A Novel Nonsense Mutation in KDM5C/JARID1C Gene Causing Intellectual

Neuroscience Letters 498 (2011) 67–71

Contents lists available at ScienceDirect

Neuroscience Letters

jou rnal homepage: www.elsevier.com/locate/neulet

A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual

disability, short stature and speech delay

a,∗ a b b

Cíntia B. Santos-Rebouc¸ as , Natalia Fintelman-Rodrigues , Lars R. Jensen , Andreas W. Kuss ,

c a a a

Márcia G. Ribeiro , Mário Campos Jr. , Jussara M. Santos , Márcia M.G. Pimentel

Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil

Department for Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany

Clinical Genetics Service, IPPMG, Federal University of Rio de Janeiro, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Mutations in the Jumonji AT-rich interactive domain 1C (JARID1C/SMCX/KDM5C) gene, located at Xp11.22,

Received 23 March 2011

are emerging as frequent causes of X-linked intellectual disability (XLID). KDM5C encodes for a member

Received in revised form 11 April 2011

of an ARID protein family that harbors conserved DNA-binding motifs and acts as a histone H3 lysine 4

Accepted 25 April 2011

demethylase, suggesting a potential role in epigenetic regulation during development, cell growth and

differentiation. In this study, we describe clinical and genetic ﬁndings of a Brazilian family co-segregating

Keywords:

a novel nonsense mutation (c.2172C > A) in exon 15 of KDM5C gene with the intellectual disability phe-

X-linked intellectual disability

notype. The transition resulted in replacement of the normal cysteine by a premature termination codon

JARID1C

KDM5C at position 724 of the protein (p.Cys724X), leading to reduced levels of KDM5C transcript probably due to

nonsense mediated mRNA decay. The clinical phenotype of the proband, who has two affected brothers

Histone demethylase

Epigenetics and a mild cognitively impaired mother, consisted of short stature, speech delay, hyperactivity, vio-

Chromatin remodeling lent behavior and high palate, besides severe mental retardation. Our ﬁndings extend the number of

KDM5C mutations implicated in XLID and highlight its promise for understanding neural function and

unexplained cases of XLID.

Intellectual disability (ID), formerly known as mental retardation [16]. Genes located at these regions have been shown to encode for

(MR), is characterized by substantial limitations in both intellectual proteins involved in signaling pathways, responsible for regulat-

functioning and adaptative behavior before the age of 18 years, and ing cytoskeleton organization and synaptic efﬁcacy, besides acting

has long been recognized as a common and etiologically hetero- in other essential functions, like chromatin remodeling dynamics

geneous disorder, affecting 1–3% of the general population [4,12]. [19].

Over 10% of ID cases with a Mendelian inheritance pattern have Conversely to other NS-XLID genes, mutations in Jumonji AT-

been assigned to the X chromosome, even though it carries only rich interactive domain 1C (JARID1C/SMCX/KDM5C; MIM #300534),

about 4% of all human protein-coding genes, leading to a marked a non-pseudoautosomal brain-expressed gene located at Xp11.22,

excess of hemizygous males with intellectual disability as com- have emerged as a potential common cause for XLID. KDM5C con-

pared to females [15]. Up to now, more than 90 genes have been tains 26 exons and encodes an ubiquitinous 1560-aa protein that

associated to X-Linked Intellectual Disability (XLID) [6]. Therefore, catalyzes the removal of methyl groups from di- and tri-methylated

mutation frequencies in the majority of them are low, especially lysine 4 on histone H3 lysine 4 (H3K4). It suggests a central tran-

for the non syndromic forms of XLID (NS-XLID), which represent scriptional repressive role for KDM5C in chromatin dynamics and

∼

2/3 of all XLID cases. Consequently, many of the genetic deter- epigenetic regulation during cell growth, differentiation and devel-

minants of NS-XLID remain to be elucidated. Mutations that give opment [5,9,21,24]. Furthermore, the strongest expression of the

rise to NS-XLID are not evenly distributed along the X-chromosome predominant KDM5C transcript was observed in skeletal muscle

and seem to be clustered in regions Xp11, Xp22 and Xq26-q28 [8] and brain, mainly in the hippocampus [23] and a biological role

for this gene in neuronal survival and dendritic development has

been provided [7].

