PubMed  Google Scholar 

  • Hayes S, Turecki G, Brisebois K, Lopes-Cendes I, Gaspar C, Riess O, Ranum LPW, Pulst S-M, Rouleau GA (2000) CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2). Hum Mol Genet 9:1753–1758

    Article  CAS  PubMed  Google Scholar 

  • Higgins CF, Hyde SC, Mimmack MM, Gileadi U, Gill DR, Gallagher MP (1990) Binding protein-dependent transport systems. J Bioenerg Biomembr 22:571–592

    CAS  PubMed  Google Scholar 

  • Hsieh JJ-D, Cheng EH-Y, Korsmeyer SJ (2003) Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression. Cell 115:293–303

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Suzuki Y, Matsui T, Tohyama M, Wanaka A, Takagi T (1995) Cloning of a retinoic acid-induced gene, GT1, in the embryonal carcinoma cell line P19: neuron-specific expression in the mouse brain. Mol Brain Res 31:1–9

    Article  CAS  PubMed  Google Scholar 

  • Inoue K, Khajavi M, Ohyama T, Hirabayashi SI, Wilson J, Reggin JD, Mancias P, Butler IJ, Wilkinson MF, Wegner M, Lupski JR (2004) Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 36:361–369

    Article  CAS  PubMed  Google Scholar 

  • Joober R, Benkelfat C, Toulouse A, Lafrenière RGA, Lal S, Ajroud S, Turecki G, Bloom D, Labelle A, Lalonde P, Alda M, Morgan K, Palmour R, Rouleau GA (1999) Analysis of 14 CAG repeat-containing genes in schizophrenia. Am J Med Genet 88:694–699

    Article  CAS  PubMed  Google Scholar 

  • Juyal RC, Figuera LE, Hauge X, Elsea SH, Lupski JR, Greenberg F, Baldini A, Patel PI (1996) Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 58:998–1007

    CAS  PubMed  Google Scholar 

  • Kieliszewski MJ, Lamport DTA (1994) Extensin: repetitive motifs, functional sites, post-translational codes, and phylogeny. Plant J 5:157–172

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S (2003) The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 113:905–917

    Article  CAS  PubMed  Google Scholar 

  • Liburd N, Ghosh M, Riazuddin S, Naz S, Khan S, Ahmed Z, Riazuddin S, Liang Y, Menon PSN, Smith T, Smith ACM, Chen K-S, Lupski JR, Wilcox ER, Potocki L, Friedman TB (2001) Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum Genet 109:535–541

    Article  CAS  PubMed  Google Scholar 

  • Mendell JT, Dietz HC (2001) When the message goes awry: disease-producing mutations that influence mRNA content and performance. Cell 107:411–414

    Article  CAS  PubMed  Google Scholar 

  • Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, Hess JL (2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10:1107–1117

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, Dubois G, Mazo A, Croce CM, Canaani E (2002) ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell 10:1119–1128

    Article  CAS  PubMed  Google Scholar 

  • Park S-S, Stankiewicz P, Bi W, Shaw C, Lehoczky J, Dewar K, Birren B, Lupski JR (2002) Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs. Genome Res 12:729–738

    Article  PubMed  Google Scholar 

  • Pascual J, Martinez-Yamout M, Dyson HJ, Wright PE (2000) Structure of the PHD zinc finger from human Williams-Beuren syndrome transcription factor. J Mol Biol 304:723–729

    Article  PubMed  Google Scholar 

  • Perriere G, Gouy M (1996) WWW-query: an on-line retrieval system for biological sequence banks. Biochimie 78:364–369

    Article  CAS  PubMed  Google Scholar 

  • Potocki L, Shaw CJ, Stankiewicz P, Lupski JR (2003) Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med 5:430–434

    Article  PubMed  Google Scholar 

  • Rekdal C, Sjøttem E, Johansen T (2000) The nuclear factor SPBP contains different functional domains and stimulates the activity of various transcriptional activators. J Biol Chem 275:40288–40300

    Article  CAS  PubMed  Google Scholar 

  • Seranski P, Hoff C, Radelof U, Hennig S, Reinhardt R, Schwartz CE, Heiss NS, Poustka A (2001) RAI1 is a novel polyglutamine encoding gene that is deleted in Smith-Magenis syndrome patients. Gene 270:69–76

