The Role of Neuronal Complexes in Human X-Linked Brain Diseases
2007; Elsevier BV; Volume: 80; Issue: 2 Linguagem: Inglês
10.1086/511441
ISSN1537-6605
AutoresFrédéric Laumonnier, Peter C. Cuthbert, Seth G. N. Grant,
Tópico(s)Nuclear Receptors and Signaling
ResumoBeyond finding individual genes that are involved in medical disorders, an important challenge is the integration of sets of disease genes with the complexities of basic biological processes. We examine this issue by focusing on neuronal multiprotein complexes and their components encoded on the human X chromosome. Multiprotein signaling complexes in the postsynaptic terminal of central nervous system synapses are essential for the induction of neuronal plasticity and cognitive processes in animals. The prototype complex is the N-methyl-d-aspartate receptor complex/membrane-associated guanylate kinase–associated signaling complex (NRC/MASC) comprising 185 proteins and embedded within the postsynaptic density (PSD), which is a set of complexes totaling ∼1,100 proteins. It is striking that 86% (6 of 7) of X-linked NRC/MASC genes and 49% (19 of 39) of X-chromosomal PSD genes are already known to be involved in human psychiatric disorders. Moreover, of the 69 known proteins mutated in X-linked mental retardation, 19 (28%) encode postsynaptic proteins. The high incidence of involvement in cognitive disorders is also found in mouse mutants and indicates that the complexes are functioning as integrated entities or molecular machines and that disruption of different components impairs their overall role in cognitive processes. We also noticed that NRC/MASC genes appear to be more strongly associated with mental retardation and autism spectrum disorders. We propose that systematic studies of PSD and NRC/MASC genes in mice and humans will give a high yield of novel genes important for human disease and new mechanistic insights into higher cognitive functions. Beyond finding individual genes that are involved in medical disorders, an important challenge is the integration of sets of disease genes with the complexities of basic biological processes. We examine this issue by focusing on neuronal multiprotein complexes and their components encoded on the human X chromosome. Multiprotein signaling complexes in the postsynaptic terminal of central nervous system synapses are essential for the induction of neuronal plasticity and cognitive processes in animals. The prototype complex is the N-methyl-d-aspartate receptor complex/membrane-associated guanylate kinase–associated signaling complex (NRC/MASC) comprising 185 proteins and embedded within the postsynaptic density (PSD), which is a set of complexes totaling ∼1,100 proteins. It is striking that 86% (6 of 7) of X-linked NRC/MASC genes and 49% (19 of 39) of X-chromosomal PSD genes are already known to be involved in human psychiatric disorders. Moreover, of the 69 known proteins mutated in X-linked mental retardation, 19 (28%) encode postsynaptic proteins. The high incidence of involvement in cognitive disorders is also found in mouse mutants and indicates that the complexes are functioning as integrated entities or molecular machines and that disruption of different components impairs their overall role in cognitive processes. We also noticed that NRC/MASC genes appear to be more strongly associated with mental retardation and autism spectrum disorders. We propose that systematic studies of PSD and NRC/MASC genes in mice and humans will give a high yield of novel genes important for human disease and new mechanistic insights into higher cognitive functions. 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The primary role of AMPA receptors is to mediate the membrane depolarization that is necessary to initiate action potentials in the postsynaptic neuron. By contrast, the NMDA and mGluR receptors do not significantly contribute to the depolarization but do initiate signal transduction–pathway signaling. Moreover, NMDA and mGluR receptors are physically linked by scaffolding proteins and are found within multiprotein complexes, along with signaling enzymes and other proteins.10Husi H Ward MA Choudhary JS Blackstock WP Grant SG Proteomic analysis of NMDA receptor-adhesion protein signalling complexes.Nat Neurosci. 