KDM5C protein is homologous to three other proteins of the

∗

Corresponding author at: Servic¸ o de Genética Humana, Departamento de

human JARID1 family (JARID1A, JARID1B and JARID1C). This fam-

Genética, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do

ily shares several evolutionarily conserved domains, including the

Rio de Janeiro, Rua São Francisco Xavier, 524, PHLC – sala 501, Maracanã 20550-013,

catalytic JmjC domain, JmjN domain, Arid/Bright domain, C5HC2

Rio de Janeiro, RJ, Brazil. Tel.: +55 21 23340039; fax: +55 21 23340499.

E-mail addresses: [email protected], [email protected] (C.B. Santos-Rebouc¸ as). zinc-ﬁnger domain and two plant homeodomains (PHD), a motif

68 C.B. Santos-Rebouc¸ as et al. / Neuroscience Letters 498 (2011) 67–71

Fig. 1. Family pedigree showing the segregation of the c.2172C > A in the KDM5C gene. Solid squares represent boys with intellectual disability and circle with a dot represents

their mother, who has mild intellectual impairment. Open squares represent unaffected males. An arrow indicates the proband (II-4). A diamond represents a pregnancy

ended at the ﬁfth month, whose malformed newborn died 24 h after being born. “N” indicates KDM5C gene without the mutation. NT, is for ‘not available to be tested’.

Chromatograms showing the mutations or wild-type sequences are shown below the tested individuals.

that binds methyl-lysine residues [5,7]. Recent evidence demon- siblings are similar to the proband’s, including severe ID and short

strates that KDM5C protein can be post translationally modiﬁed stature (Fig. 1). Both are institutionalized, but biological samples

by ubiquitin in vitro, suggesting that this modiﬁcation is function- were available for only one of them.

ally relevant for maintaining the proper balance between histone As a short stature phenotype segregates with ID in the family,

demethylase and methyltransferase activities [13]. molecular analysis of KDM5C coding sequence and ﬂanking intronic

Herein, we describe clinical and genetic ﬁndings from a Brazil- regions was performed by standard PCR according to Jensen et al.

ian family segregating a novel nonsense mutation (c.2172C > A) in [8], followed by bidirectional direct sequencing with the BigDye

KDM5C gene compatible with ID phenotype. The mutation gener- Terminator kit on an ABI3100 automated sequencer (Applied

ates a premature termination codon at position 724 of the protein Biosystems, Foster City, USA). We found a novel c.2172C > A transi-

(p.Cys724X) in the C5HC2 zinger ﬁnger domain, leading to reduction in exon 15 of KDM5C gene, which was conﬁrmed in a new PCR

tion of KDM5C expression levels. from a second DNA sample from the patient. KDM5C sequencing

The Brazilian family described here consists of three affected from available members of the family proved that the truncating

brothers and a mild cognitively impaired mother. The propositus mutation segregates completely with the ID phenotype, since the

(TRP), a 13-year-old boy (year of birth 1996), is the fourth of ﬁve variant was present in all genotyped individuals with ID (Fig. 2;

children of a young and unrelated couple. He was born by vaginal individuals II.2 and II.4) and absent in unaffected males (Fig. 2;

delivery after an uncomplicated pregnancy with no major inter- individuals II.3 and II.6).

currence during neonatal period (birth weight = 2.54 kg; unknown For KDM5C expression analysis, total RNA was obtained from

length), except for the fact that he was submitted to photother- whole blood of two affected brothers and two unaffected brothers

apy during the ﬁrst week of life due to jaundice. At the age of using the RiboPure-Blood kit (Ambion, Austin, TX). The integrity

24 months, a general developmental delay was recognized (head of the RNA was visualized on ethidium stained agarose gels and

control at 6th month of age; sitting position at 8th month of age; quantiﬁed using a ND-1000 Spectrophotometer (NanoDrop Tech-

walking at 24th month of age and ﬁrst words at 24th month of nologies, Wilmington, DE). For quantitative RT-PCR, 50 ng total

age), as well as other features such as failure to thrive, learning RNA was reverse transcribed into cDNA in the presence of 1.5 ␮g

difﬁculties, aggressive behavior, hyperactivity and regular respi- random hexamers pdN 6 (Invitrogen, Carlsbad, CA) and 0.33 mM

ratory/urinary infections. Clinical investigation included normal dNTP in a total volume of 30 ␮l using the Roche (Mannheim,

results for inborn errors of metabolism, computed tomography (CT) Germany) First Strand cDNA Synthesis Kit. PCR ampliﬁcations

scan and abdominal ultrasonography. Due to an idiopathic familial were performed in triplicates of 25 ␮l reactions in the presence of

history of intellectual disability, compatible with an X-linked pat- SYBR green (Applied Biosystems, Foster City, CA). Quantitations

tern, TRP was referred to the Human Genetics Service of the State were performed using the absolute quantiﬁcation setting on an

