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Article: Epigenetics of autism spectrum disorders.

Schanen, N Carolyn

2006 Volume 15 Spec No 2, Page(s) R138–50

Abstract: The autism spectrum disorders (ASD) comprise a complex group of behaviorally related disorders that are primarily genetic in origin. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by the occurrence of ASD in ...

Abstract	The autism spectrum disorders (ASD) comprise a complex group of behaviorally related disorders that are primarily genetic in origin. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by the occurrence of ASD in patients with disorders arising from epigenetic mutations (fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome). Moreover, the most common recurrent cytogenetic abnormalities in ASD involve maternally derived duplications of the imprinted domain on chromosome 15q11-13. Thus, parent of origin effects on sharing and linkage to imprinted regions on chromosomes 15q and 7q suggest that these regions warrant specific examination from an epigenetic perspective, particularly because epigenetic modifications do not change the primary genomic sequence, allowing risk epialleles to evade detection using standard screening strategies. This review examines the potential role of epigenetic factors in the etiology of ASD.
MeSH term(s)	Autistic Disorder/genetics ; Child ; Child Development Disorders, Pervasive/genetics ; Chromosome Aberrations ; Chromosomes, Human, Pair 15/genetics ; Chromosomes, Human, Pair 7/genetics ; Chromosomes, Human, X/genetics ; Epigenesis, Genetic ; Female ; Genomic Imprinting ; Humans ; Male ; Syndrome
Language	English
Publishing date	2006-10-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddl213
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Article ; Online: The link between intraneuronal N-truncated amyloid-β peptide and oxidatively modified lipids in idiopathic autism and dup(15q11.2-q13)/autism.

Frackowiak, Janusz / Mazur-Kolecka, Bozena / Schanen, N Carolyn / Brown, W Ted / Wegiel, Jerzy

Acta neuropathologica communications

2013 Volume 1, Page(s) 61

Abstract: ... higher levels of neuronal N-truncated Aβ and HNE and MDA in idiopathic autism and dup(15)/autism ... deposition of N-truncated Aβ in childhood. The cascade of events includes altered APP metabolism and abnormal ... intracellular accumulation of N-terminally truncated Aβ which is a source of reactive oxygen species ...

Abstract	Background: Autism is a neurodevelopmental disorder of unknown etiopathogenesis associated with structural and functional abnormalities of neurons and increased formation of reactive oxygen species. Our previous study revealed enhanced accumulation of amino-terminally truncated amyloid-β (Aβ) in brain neurons and glia in children and adults with autism. Verification of the hypothesis that intraneuronal Aβ may cause oxidative stress was the aim of this study. Results: The relationships between neuronal Aβ and oxidative stress markers-4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA)-were examined in the frontal cortex from individuals aged 7-32 years with idiopathic autism or with chromosome 15q11.2-q13 duplications (dup(15)) with autism, and age-matched controls. Quantification of confocal microscopy images revealed significantly higher levels of neuronal N-truncated Aβ and HNE and MDA in idiopathic autism and dup(15)/autism than in controls. Lipid peroxidation products were detected in all mitochondria and lipofuscin deposits, in numerous autophagic vacuoles and lysosomes, and in less than 5% of synapses. Neuronal Aβ was co-localized with HNE and MDA, and increased Aβ levels correlated with higher levels of HNE and MDA. Conclusions: The results suggest a self-enhancing pathological process in autism that is initiated by intraneuronal deposition of N-truncated Aβ in childhood. The cascade of events includes altered APP metabolism and abnormal intracellular accumulation of N-terminally truncated Aβ which is a source of reactive oxygen species, which in turn increase the formation of lipid peroxidation products. The latter enhance Aβ deposition and sustain the cascade of changes contributing to metabolic and functional impairments of neurons in autism of an unknown etiology and caused by chromosome 15q11.2-q13 duplication.
MeSH term(s)	Adolescent ; Adult ; Aldehydes/metabolism ; Amyloid beta-Peptides/metabolism ; Autistic Disorder/complications ; Autistic Disorder/metabolism ; Brain/metabolism ; Child ; Chromosome Aberrations ; Chromosomes, Human, Pair 15/metabolism ; Female ; Humans ; Intellectual Disability/complications ; Intellectual Disability/metabolism ; Lipid Peroxidation/physiology ; Lysosomes/metabolism ; Male ; Malondialdehyde/metabolism ; Mitochondria/metabolism ; Neurons/metabolism ; Synapses/metabolism ; Vacuoles/metabolism ; Young Adult
Chemical Substances	Aldehydes ; Amyloid beta-Peptides ; Malondialdehyde (4Y8F71G49Q) ; 4-hydroxy-2-nonenal (K1CVM13F96)
Language	English
Publishing date	2013-09-16
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/2051-5960-1-61
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Article ; Online: The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13.