2000; 3: 661-669Crossref PubMed Scopus (994) Google Scholar, 11Collins MO Yu L Coba MP Husi H Campuzano I Blackstock WP Choudhary JS Grant SG Proteomic analysis of in vivo phosphorylated synaptic proteins.J Biol Chem. 2005; 280: 5972-5982Crossref PubMed Scopus (275) Google Scholar, 12Kandel ER The molecular biology of memory storage: a dialogue between genes and synapses.Science. 2001; 294: 1030-1038Crossref PubMed Scopus (2542) Google Scholar, 13Grant SGN Husi H Choudhary J Cumiskey M Blackstock W Armstrong JD The organization and integrative function of the post-synaptic proteome.in: Hensch TK Fagiolini M Excitatory-inhibitory balance: synapses, circuits, systems. Kluwer Academic/Plenum Publishers, New York2004: 13-44Google Scholar Pharmacological antagonists for the glutamate receptors have been available for >20 years and have been used extensively in animal and human studies, and it is clear that these receptors play a role in a diverse set of behaviors.14Kemp JA McKernan RM NMDA receptor pathways as drug targets.Nat Neurosci. 2002; 5: 1039-1042Crossref PubMed Scopus (412) Google Scholar, 15Robbins TW Murphy ER Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition.Trends Pharmacol Sci. 2006; 27: 141-148Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar These findings have led to the “glutamate hypothesis” of mental illnesses.16Bear MF Huber KM Warren ST The mGluR theory of fragile X mental retardation.Trends Neurosci. 2004; 27: 370-377Abstract Full Text Full Text PDF PubMed Scopus (1197) Google Scholar, 17Persico AM Bourgeron T Searching for ways out of the autism maze: genetic, epigenetic and environmental clues.Trends Neurosci. 2006; 29: 349-358Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar Although there is no doubt that glutamate receptors are physiologically important, progress in several areas has dramatically expanded our understanding of their role in synapse biology. First, it is known that the receptors physically link to a plethora of proteins and form signaling and trafficking complexes (discussed in detail below); second, synapse proteomics has characterized multiprotein complexes and has discovered hundreds of postsynaptic proteins, many of which are involved with human disease; and, third, genetic manipulation of synapse proteins in mouse has overcome the limited availability of pharmacological antagonists and, hence, has allowed the functional testing of specific genes in behaviors. Given the large amount of available data within these different areas of investigation, it is timely to integrate these data sets and to ask how they might be useful in future human genetic studies of brain diseases. We will address a number of general issues relevant to any tissue or disease, using the extensive information on synapse proteins and specific multiprotein complexes. Interrogating these lists and models with human genetic data allows several questions to be addressed. First, how many of the genes encoding the components of a complex are involved with human disease? Second, are there similarities in the phenotypes that might indicate that the mutations have interfered with the overall function of the complex? Third, what do the human phenotypes reveal about the physiological or cellular functions of the complex? Fourth, can we confidently use the gene lists to hunt for further disease-causing mutations? Fifth, can understanding the interaction of proteins in the complexes provide useful models for understanding genetic interactions, such as epistasis, or polygenic disorders? We will address these issues, using data on neurological phenotypes in humans with X-linked disorders and data from studies of proteins found on the postsynaptic side of mammalian brain synapses. This focus provides a more in-depth view from which we can learn lessons used to guide studies on all autosomes as well as larger sets of brain genes. By analogy with genome projects that aim to provide comprehensive lists of genes, synapse proteomics aims to produce comprehensive lists of proteins that are found in synapses. The postsynaptic proteome (PSP) is the complement of proteins localized within the postsynaptic terminal, and recent large-scale efforts to characterize the PSP have produced a comprehensive description of its constituents.18Jordan BA Fernholz BD Boussac M Xu C Grigorean G Ziff EB Neubert TA Identification and verification of novel rodent postsynaptic density proteins.Mol Cell Proteomics. 