• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jmedgeneJournal of Medical GeneticsVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
J Med Genet. Apr 2005; 42(4): 299–306.
PMCID: PMC1736026

Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome


Background: A new syndrome has been recognised following thorough analysis of patients with a terminal submicroscopic subtelomeric deletion of chromosome 9q. These have in common severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, thickened lower lip, carp mouth with macroglossia, and conotruncal heart defects. The minimum critical region responsible for this 9q subtelomeric deletion syndrome (9q–) is approximately 1.2 Mb and encompasses at least 14 genes.

Objective: To characterise the breakpoints of a de novo balanced translocation t(X;9)(p11.23;q34.3) in a mentally retarded female patient with clinical features similar to the 9q– syndrome.

Results: Sequence analysis of the break points showed that the translocation was fully balanced and only one gene on chromosome 9 was disrupted—Euchromatin Histone Methyl Transferase1 (Eu-HMTase1)—encoding a histone H3 lysine 9 methyltransferase (H3-K9 HMTase). This indicates that haploinsufficiency of Eu-HMTase1 is responsible for the 9q submicroscopic subtelomeric deletion syndrome. This observation was further supported by the spatio-temporal expression of the gene. Using tissue in situ hybridisation studies in mouse embryos and adult brain, Eu-HMTase1 was shown to be expressed in the developing nervous system and in specific peripheral tissues. While expression is selectively downregulated in adult brain, substantial expression is retained in the olfactory bulb, anterior/ventral lateral ventricular wall, and hippocampus and weakly in the piriform cortex.

Conclusions: The expression pattern of this gene suggests a role in the CNS development and function, which is in line with the severe mental retardation and behaviour problems in patients who lack one copy of the gene.