University of Rio de Janeiro in 2005. He exhibited a normal 550 ABI PRISM 7900HT Sequence Detection System (Applied Biosys-

band resolution karyotype. Mutations in FMR1, FMR2, MECP2 and tems, Foster City, CA) and a standard curve generated by serial

ARX genes were subsequently ruled out, as well as, submicroscopic dilution (factor 2) of a control cDNA. The PCR primers contain the

duplications/deletions across chromosome X (through Multiplex following sequences: KDM5C F: 5 -CATCATGGTGCAAGAAGAGC-

Ligation-dependent Probe Ampliﬁcation). At the age of 12 years 3 ; KDM5C R: 5 - ATGTGGGAAAGGCAGACAAG-3 ;

and 6 months, he spoke just some words, without making a sen- GAPDH F: 5 -CCACCCATGGCAAATTCC-3 and GAPDH R: 5 -

tence and exhibited proportionate short stature (height = 130 cm, TGGGATTTCCATTGATGACAAG-3 . The institutional Ethics Com-

below 3rd percentile), low weight (28.85 kg, below 3rd percentile), mittee has approved all procedures and samples from TRP patient

microcephaly (head circumference = 51 cm, below 3rd percentile), and relatives were obtained after receiving informed consent.

high palate, slight maxillary hypoplasia and small feet, besides We identiﬁed a novel c.2172C > A transition in exon 15 of KDM5C

being severely mental retarded. Clinical features of two affected gene, which resulted in substitution of the original cysteine by

C.B. Santos-Rebouc¸ as et al. / Neuroscience Letters 498 (2011) 67–71 69

Fig. 2. The clinical picture showing the individuals (II-2 and II-4) who presented the c.2172C > A mutation in KDM5C gene.

a premature termination codon at position 724 of the protein mature termination codon [17]. Moreover, speech delay has been

(p.Cys724X) in the evolutionarily conserved C5HC2 zinger ﬁnger also related to JARIDIC missense mutations among patients with ID

domain. The mutation was not present in the latest dbSNP build [22] or autism [2]. Furthermore, the violent behavior exhibited by

132 database and was detected in all available affected brothers TRP and by other KDM5C mutated patients [8] is consistent with

and their mother, an obligate carrier. the higher expression of Jarid1c mRNA in certain brain regions of

As nonsense mutations in KDM5C have previously been shown rodents, like bed nucleus of stria terminalis [23].

to result in reduced KDM5C mRNA levels [8], we test whether the Among the ID-related truncating KDM5C mutations, only those

novel nonsense c.2172C > A mutation found in the present fam- reported by Jensen et al. [8] (p.R68fsX7, p.Arg694X and p.Trp1288X)

ily also affect the KDM5C mRNA level. Therefore, we performed and Rujirabanjerd et al. [17] (p.K1087fs(*)43) were evaluated for

RT-qPCR on RNA extracted from two affected brothers and two KDM5C expression stability, in addition to that reported in this

unaffected brothers. The two affected brothers both show reduced study (p.Cys724X). Conversely to p.R68fsX7 and p.K1087fs(*)43

levels of KDM5C transcript as compared to the unaffected broth- mutations, a signiﬁcant reduction of KDM5C expression was seen

ers (Table 1), which strongly suggests that this novel nonsense for p.Arg694X, p.Trp1288X and p.Cys724X (see also Table 2), sug-

mutation is implicated in the phenotype observed in the patients. gesting that the ID phenotype in the individuals carrying these

Within the last ﬁve years, twenty putative ID-related and one mutations resulted from functional loss of KDM5C protein likely

autism-related mutations were described along the KDM5C gene due to nonsense mediated mRNA decay (NMD) [3,20]. This mech-

in peer-reviewed publications, including the one reported in this anism ensures the destruction of transcripts containing premature

study. Among them, eight represent variants that lead to prema- termination codons to prevent more harmful consequences for the

ture termination codons, including nonsense variants, small out-of- cell. As to p.R68fsX7, where a loss of transcription was not observed,

frame deletions/insertions or intronic mutation [1,8,17,18,22] it is possible that the mutation leads to ID phenotype due to severe