    Article  CAS  PubMed  Google Scholar 

  • Shaw CJ, Shaw CA, Yu W, Stankiewicz P, White LD, Beaudet AL, Lupski JR (2004) Comparative genomic hybridisation using a proximal 17p BAC/PAC array detects rearrangements responsible for four genomic disorders. J Med Genet 41:113–119

    Article  CAS  PubMed  Google Scholar 

  • Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH (2003) Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet 33:466–468

    Article  CAS  PubMed  Google Scholar 

  • Smith ACM, McGavran L, Robinson J, Waldstein G, Macfarlane J, Zonona J, Reiss J, Lahr M, Allen L, Magenis E (1986) Interstitial deletion of (17)(p11.2p11.2) in nine patients. Am J Med Genet 24:393–414

    CAS  PubMed  Google Scholar 

  • Smith ACM, Gropman AL, Bailey-Wilson JE, Goker-Alpan O, Elsea SH, Blancato J, Lupski JR, Potocki L (2002) Hypercholesterolemia in children with Smith-Magenis syndrome: del (17) (p11.2p11.2). Genet Med 4:118–125

    Article  CAS  PubMed  Google Scholar 

  • Stankiewicz P, Shaw CJ, Dapper JD, Wakui K, Shaffer LG, Withers M, Elizondo L, Park S-S, Lupski JR (2003) Genome architecture catalyzes non-recurrent chromosomal rearrangements. Am J Hum Genet 72:1101–1116

    Article  CAS  PubMed  Google Scholar 

  • Stratton RF, Dobyns WB, Greenberg F, DeSana JB, Moore C, Fidone G, Runge GH, Feldman P, Sekhon GS, Pauli RM, Ledbetter DH (1986) Interstitial deletion of (17)(p11.2p11.2): report of six additional patients with a new chromosome deletion syndrome. Am J Med Genet 24:421–432

    CAS  PubMed  Google Scholar 

  • Toulouse A, Rochefort D, Roussel J, Joober R, Rouleau GA (2003) Molecular cloning and characterization of human RAI1, a gene associated with schizophrenia. Genomics 82:162–171

    Article  CAS  PubMed  Google Scholar 

  • Trask BJ, Mefford H, van den Engh G, Massa HF, Juyal RC, Potocki L, Finucane B, Abuelo DN, Witt DR, Magenis E, Baldini A, Greenberg F, Lupski JR, Patel PI (1996) Quantification by flow cytometry of chromosome-17 deletions in Smith-Magenis syndrome patients. Hum Genet 98:710–718

    Article  CAS  PubMed  Google Scholar 

  • Vlangos CN, Yim DKC, Elsea SH (2003) Refinement of the Smith-Magenis syndrome critical region to ~950 kb and assessment of 17p11.2 deletions. Are all deletions created equally? Mol Genet Metab 79:134–141

    Article  CAS  PubMed  Google Scholar 

  • Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, Morton CC, Morell RJ, Noben-Trauth K, Camper SA, Friedman TB (1998) Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science 280:1447–1451

    Article  CAS  PubMed  Google Scholar 

  • Wu H, de Graaf B, Mariani C, Cheung AY (2001) Hydroxyproline-rich glycoproteins in plant reproductive tissues: structure, functions and regulation. Cell Mol Life Sci 58:1418–1429

    CAS  PubMed  Google Scholar 

  • Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW (2002) Allelic variation in human gene expression. Science 297:1143

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS (1993) SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 75:187–197

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate the participation of patients and their families, the critical review of Dr. K. Inoue and the excellent technical assistance of M. Withers and T. Ohyama. This research was supported in part by grants from the National Institute of Child Health and Human Development (NIH) (P01 HD38420) (J.R.L.) and (K08 HD01149) (L.P.), the Baylor College of Medicine Mental Retardation Research Center (HD 2406407), and the Texas Children’s Hospital General Clinical Research Center (M01 RR00188).

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Correspondence to James R. Lupski.

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W. Bi and G.M. Saifi contributed equally to this work

DDBJ/EMBL/GenBank accession no. AY548172

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Bi, W., Saifi, G.M., Shaw, C.J. et al. Mutations of RAI1, a PHD-containing protein, in nondeletion patients with Smith-Magenis syndrome. Hum Genet 115, 515–524 (2004). https://doi.org/10.1007/s00439-004-1187-6

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