2004; 3: 857-871Crossref PubMed Scopus (143) Google Scholar, 19Li KW Hornshaw MP Van Der Schors RC Watson R Tate S Casetta B Jimenez CR Gouwenberg Y Gundelfinger ED Smalla KH et al.Proteomics analysis of rat brain postsynaptic density: implications of the diverse protein functional groups for the integration of synaptic physiology.J Biol Chem. 2004; 279: 987-1002Crossref PubMed Scopus (219) Google Scholar, 20Collins MO Husi H Yu L Brandon JM Anderson CN Blackstock WP Choudhary JS Grant SG Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.J Neurochem. 2006; 97: 16-23Crossref PubMed Scopus (329) Google Scholar, 21Yoshimura Y Yamauchi Y Shinkawa T Taoka M Donai H Takahashi N Isobe T Yamauchi T Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography-tandem mass spectrometry.J Neurochem. 2004; 88: 759-768Crossref PubMed Scopus (176) Google Scholar, 22Jordan BA Fernholz BD Boussac M Xu C Grigorean G Ziff EB Neubert TA Identification and verification of novel rodent postsynaptic density proteins.Mol Cell Proteomics. 2004; 3: 857-871Crossref PubMed Scopus (238) Google Scholar, 23Peng J Kim MJ Cheng D Duong DM Gygi SP Sheng M Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry.J Biol Chem. 2004; 279: 21003-21011Crossref PubMed Scopus (372) Google Scholar These studies were performed by the biochemical fractionation of the synapse and by subsequent protein identification with the use of mass spectrometry and antibody-based methods. Meta-analysis of these data sets indicates that the PSP contains ∼1,180 proteins in a number of distinct structural and functional complexes (fig. 1B and table A1). The largest of these complexes is the postsynaptic density (PSD), a dense structure directly below the postsynaptic membrane that is visible by electron microscopy24Banker G Churchill L Cotman CW Proteins of the postsynaptic density.J Cell Biol. 1974; 63: 456-465Crossref PubMed Scopus (80) Google Scholar, 25Cotman CW Banker G Churchill L Taylor D Isolation of postsynaptic densities from rat brain.J Cell Biol. 1974; 63: 441-455Crossref PubMed Scopus (168) Google Scholar and that comprises ∼1,124 proteins (table A1 and the Genes to Cognition [G2C] Web site). It is worth noting that these lists are not definitive, since some proteins escape detection and some proteins will be contaminants from the fractionation procedure. The PSD contains many different classes of proteins representing a broad range of cell biological functions, including membrane-bound receptors (including the glutamate receptors), adhesion proteins and channels, signaling proteins and adaptors, and proteins involved in transport, RNA metabolism, and transcription and translation (table A1).18Jordan BA Fernholz BD Boussac M Xu C Grigorean G Ziff EB Neubert TA Identification and verification of novel rodent postsynaptic density proteins.Mol Cell Proteomics. 2004; 3: 857-871Crossref PubMed Scopus (143) Google Scholar, 19Li KW Hornshaw MP Van Der Schors RC Watson R Tate S Casetta B Jimenez CR Gouwenberg Y Gundelfinger ED Smalla KH et al.Proteomics analysis of rat brain postsynaptic density: implications of the diverse protein functional groups for the integration of synaptic physiology.J Biol Chem. 2004; 279: 987-1002Crossref PubMed Scopus (219) Google Scholar, 20Collins MO Husi H Yu L Brandon JM Anderson CN Blackstock WP Choudhary JS Grant SG Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.J Neurochem. 2006; 97: 16-23Crossref PubMed Scopus (329) Google Scholar, 21Yoshimura Y Yamauchi Y Shinkawa T Taoka M Donai H Takahashi N Isobe T Yamauchi T Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography-tandem mass spectrometry.J Neurochem. 2004; 88: 759-768Crossref PubMed Scopus (176) Google Scholar, 22Jordan BA Fernholz BD Boussac M Xu C Grigorean G Ziff EB Neubert TA Identification and verification of novel rodent postsynaptic density proteins.Mol Cell Proteomics. 2004; 3: 857-871Crossref PubMed Scopus (238) Google Scholar, 23Peng J Kim MJ Cheng D Duong DM Gygi SP Sheng M Semiquantitative proteomic analysis of rat forebrain postsynaptic density fractions by mass spectrometry.J Biol Chem. 2004; 279: 21003-21011Crossref PubMed Scopus (372) Google Scholar Compared with the entire mouse proteome, PSD proteins are enriched in protein interaction domains and, in particular, in PDZ (PSD-95, Discs-large, ZO-1) and SH3 (Src homology 3) domains, consistent with the abundance of adaptor and scaffolding proteins. There is also enrichment of kinase, calcium-dependent signaling, and Ras guanosine triphosphatase (GTPase) domains.20Collins MO Husi H Yu L Brandon JM Anderson CN Blackstock WP Choudhary JS Grant SG Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.J Neurochem. 