(Table 2). The phenotype variability seen within and between fam- loss of essential JARIDIC protein domains or to the production of

ilies is probably due to the functional severity of the mutations, an anomalous protein from the alternative use of a methionine

the existence of possible compensatory mechanisms by alternative downstream of exon 2 [8]. In case of p.K1087fs(*)43, the prema-

histone demethylases and to other epigenetic and environmental ture termination codon associated with the mutation did not lead to

modifying factors. Shared features among patients harboring these degradation of the mRNA, probably because the insertion is only 52

truncating mutations include mainly moderate to severe ID and nucleotides from the exon 22 to 23 boundary and thus insensitive

short stature. Developmental delay in the language domain present or only partially sensitive to NMD [17].

in our patient has been previously reported in a family, in which Nonsense mutations not just impair KDM5C activity, but can

ID segregates with a single-nucleotide insertion resulting in a pre- also disturb the functions of its target genes. Recently, a KDM5C

expression proﬁling performed on lymphoblastoid cell lines and

blood from patients with ID-related mutations in KDM5C identi-

Table 1

ﬁed several deregulated genes, including CMKOR1, KDM5B and the

Differential expression of JARID1C transcript between patients and controls.

brain expressed KIAA0469 [9]. Also, a KDM5C complex isolated from

Individual Expression HeLa cells showed additional components as chromatin modiﬁers

(e.g. histone deacetylases HDAC1 and HDAC2, and the histone H3K9

II:2 (affected) 0.313

II:4 (affected) 0.322 methyltransferase G9a) and the RE-1 silencing transcription fac-

II:3 (unaffected) 0.747 tor (REST) [21]. REST regulates the expression of many neuronal

II:6 (unaffected) 0.703

genes, of which some were already implicated in mental retar-

Normalized against GAPDH expression. dation, like brain-derived neurotropic factor (BDNF) [14] and the

70 C.B. Santos-Rebouc¸ as et al. / Neuroscience Letters 498 (2011) 67–71

Table 2

Variants found in JARID1C gene that lead to premature stop codons in patients with MR phenotype and their consequences.

Nucleotide change Position Amino acid variation Domain Main clinical characteristics Expression analysis Reference

c.202 203insC Exon 2 p.R68fsX7 Inter domains Severe MR, strabismus, violent Without reduction [8]

behavior, diastema of teeth of transcript levels

c.994C > T Exon 8 p.Arg332X PHD zinc ﬁnger Moderate to severe MR, short – [22]

stature

c.1583 + 5G > A Intron 11 p.E468GfsX2 JmjC Severe MR, short stature, RT-PCR analysis [1]

microcephaly, maxillary and cDNA

hypoplasia, hyperreﬂexia sequencing

showed skipping of

exon 11

c.2080C > T Exon 15 p.Arg694X Inter domains MR, strabismus, myopia, short Reduction of [8]

stature transcript levels

c.3864G > A Exon 23 p.Trp1288X Inter domains Severe MR, spasticity, epilepsy, Reduction of [8]

short stature, microcephaly, transcript level

cryptorchidism, alopecia areata

c.4441 4442delAG Exon 26 p.R1481GfsX9 C-terminal end Severe MR, short stature, – [1]

macrocephaly, hyperreﬂexia,

seizures, high palate

c.3258 3259insC Exon 21 p.K1087fs(*)43 C-terminal end Severe MR, short stature, Without reduction [17]

speech delay, of transcript levels

hyperreﬂexia/spasticity

c.2172C > A Exon 15 p.Cys724X C5HC2 zinc ﬁnger Severe MR, short stature, Reduction of This study

domain speech delay, hyperactivity, transcript levels

high palate

sodium channel gene SCN2A [10]. Furthermore, RNA interference [3] M.D. Bashyam, Nonsense-mediated decay: linking a basic cellular process to

human disease, Expert Rev. Mol. Diagn. 9 (2009) 299–303.