Hogart, Amber / Wu, David / LaSalle, Janine M / Schanen, N Carolyn

Neurobiology of disease

2010 Volume 38, Issue 2, Page(s) 181–191

Abstract: A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders ...

Abstract	A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.
MeSH term(s)	Angelman Syndrome/complications ; Angelman Syndrome/genetics ; Autistic Disorder/complications ; Autistic Disorder/genetics ; Child ; Chromosome Aberrations ; Chromosomes, Human, Pair 15/genetics ; Humans ; Prader-Willi Syndrome/complications ; Prader-Willi Syndrome/genetics
Language	English
Publishing date	2010-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2008.08.011
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Article: Pathophysiological mechanisms for actions of the neurotrophins.

Twiss, Jeffery L / Chang, Jay H / Schanen, N Carolyn

Brain pathology (Zurich, Switzerland)

2006 Volume 16, Issue 4, Page(s) 320–332

Abstract: Neurotrophins provide trophic and tropic support for different neuronal subpopulations in the developing and adult nervous systems. Expression of the neurotrophins and their receptors can be altered in several different disease or injury states that ... ...

Abstract	Neurotrophins provide trophic and tropic support for different neuronal subpopulations in the developing and adult nervous systems. Expression of the neurotrophins and their receptors can be altered in several different disease or injury states that impact upon the functions in the central and peripheral nervous systems. The intracellular signals used by the neurotrophins are triggered by ligand binding to the cell surface Trk and p75NTR receptors. In general, signals emanating from Trk receptors support survival, growth and synaptic strengthening, while those emanating from p75NTR induce apoptosis, attenuate growth and weaken synaptic signaling. Mature neurotrophins are the preferred ligand for Trk proteins while p75NTR binds preferentially to the proneurotrophins and serves as a signaling component of the receptor complex for growth inhibitory molecules of central nervous system myelin [ie, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgP) and Nogo]. The functional antagonism between Trk and p75NTR signaling may significantly impact the pathogenesis of human neurodevelopmental and neurodegenerative diseases and further complicate therapeutic uses of exogenous neurotrophins. The potential for each is discussed in this review.
MeSH term(s)	Animals ; Humans ; Nerve Growth Factors/metabolism ; Nerve Regeneration/physiology ; Nervous System Diseases/metabolism ; Nervous System Diseases/physiopathology ; Neuronal Plasticity/physiology ; Neurons/metabolism ; Receptors, Nerve Growth Factor/metabolism ; Signal Transduction/physiology
Chemical Substances	Nerve Growth Factors ; Receptors, Nerve Growth Factor
Language	English
Publishing date	2006-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/j.1750-3639.2006.00039.x
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Article ; Online: A single-tube quantitative high-resolution melting curve method for parent-of-origin determination of 15q duplications.

Urraca, Nora / Davis, Lea / Cook, Edwin H / Schanen, N Carolyn / Reiter, Lawrence T

Genetic testing and molecular biomarkers

2010 Volume 14, Issue 4, Page(s) 571–576

Abstract: The most common chromosomal abnormalities associated with autism are 15q11-q13 duplications. Maternally derived or inherited duplications of 15q pose a substantial risk for an autism phenotype, while paternally derived duplications may be incompletely ... ...