2006; 97: 16-23Crossref PubMed Scopus (329) Google Scholar The glutamate receptor complexes are subsets of the PSP, and there is considerable overlap between the various complexes (fig. 1B). Affinity purification of NMDA receptor complexes (NRC) or affinity isolation of membrane-associated guanylate kinase (MAGUK) proteins, which directly bind NMDA receptors, resulted in 185 proteins.10Husi H Ward MA Choudhary JS Blackstock WP Grant SG Proteomic analysis of NMDA receptor-adhesion protein signalling complexes.Nat Neurosci. 2000; 3: 661-669Crossref PubMed Scopus (994) Google Scholar, 20Collins MO Husi H Yu L Brandon JM Anderson CN Blackstock WP Choudhary JS Grant SG Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.J Neurochem. 2006; 97: 16-23Crossref PubMed Scopus (329) Google Scholar These complexes are alternatively known as the “NRC” or the “MASC” (MAGUK-associated signaling complexes), since both isolation procedures result in a similar set of proteins. Within the NRC/MASC can be found the NMDA and mGluR subunits, whereas AMPA-receptor subunits are in separate and smaller complexes (nine proteins).20Collins MO Husi H Yu L Brandon JM Anderson CN Blackstock WP Choudhary JS Grant SG Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome.J Neurochem. 2006; 97: 16-23Crossref PubMed Scopus (329) Google Scholar Through affinity isolation, mGluR5 receptor complexes were found to contain 76 proteins.26Farr CD Gafken PR Norbeck AD Doneanu CE Stapels MD Barofsky DF Minami M Saugstad JA Proteomic analysis of native metabotropic glutamate receptor 5 protein complexes reveals novel molecular constituents.J Neurochem. 2004; 91: 438-450Crossref PubMed Scopus (64) Google Scholar The initial observations that NMDA and mGluR receptors were associated with dozens of proteins were surprising; however, since then, a substantial number of binary protein-interaction studies have mapped the interactions in detail. Moreover, many of the proteins in the NRC/MASC are known to mediate the signaling functions of the receptors.27Pocklington AJ Armstrong JD Grant SG Organization of brain complexity—synapse proteome form and function.Brief Funct Genomic Proteomic. 2006; 5: 66-73Crossref PubMed Scopus (27) Google Scholar, 28Pocklington AJ Cumiskey M Armstrong JD Grant SG The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.Mol Syst Biol. 2006; (electronically published January 17, 2006; accessed December 15, 2006)(http://www.nature.com/msb/journal/v2/n1/full/msb4100041.html)PubMed Google Scholar As suggested by the Venn diagram in figure 1B, the PSP is a set of complexes embedded within the PSD and has often been referred to as a “supramolecular” complex.29Sheng M Sala C PDZ domains and the organization of supramolecular complexes.Annu Rev Neurosci. 2001; 24: 1-29Crossref PubMed Scopus (1008) Google Scholar The NRC/MASC is the most well studied of these large postsynaptic complexes and can be considered a prototype for the overall PSP. The physiological role of NRC/MASC proteins has been investigated using knockout mice and pharmacological intervention, most typically with the use of brain slices in which synaptic plasticity has been induced. More than 40 NRC proteins are necessary for the process of converting patterns of neuronal activity into long-lasting changes in neuronal function, and a similar number are required for behavioral forms of plasticity in rodents, such as learning or fear conditioning.27Pocklington AJ Armstrong JD Grant SG Organization of brain complexity—synapse proteome form and function.Brief Funct Genomic Proteomic. 2006; 5: 66-73Crossref PubMed Scopus (27) Google Scholar, 28Pocklington AJ Cumiskey M Armstrong JD Grant SG The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.Mol Syst Biol. 2006; (electronically published January 17, 2006; accessed December 15, 2006)(http://www.nature.com/msb/journal/v2/n1/full/msb4100041.html)PubMed Google Scholar, 30Grant SG Marshall MC Page KL Cumiskey MA Armstrong JD Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases.Hum Mol Genet. 