Full Text

The Full Text of this article is available as a PDF (374K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Slavotinek A, Rosenberg M, Knight S, Gaunt L, Fergusson W, Killoran C, Clayton-Smith J, Kingston H, Campbell RH, Flint J, et al. Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres. J Med Genet. 1999 May;36(5):405–411. [PMC free article] [PubMed]
  • De Vries BBA, Winter R, Schinzel A, van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003 Jun;40(6):385–398. [PMC free article] [PubMed]
  • Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, Winter RM, Bolton P, Flint J. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet. 1999 Nov 13;354(9191):1676–1681. [PubMed]
  • Cormier-Daire V, Molinari F, Rio M, Raoul O, de Blois M-C, Romana S, Vekemans M, Munnich A, Colleaux L. Cryptic terminal deletion of chromosome 9q34: a novel cause of syndromic obesity in childhood? J Med Genet. 2003 Apr;40(4):300–303. [PMC free article] [PubMed]
  • Anderlid Britt-Marie, Schoumans Jacqueline, Annerén Göran, Sahlén Sigrid, Kyllerman Mårten, Vujic Mihailo, Hagberg Bengt, Blennow Elisabeth, Nordenskjöld Magnus. Subtelomeric rearrangements detected in patients with idiopathic mental retardation. Am J Med Genet. 2002 Feb 1;107(4):275–284. [PubMed]
  • Iwakoshi Mie, Okamoto Nobuhiko, Harada Naoki, Nakamura Tsuyoshi, Yamamori Shunji, Fujita Hiroko, Niikawa Norio, Matsumoto Naomichi. 9q34.3 deletion syndrome in three unrelated children. Am J Med Genet A. 2004 Apr 30;126A(3):278–283. [PubMed]
  • Stewart Douglas R, Huang Alina, Faravelli Francesca, Anderlid Britt-Marie, Medne Livija, Ciprero Karen, Kaur Maninder, Rossi Elena, Tenconi Romano, Nordenskjöld Magnus, et al. Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome. Am J Med Genet A. 2004 Aug 1;128A(4):340–351. [PubMed]
  • Dawson AJ, Putnam S, Schultz J, Riordan D, Prasad C, Greenberg CR, Chodirker BN, Mhanni AA, Chudley AE. Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features. Clin Genet. 2002 Dec;62(6):488–494. [PubMed]
  • Rossi E, Piccini F, Zollino M, Neri G, Caselli D, Tenconi R, Castellan C, Carrozzo R, Danesino C, Zuffardi O, et al. Cryptic telomeric rearrangements in subjects with mental retardation associated with dysmorphism and congenital malformations. J Med Genet. 2001 Jun;38(6):417–420. [PMC free article] [PubMed]
  • Fauth C, Zhang H, Harabacz S, Brown J, Saracoglu K, Lederer G, Rittinger O, Rost I, Eils R, Kearney L, et al. A new strategy for the detection of subtelomeric rearrangements. Hum Genet. 2001 Dec;109(6):576–583. [PubMed]
  • Kleefstra T, Yntema HG, Oudakker AR, Banning MJG, Kalscheuer VM, Chelly J, Moraine C, Ropers H-H, Fryns J-P, Janssen IM, et al. Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation. J Med Genet. 2004 May;41(5):394–399. [PMC free article] [PubMed]
  • Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. [PMC free article] [PubMed]
  • Koolen DA, Nillesen WM, Versteeg MHA, Merkx GFM, Knoers NVAM, Kets M, Vermeer S, van Ravenswaaij CMA, de Kovel CG, Brunner HG, et al. Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA). J Med Genet. 2004 Dec;41(12):892–899. [PMC free article] [PubMed]
  • Smidt MP, van Schaick HS, Lanctôt C, Tremblay JJ, Cox JJ, van der Kleij AA, Wolterink G, Drouin J, Burbach JP. A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13305–13310. [PMC free article] [PubMed]
  • Yatsenko SA, Cheung SW, Scott DA, Nowaczyk MJM, Tarnopolsky M, Naidu S, Bibat G, Patel A, Leroy JG, Scaglia F, et al. Deletion 9q34.3 syndrome: genotype-phenotype correlations and an extended deletion in a patient with features of Opitz C trigonocephaly. J Med Genet. 2005 Apr;42(4):328–335. [PMC free article] [PubMed]
  • Bernier Patrick J, Bedard Andreanne, Vinet Jonathan, Levesque Martin, Parent Andre. Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11464–11469. [PMC free article] [PubMed]
  • Bédard Andréanne, Parent André Evidence of newly generated neurons in the human olfactory bulb. Brain Res Dev Brain Res. 2004 Jul 19;151(1-2):159–168. [PubMed]
  • Prickaerts Jos, Koopmans Guido, Blokland Arjan, Scheepens Arjan. Learning and adult neurogenesis: survival with or without proliferation? Neurobiol Learn Mem. 2004 Jan;81(1):1–11. [PubMed]
  • Ogawa Hidesato, Ishiguro Kei-Ichiro, Gaubatz Stefan, Livingston David M, Nakatani Yoshihiro. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 2002 May 10;296(5570):1132–1136. [PubMed]