Abstract	The most common chromosomal abnormalities associated with autism are 15q11-q13 duplications. Maternally derived or inherited duplications of 15q pose a substantial risk for an autism phenotype, while paternally derived duplications may be incompletely penetrant or result in other neurodevelopmental problems. Therefore, the determination of maternal versus paternal origin of this duplication is important for early intervention therapies and for appropriate genetic counseling to the families. We adapted a previous single-reaction tube assay (high-resolution melting curve analysis) to determine the parent of origin of 15q duplications in 28 interstitial duplication 15q samples, one family and two isodicentric subjects. Our method distinguished parent origin in 92% of the independent samples as well as in the familial inherited duplication and in the two isodicentric samples. This method accurately determines parental origin of the duplicated segment and measures the dosage of these alleles in the sample. In addition, it can be performed on samples where parental DNA is not available for microsatellite analysis. The development of this single-tube assay will make it easier for genetic testing laboratories to provide parent-of-origin information and will provide important information to clinical geneticists about autism risk in these individuals.
MeSH term(s)	Adult ; Child ; Chromosome Duplication ; Chromosomes, Human, Pair 15/genetics ; DNA Mutational Analysis/instrumentation ; DNA Mutational Analysis/methods ; DNA Mutational Analysis/standards ; Female ; Humans ; Inheritance Patterns/genetics ; Male ; Molecular Diagnostic Techniques/methods ; Molecular Diagnostic Techniques/standards ; Mosaicism ; Nucleic Acid Denaturation ; Parents ; Reference Standards ; Trisomy/diagnosis ; Trisomy/genetics ; Uniparental Disomy/diagnosis ; Uniparental Disomy/genetics
Language	English
Publishing date	2010-07-16
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2486664-7
ISSN	1945-0257 ; 1945-0265
ISSN (online)	1945-0257
ISSN	1945-0265
DOI	10.1089/gtmb.2010.0030
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Article: Differential distribution of the MeCP2 splice variants in the postnatal mouse brain.

Dragich, Joanna M / Kim, Yong-Hwan / Arnold, Arthur P / Schanen, N Carolyn

The Journal of comparative neurology

2007 Volume 501, Issue 4, Page(s) 526–542

Abstract: Mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) are the primary cause of the neurodevelopmental disorder Rett syndrome (RTT). Mecp2-deficient mice develop a neurological phenotype that recapitulates many of the symptoms of RTT, ... ...

Abstract	Mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) are the primary cause of the neurodevelopmental disorder Rett syndrome (RTT). Mecp2-deficient mice develop a neurological phenotype that recapitulates many of the symptoms of RTT, including postnatal onset of the neurological deficits. MeCP2 has two isoforms, MeCP2e1 and MeCP2e2, with distinct amino termini, which are generated by alternative splicing. We examined the distribution of the Mecp2 splice variants in the postnatal mouse brain by in situ hybridization and found regional and age-related differences in transcript abundance. In newborn mice, signals for total Mecp2 and the Mecp2e2 transcripts were widely distributed, with overlapping expression patterns throughout the brain. Expression of the Mecp2e2 splice variant became largely restricted to nuclei within the dorsal thalamus (DT) and cortical layer V in juvenile animals, a pattern that was maintained into adulthood. In contrast, the total Mecp2 riboprobe only weakly labeled the DT and cortical layer V in juvenile and adult animals, although it heavily labeled surrounding brain regions, suggesting that Mecp2e1 is the predominant transcript outside the thalamus. Quantitative real-time PCR was used to measure Mecp2e1 and Mecp2e2 abundance in the diencephalon of adult mice, demonstrating significantly more Mecp2e2 in the DT than in the hypothalamus, which is in agreement with the Mecp2e2 in situ hybridization. The differential distribution of the Mecp2e1 and Mecp2e2 transcripts indicates regional and developmental regulation of Mecp2 splicing in the postnatal mouse brain.
MeSH term(s)	Age Factors ; Alternative Splicing ; Animals ; Animals, Newborn ; Brain/growth & development ; Brain/metabolism ; Brain Mapping ; Female ; Gene Expression Regulation, Developmental/physiology ; In Situ Hybridization/methods ; Male ; Methyl-CpG-Binding Protein 2/genetics ; Mice ; Mice, Inbred C57BL ; RNA, Messenger ; Reverse Transcriptase Polymerase Chain Reaction/methods
Chemical Substances	Mecp2 protein, mouse ; Methyl-CpG-Binding Protein 2 ; RNA, Messenger
Language	English
Publishing date	2007-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.21264
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Article ; Online: Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.

Yasui, Dag H / Gonzales, Michael L / Aflatooni, Justin O / Crary, Florence K / Hu, Daniel J / Gavino, Bryant J / Golub, Mari S / Vincent, John B / Schanen, N Carolyn / Olson, Carl O / Rastegar, Mojgan / Lasalle, Janine M

Human molecular genetics

2014 Volume 23, Issue 24, Page(s) 6695

Language	English
Publishing date	2014-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddu496
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Article: Does genotype predict phenotype in Rett syndrome?