2005; 14: R225-R234Crossref PubMed Scopus (57) Google Scholar These numbers continue to increase as further genes are tested, which reinforces the model that the NRC/MASC is a signaling complex involved with the basic process of neural plasticity. In addition to the accumulation of mouse genetic and phenotypic data on NRC/MASC proteins, the binary interactions of proteins within the complexes have been mapped and used to generate protein-interaction networks.27Pocklington AJ Armstrong JD Grant SG Organization of brain complexity—synapse proteome form and function.Brief Funct Genomic Proteomic. 2006; 5: 66-73Crossref PubMed Scopus (27) Google Scholar, 28Pocklington AJ Cumiskey M Armstrong JD Grant SG The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.Mol Syst Biol. 2006; (electronically published January 17, 2006; accessed December 15, 2006)(http://www.nature.com/msb/journal/v2/n1/full/msb4100041.html)PubMed Google Scholar The average number of protein interactions separating any pair of NRC/MASC proteins is very low (average shortest path length 3.3), suggesting that the complex consists of a large network containing multiple clusters of well-connected proteins rather than a system of linear pathways with occasional interconnections. Algorithm-based network cluster analysis indicates that the complex contains 13 clusters, each with distinct functional characteristics and phenotypic associations (fig. 2). The flow of information through the complex is modeled in figure 3. In essence, the glutamate receptors and their proximal associated proteins form “input” modules, which then connect to a large set of general signaling proteins referred to as “processing” modules, which then signal to “output” modules comprising some well-known effector-pathway components, such as the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway (see the work of Pocklington et al.27Pocklington AJ Armstrong JD Grant SG Organization of brain complexity—synapse proteome form and function.Brief Funct Genomic Proteomic. 2006; 5: 66-73Crossref PubMed Scopus (27) Google Scholar and Pocklington et al.28Pocklington AJ Cumiskey M Armstrong JD Grant SG The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.Mol Syst Biol. 2006; (electronically published January 17, 2006; accessed December 15, 2006)(http://www.nature.com/msb/journal/v2/n1/full/msb4100041.html)PubMed Google Scholar for details of the networks). The mouse and human mutations that result in plasticity or behavioral deficits were mapped onto this network, and some interesting distributions of phenotypes were seen in particular modules. Although it is clear that this type of systems-biology approach will benefit from systematic mutational studies like those done in yeast,31Sweigard JA Ebbole DJ Functional analysis of pathogenicity genes in a genomics world.Curr Opin Microbiol. 2001; 4: 387-392Crossref PubMed Scopus (21) Google Scholar, 32Vidan S Snyder M Large-scale mutagenesis: yeast genetics in the genome area.Curr Opin Biotechnol. 2001; 12: 28-34Crossref PubMed Scopus (27) Google Scholar it demonstrates that molecular network maps of synaptic protein complexes can be used to help understand the functional relationships between proteins. At the very least, it provides a logic for assembling a disparate set of genetic studies into a unified model.Figure 3.Modular signaling mechanisms of postsynaptic complexes. The modules of clustered proteins are organized into layers of signaling, with synaptic cleft at the top. Presynaptic information, in the form of a neurotransmitter, enters the postsynaptic signaling machinery via activation of ionotropic and metabotropic transmembrane receptors that are in modules of proximal signaling proteins (blue). From there, signals are passed to a large information-processing module (red) and then are distributed to effector mechanism networks (green), which mediate a functional outcome (dark blue arrow).28Pocklington AJ Cumiskey M Armstrong JD Grant SG The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.Mol Syst Biol. 2006; (electronically published January 17, 2006; accessed December 15, 2006)(http://www.nature.com/msb/journal/v2/n1/full/msb4100041.html)PubMed Google Scholar This signaling machinery provides a high degree of signal integration by protein interaction and orchestration of output responses.View Large Image Figure ViewerDownload Hi-res image Download (PPT) These proteomic and mouse genetic studies serve as a driver for human genetic studies, since it would seem likely that many of the proteins would be involved in human disease. Indeed, when the NRC was first characterized, it was recognized that three proteins were well known to be mutated in neurological diseases.10Husi H Ward MA Choudhary JS Blackstock WP Grant SG Proteomic analysis of NMDA receptor-adhesion protein signalling complexes.Nat Neurosci. 