(RNAi)-mediated of KDM5C gene resulted in derepression of SCN2A

[4] J.P. Brosco, M. Mattingly, L.M. Sanders, X-linked mental retardation: many

and at least other ﬁve genes distributed into three categories:

genes for a complex disorder, Arch. Pediatr. Adolesc. Med. 160 (2006) 302–309.

CACNA1B and CACNA1H, encoding calcium channels; SCL6A3 and [5] J. Christensen, K. Agger, P.A. Cloos, D. Pasini, S. Rose, L. Sennels, J. Rappsilber,

K.H. Hansen, A.E. Salcini, K.K. Helin, RBP2 belongs to a family of demethy-

SLC18A1, encoding monoamine transporters; and SLC6A12, encod-

lases, speciﬁc for tri-and dimethylated lysine 4 on histone 3, Cell 128 (2007)

ing a GABA transporter. All these last six KDM5C target genes 1063–1076.

have been previously implicated in neurological disorders such as [6] J Gécz, C. Shoubridge, M. Corbett, The genetic landscape of intellectual disability

arising from chromosome X, Trends Genet. 25 (2009) 308–316.

epilepsy, autism or schizophrenia [21]. KDM5C also interacts with

[7] S. Iwase, F. Lan, P. Bayliss, L. de la Torre-Ubieta, M. Huarte, H.H. Qi, J.R. Whet-

Smad3, a DNA-binding transcription factor that mediates the trans-

stine, A. Bonni, T.M. Roberts, Y. Shi, The X-linked mental retardation gene

␤ ␤

formation growth factor- (TGF- ) signaling. It suggests a role of SMCX/JARID1C deﬁnes a family of histone H3 lysine 4 demethylases, Cell 128

KDM5C in tumorigenesis and in silico expression analysis showed (2007) 1077–1088.

[8] L.R. Jensen, M. Amende, U. Gurok, B. Moser, V. Gimmel, A. Tzschach, A.R. Janecke,

an overexpression of this gene in prostate tumors and seminomas

G. Tariverdian, J. Chelly, J.P. Fryns, H. Van Esch, T. Kleefstra, B. Hamel, C. Moraine,

[11]. However, to the best of our knowledge, none of the mentally

J. Gecz, G. Turner, R. Reinhardt, V.M. Kalscheuer, H.H. Ropers, S. Lenzner, Muta-

handicapped harboring KDM5C mutations manifested any kind of tions in the JARID1C gene, which is involved in transcriptional regulation and

tumors. chromatin remodeling, cause X-linked mental retardation, Am. J. Hum. Genet.

76 (2005) 227–236.

In contrast to other XLID genes, KDM5C has been highlighted as

[9] L.R. Jensen, H. Bartenschlager, S. Rujirabanjerd, A. Tzschach, A. Nümann, A.R.

one of the most commonly mutated, justifying the time consum- Janecke, R. Spörle, S. Stricker, M. Raynaud, J. Nelson, A. Hackett, J.P. Fryns, J.

Chelly, A.P. de Brouwer, B. Hamel, J. Gecz, H.H. Ropers, A.W. Kuss, A distinctive

ing evaluation of the whole gene and/or routine KDM5C expression

gene expression ﬁngerprint in mentally retarded male patients reﬂects disease-

analysis, mainly when a short stature phenotype segregates with

causing defects in the histone demethylase KDM5C, Pathogenetics 3 (2010)

ID in families with at least two affected male siblings. Furthermore, 2.

[10] K. Kamiya, M. Kaneda, T. Sugawara, E. Mazaki, N. Okamura, M. Montal, N.

the identiﬁcation of novel putatively disease-causing mechanisms

Makita, M. Tanaka, K. Fukushima, T. Fujiwara, Y. Inoue, K. Yamakawa, A non-

associated to KDM5C can bring new clues to unravel the genetic

sense mutation of the sodium channel gene SCN2A in a patient with intractable

causes of ID, besides it contributes to the understanding of the epilepsy and mental decline, J. Neurosci. 24 (2004) 2690–2698.

[11] T.D. Kim, S. Shin, R. Janknecht, Repression of Smad3 activity by histone

epigenetic network involved in neural function and learning. In

demethylase SMCX/JARID1C, Biochem. Biophys. Res. Commun. 366 (2008)

addition, the perspective of reversing epigenetic marks may pro-

563–567.

vide new pharmacological tools for therapeutic intervention. [12] S.A. Larson, K.C. Lakin, L. Anderson, N. Kwak, J.H. Lee, D. Anderson, Preva-

lence of mental retardation and developmental disabilities: estimates from

the 1994/1995 National Health Interview Survey Disability Supplements, Am.