Ham, Andrea L / Kumar, Asmita / Deeter, Rose / Schanen, N Carolyn

Journal of child neurology

2005 Volume 20, Issue 9, Page(s) 768–778

Abstract: Mutations in the X-linked gene encoding the methyl-CpG binding protein MeCP2 are the primary cause of classic and atypical Rett syndrome and have recently been shown to contribute to other neurodevelopmental disorders of varying severity. To determine ... ...

Abstract	Mutations in the X-linked gene encoding the methyl-CpG binding protein MeCP2 are the primary cause of classic and atypical Rett syndrome and have recently been shown to contribute to other neurodevelopmental disorders of varying severity. To determine whether there are molecular correlates to the phenotypic heterogeneity, numerous groups have performed genotype-phenotype correlation studies. These studies have yielded conflicting results, in part because they used different criteria for determining severity and classifying mutations. Evolution of the phenotype with age and variable expressivity arising from individual variability in X-chromosome inactivation patterns are among other reasons the findings varied. Nonetheless, evidence of differences in the phenotypic consequences of specific types of mutations is emerging. This review analyzes the available literature and makes recommendations for future studies.
MeSH term(s)	Brain Diseases/genetics ; Brain Diseases/pathology ; Female ; Genotype ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/pathology ; Male ; Mutation/genetics ; Phenotype ; Rett Syndrome/complications ; Rett Syndrome/genetics ; Rett Syndrome/pathology
Language	English
Publishing date	2005-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	639288-x
ISSN	1708-8283 ; 0883-0738
ISSN (online)	1708-8283
ISSN	0883-0738
DOI	10.1177/08830738050200091301
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Article ; Online: Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene.

Pitcher, Meagan R / Herrera, José A / Buffington, Shelly A / Kochukov, Mikhail Y / Merritt, Jonathan K / Fisher, Amanda R / Schanen, N Carolyn / Costa-Mattioli, Mauro / Neul, Jeffrey L

Human molecular genetics

2015 Volume 24, Issue 9, Page(s) 2662–2672

Abstract: Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% ... ...

Abstract	Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2(R255X)). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2(R255X) mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2(R255X) allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2(R255X) embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein.
MeSH term(s)	Alleles ; Amino Acid Substitution ; Animals ; Behavior, Animal ; Disease Models, Animal ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Expression ; Genetic Association Studies ; Gentamicins/pharmacology ; Mechanistic Target of Rapamycin Complex 1 ; Methyl-CpG-Binding Protein 2/genetics ; Methyl-CpG-Binding Protein 2/metabolism ; Mice ; Mice, Transgenic ; Multiprotein Complexes/metabolism ; Mutation ; Phenotype ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rett Syndrome/diagnosis ; Rett Syndrome/genetics ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; Transgenes
Chemical Substances	Gentamicins ; Methyl-CpG-Binding Protein 2 ; Multiprotein Complexes ; RNA, Messenger ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2015-05-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddv030
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Article ; Online: Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.

Yasui, Dag H / Gonzales, Michael L / Aflatooni, Justin O / Crary, Florence K / Hu, Daniel J / Gavino, Bryant J / Golub, Mari S / Vincent, John B / Carolyn Schanen, N / Olson, Carl O / Rastegar, Mojgan / Lasalle, Janine M

Human molecular genetics

2013 Volume 23, Issue 9, Page(s) 2447–2458

Abstract: Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations ... ...

Abstract	Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulates RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here, a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon 1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hindlimb clasping, excessive grooming and hypo-activity prior to death between 7 and 31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing, 96% amino acid identity, differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in subnuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole contributor to RTT with non-redundant functions.
MeSH term(s)	Animals ; Blotting, Western ; Exons/genetics ; Female ; Fluorescent Antibody Technique ; Male ; Methyl-CpG-Binding Protein 2/genetics ; Mice ; Mice, Transgenic ; Mutation/genetics ; Rett Syndrome/genetics
Chemical Substances	Methyl-CpG-Binding Protein 2
Language	English
Publishing date	2013-12-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddt640
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