2000; 3: 661-669Crossref PubMed Scopus (994) Google Scholar A recent data-mining and literature-curation study revealed that 54 NRC/MASC proteins are involved with both psychiatric and neurological conditions.27Pocklington AJ Armstrong JD Grant SG Organization of brain complexity—synapse proteome form and function.Brief Funct Genomic Proteomic. 2006; 5: 66-73Crossref PubMed Scopus (27) Google Scholar, 30Grant SG Marshall MC Page KL Cumiskey MA Armstrong JD Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases.Hum Mol Genet. 2005; 14: R225-R234Crossref PubMed Scopus (57) Google Scholar A considerable number of these disorders have cognitive components (e.g., autism, schizophrenia, and mental retardation [MR]) consistent with mouse genetic studies showing specific impairments in cognitive function.27Pocklington AJ Armstrong JD Grant SG Organization of brain complexity—synapse proteome form and function.Brief Funct Genomic Proteomic. 2006; 5: 66-73Crossref PubMed Scopus (27) Google Scholar, 30Grant SG Marshall MC Page KL Cumiskey MA Armstrong JD Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases.Hum Mol Genet. 2005; 14: R225-R234Crossref PubMed Scopus (57) Google Scholar In recent decades, the role of the X chromosome in cognition has been extensively studied. Although it is known that genes influencing cognitive function are distributed throughout the human genome, many more “cognition genes” have been found on the X chromosome than on comparable segments of the autosomes.33Skuse DH X-linked genes and mental functioning.Hum Mol Genet. 2005; 14: R27-R32Crossref PubMed Scopus (164) Google Scholar In parallel with these observations, numerous epidemiological studies performed to evaluate the sex ratio in autism and MR have indicated an excess of males, suggesting a preferential association between genetic defects and cognitive disorders in males.34McLaren J Bryson SE Review of recent epidemiological studies of mental retardation: prevalence, associated disorders, and etiology.Am J Ment Retard. 1987; 92: 243-254PubMed Google Scholar, 35Kleefstra T Hamel BCJ X-linked mental retardation: further lumping, splitting and emerging phenotypes.Clin Genet. 2005; 67: 451-467Crossref PubMed Scopus (49) Google Scholar, 36Stoller A Epidemiology of mental deficiency in Victoria.in: Van Zelt JD Proceedings of the Fourth Interstate Conference on Mental Deficiency. 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X-linked MR (XLMR) is a common cause of moderate to severe intellectual disability in males, with a prevalence of 2.6 cases per 1,000 in the general population, accounting for >10% of all cases of MR.39Stevenson RE Schwartz CE Clinical and molecular contributions to the understanding of X-linked mental retardation.Cytogenet Genome Res. 2002; 99: 265-275Crossref PubMed Scopus (42) Google Scholar, 40Ropers HH Hamel BC X-linked mental retardation.Nat Rev Genet. 2005; 6: 46-57Crossref PubMed Scopus (355) Google Scholar Although highly heterogeneous, XLMR is usually divided into syndromic forms (MRXS), which have associated musculoskeletal or metabolic symptoms, and nonsyndromic (or nonspecific) forms (MRX) in which MR is the sole feature, although accumulating evidence suggests that this boundary is less evident than was previously expected.35Kleefstra T Hamel BCJ X-linked mental retardation: further lumping, splitting and emerging phenotypes.Clin Genet. 2005; 67: 451-467Crossref PubMed Scopus (49) Google Scholar, 41Ropers HH X-linked mental retardation: many genes for a complex disorder.Curr Opin Genet Dev. 2006; 16: 260-269Crossref PubMed Scopus (128) Google Scholar So far, >140 MRXS conditions have been reported; in almost half of these, causative mutations in genes have been described.40Ropers HH Hamel BC X-linked mental retardation.Nat Rev Genet. 2005; 6: 46-57Crossref PubMed Scopus (355) Google Scholar, 41Ropers HH X-linked mental retardation: many genes for a complex disorder.Curr Opin
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