  • Tachibana Makoto, Sugimoto Kenji, Nozaki Masami, Ueda Jun, Ohta Tsutomu, Ohki Misao, Fukuda Mikiko, Takeda Naoki, Niida Hiroyuki, Kato Hiroyuki, et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 2002 Jul 15;16(14):1779–1791. [PMC free article] [PubMed]
  • Dodge Jonathan E, Kang Yong-Kook, Beppu Hideyuki, Lei Hong, Li En. Histone H3-K9 methyltransferase ESET is essential for early development. Mol Cell Biol. 2004 Mar;24(6):2478–2486. [PMC free article] [PubMed]
  • Xin Zhenghan, Tachibana Makoto, Guggiari Michele, Heard Edith, Shinkai Yoichi, Wagstaff Joseph. Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center. J Biol Chem. 2003 Apr 25;278(17):14996–15000. [PubMed]
  • Tamaru H, Selker EU. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature. 2001 Nov 15;414(6861):277–283. [PubMed]
  • Lachner Monika, O'Sullivan Roderick J, Jenuwein Thomas. An epigenetic road map for histone lysine methylation. J Cell Sci. 2003 Jun 1;116(Pt 11):2117–2124. [PubMed]
  • Lachner Monika, Jenuwein Thomas. The many faces of histone lysine methylation. Curr Opin Cell Biol. 2002 Jun;14(3):286–298. [PubMed]
  • Feng Qin, Wang Hengbin, Ng Huck Hui, Erdjument-Bromage Hediye, Tempst Paul, Struhl Kevin, Zhang Yi. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol. 2002 Jun 25;12(12):1052–1058. [PubMed]
  • Richards Eric J, Elgin Sarah C R. Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects. Cell. 2002 Feb 22;108(4):489–500. [PubMed]
  • Ausió J, Levin DB, De Amorim GV, Bakker S, Macleod PM. Syndromes of disordered chromatin remodeling. Clin Genet. 2003 Aug;64(2):83–95. [PubMed]
  • Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999 Oct;23(2):185–188. [PubMed]
  • Couvert P, Bienvenu T, Aquaviva C, Poirier K, Moraine C, Gendrot C, Verloes A, Andrès C, Le Fevre AC, Souville I, et al. MECP2 is highly mutated in X-linked mental retardation. Hum Mol Genet. 2001 Apr 15;10(9):941–946. [PubMed]
  • Yntema Helger G, Oudakker Astrid R, Kleefstra Tjitske, Hamel Ben C J, van Bokhoven Hans, Chelly Jamel, Kalscheuer Vera M, Fryns Jean-Pierre, Raynaud Martine, Moizard Marie-Pierre, et al. In-frame deletion in MECP2 causes mild nonspecific mental retardation. Am J Med Genet. 2002 Jan 1;107(1):81–83. [PubMed]
  • Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998 May 28;393(6683):386–389. [PubMed]
  • Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998 Jun;19(2):187–191. [PubMed]
  • Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I, Mandel JL, Sassone-Corsi P, Hanauer A. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature. 1996 Dec 12;384(6609):567–570. [PubMed]
  • Merienne K, Jacquot S, Pannetier S, Zeniou M, Bankier A, Gecz J, Mandel JL, Mulley J, Sassone-Corsi P, Hanauer A. A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation. Nat Genet. 1999 May;22(1):13–14. [PubMed]
  • Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S, Hanauer A, Allis CD. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science. 1999 Aug 6;285(5429):886–891. [PubMed]
  • Merienne K, Pannetier S, Harel-Bellan A, Sassone-Corsi P. Mitogen-regulated RSK2-CBP interaction controls their kinase and acetylase activities. Mol Cell Biol. 2001 Oct;21(20):7089–7096. [PMC free article] [PubMed]
  • Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature. 1995 Jul 27;376(6538):348–351. [PubMed]
  • Gibbons RJ, Higgs DR. Molecular-clinical spectrum of the ATR-X syndrome. Am J Med Genet. 2000 Fall;97(3):204–212. [PubMed]
  • Guerrini R, Shanahan JL, Carrozzo R, Bonanni P, Higgs DR, Gibbons RJ. A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy. Ann Neurol. 2000 Jan;47(1):117–121. [PubMed]
  • Yntema Helger G, Poppelaars Francis A, Derksen Esther, Oudakker Astrid R, van Roosmalen Tanja, Jacobs Anja, Obbema Hanneke, Brunner Han G, Hamel Ben C J, van Bokhoven Hans. Expanding phenotype of XNP mutations: mild to moderate mental retardation. Am J Med Genet. 2002 Jul 1;110(3):243–247. [PubMed]
  • Cardoso C, Timsit S, Villard L, Khrestchatisky M, Fontès M, Colleaux L. Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein. Hum Mol Genet. 1998 Apr;7(4):679–684. [PubMed]
  • Shoichet Sarah A, Hoffmann Kirsten, Menzel Corinna, Trautmann Udo, Moser Bettina, Hoeltzenbein Maria, Echenne Bernard, Partington Michael, Van Bokhoven Hans, Moraine Claude, et al. Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. Am J Hum Genet. 2003 Dec;73(6):1341–1354. [PMC free article] [PubMed]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...