Acknowledgements J. Ment. Retard. 106 (2001) 231–252.

[13] D.P. Mersman, H.N. Du, I.M. Fingerman, P.F. South, S.D. Briggs, Polyubiquitina-

tion of the demethylase Jhd2 controls histone methylation and gene expression,

The authors thank the reported family for their kind coopera-

Genes Dev. 23 (2009) 951–962.

tion. This work was supported by funds from CNPq (565705/2008- [14] S. Pezet, M. Malcangio, Brain-derived neurotrophic factor as a drug target for

CNS disorders, Expert Opin. Ther. Targets 8 (2004) 391–399.

3), FAPERJ (E-26/103.052/2008 and E-26/110.765/2010) and

[15] H. Ropers, B.C. Hamel, X-linked mental retardation, Nat. Rev. Genet. 6 (2005)

CEPUERJ. 46–57.

[16] H.H. Ropers, M. Hoeltzenbein, V. Kalscheuer, H. Yntema, B. Hamel, J.P. Fryns, J.

Chelly, M. Partington, J. Gecz, C. Moraine, Nonsyndromic X-linked mental retar-

References dation: where are the missing mutations? Trends Genet. 9 (2003) 316–320.

[17] S. Rujirabanjerd, J. Nelson, P.S. Tarpey, A. Hackett, S. Edkins, F.L. Raymond, C.E.

Schwartz, G. Turner, S. Iwase, Y. Shi, P.A. Futreal, M.R. Stratton, J.J. Gecz, Iden-

[1] F.E. Abidi, L. Holloway, C.A. Moore, D.D. Weaver, R.J. Simensen, R.E. Stevenson,

tiﬁcation and characterization of two novel JARID1C mutations: suggestion of

R.C. Rogers, C.E. Schwartz, Mutations in JARID1C are associated with X-linked

an emerging genotype-phenotype correlation, Eur. J. Hum. Genet. 18 (2010)

mental retardation, short stature and hyperreﬂexia, J. Med. Genet. 45 (2008)

787–793. 330–335.

[18] C. Santos, L. Rodriguez-Revenga, I. Madrigal, C. Badenas, M. Pineda, M. Milà,

[2] A. Adegbola, H. Gao, S. Sommer, M. Browning, A novel mutation in

A novel mutation in JARID1C gene associated with mental retardation, Eur. J.

JARID1C/SMCX in a patient with autism spectrum disorder (ASD), Am. J. Med.

Hum. Genet. 14 (2006) 583–586.

Genet. A 146A (2008) 505–511.

C.B. Santos-Rebouc¸ as et al. / Neuroscience Letters 498 (2011) 67–71 71

[19] C.B. Santos-Rebouc¸ as, M.M.G. Pimentel, New insights into X-linked men- [22] A. Tzschach, S. Lenzner, B. Moser, R. Reinhardt, J. Chelly, J.P. Fryns, T. Kleefstra,

tal retardation: from clinical to molecular approaches, in: M.I. Carson M. Raynaud, G. Turner, H.H. Ropers, A. Kuss, L.R. Jensen, Novel JARID1C/SMCX

(Ed.), Focus on Mental Retardation, Columbus F, New York, 2007, pp. mutations in patients with X-linked mental retardation, Hum. Mutat. 27 (2006)

153–184. 389.

[20] A.L. Silva, L. Romão, The mammalian nonsense-mediated mRNA decay path- [23] J. Xu, X. Deng, C.M. Disteche, Sex-speciﬁc expression of the X-linked histone

way: to decay or not to decay! Which players make the decision? FEBS Lett. demethylase gene Jarid1c in brain, PloS One 3 (2008) e2553.

583 (2009) 499–505. [24] L. Yi, Z. Hao, T. Yang, S. Wang, B. Xing, Y. Xu, cDNA cloning, bioinformatic and

[21] M. Tahiliani, P. Mei, R. Fang, The histone H3K4 demethylase SMCX links REST tissue-speciﬁc expression analysis of porcine JARID1C gene, J. Genet. Genomics

target genes to X-linked mental retardation, Nature 447 (2007) 601–605. 34 (2007) 1088–1096.