Comparative Analysis of Autosomal and X-Linked Genes Involved in Nonspecific Cognitive Impairment

Comparative Analysis of Autosomal and X-linked Genes Involved in Nonspecific Cognitive Impairment

Pak J Med Res Review Article Vol. 51, No. 1, 2012

Comparative Analysis of Autosomal and X-linked Genes Involved in Nonspecific Cognitive Impairment

Muzammil Ahmad Khan,1 Naureen Aslam,2 Muhammad Ansar3 Gomal Centre of Biochemistry and Biotechnology, Gomal University, D.I.Khan,1 University Institute of Biochemistry and Biotechnology, University of Arid Agriculture, Rawalpindi,2 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad.3

Abstract

The focus of research on candidate gene identification of recessive non-syndromic cognitive impairment is increasing and to date 19 genes for X-linked and 10 autosomal non-syndromic mental retardation have been reported. The X chromosome has higher proportion of cognitive genes as compared to autosomes; but the presence of 22 autosomes and the origination of X chromosome from autosome during the course of evolution is putting a mark of question on this fact and leads to the hypothesis that the number of autosomal cognitive genes should be higher in number than the genes on X chromosome. The comparative analysis of both sets (autosomal v/s X-linked) of genes revealed significant similarities with respect to their evolutionary conservation, cellular localization, molecular and biological functions, protein domain sharing, subcellular expression profiling in nervous tissues, etc. The results and observation conclude that the knowledge of X -linked cognitive genes can be utilized in a variety of ways to explore more autosomal cognitive genes comp utationally. Key words: Autosomal and X-linked cognitive genes, cognitive impairment, evolutionary conservation, molecular and biological data, subcellular localization.

Introduction inheritance). Clinical presentation categorizes mental retardation into either syndromic (accompanied with ognitive disability is a major unsolved neuro- additional clinical dysfunction) or nonsyndromic mental C developmental disorder affecting 2-3% of general retardation (only learning impairment).4 population.1 Defining feature of mental retardation Great extent of X chromosome has been include sub average general intellectual functioning explored in context of MR and so far more than 19 genes (IQ<70), limitation in at least two of the adaptive skill have been identified in case of nonspecific X-linked 5 and onset before 18 year of age.2 According to ICD-10 intellectual disability while in case of autosomal classification, mental retardation is subcategories to Mild nonsyndromic cognitive impairment merely 10 genes (50-55 to approximately 70), Moderate (35-40 to 50-55), have been reported till to-date (a literature survey). Most Severe (20-25 to 35-40) and Profound (IQ below 20-25) of the nonsyndromic mental retardation genes are on the basis of IQ score.3 The etiologies of mental involved in synaptic functioning; and their limitation 6 retardation include both genetic and environmental causes cognitive dysfunction. factors. Genetic mental retardation is caused by Genome databases are the best resources for chromosomal defects, genetic imprinting phenomenon, functional, expression and cytogenetic, evolutionary, repeat extension, inborn error of metabolism and single gene ontology data. Utilizing these resources, the current gene defect. Monogenetic mental retardation is analysis is done to overview the similarities among subcategorized as either X-linked or autosomal (on the nonspecific (nonsyndromic) X-linked and autosomal basis of responsible gene bearing chromosome) or cognitive genes and a concept is generated for future recessive and dominant (on the basis of mode of research. Corresponding Author: Muzammil Ahmad Khan Bioinformatics Resources Gomal Centre of Biochemistry and Biotechnology The Gene Ontology database 7 Gomal University (http://www.geneontology.org/) and BioGPS 8 D.I.Khan (http://biogps.gnf.org/#goto=welcome) is a good source Email: [email protected] for retrieving functional information (subcellular

Pakistan Journal of Medical Research, 2011 (January - March) 21 Muzammil Ahmad Khan, Naureen Aslam, Muhammad Ansar localization, molecular and biological functions). For Results Tissue specific gene expression data, UCSC genome 9 browser (http://genome.ucsc.edu/) , GeneCards {version Gene Conservation Data 10 3 (http://www.genecards.org/)} and BioGPS can also be Every autosomal gene has its phylogenetic explored because of reliability. HomoloGene tool of partner on X chromosome e.g. PRSS12 is conserved in 11 NCBI (http://www.ncbi.nlm.nih.gov/homologene/) and Euteleostomi like wise AGTR2, DLG3, IL1RAPL, pfam database are trustworthy sources of gene ARHGEF6, ZNF741, and FMR2 (Table-1) which are also conservation and protein domain data respectively. conserved in euteleostomi. STRING (a web based tool)12 and HPRD (Human Protein Reference Database)13 are best sites for finding protein interactor.

Table 1: Expression data was obtained from UCSC genome browser (GNF Expression Atlas 2 Data from U133A and GNF1H Chips), evolutionary conservation and protein domain data is retrieved by using HomoloGene tool of NCBI.

Gene name Expression profile Gene Protein domain or motif (OMIM) Conservation data Autosomal genes of cognition PRSS12 Superior cervical ganglian Euteleostomi 1 Kringle, 3 SRCR and 1 Trypsin like serine (606709) protease domain CRBN Amygdala, prefrontal cortex, Eukaryota ATP dependent LON domain (609262) hypothalamus CC2D1A Fetal brain, prefrontal cortex, cingulate Eutheria Contains 1 C2 domain and (610055) cortex 4 DM14 domain TUSC3 Temporal lobe Bilateria 1 Thioredoxine like domain (601385) GRIK2 High expression in whole brain Eukaryota 3 Periplasmic binding protein type1 (PBPb) (138244) TRAPPC9 Cerebellum Bilateria Trs120 domain (611966) ST3GAL3 Superior cervical ganglian and fetal brain Amniota Glycotransferase domain (606494) MAN1B1 Fetal brain, prefrontal cortex, cingulate Eukaryota Glycosyl Hydrolase domain 47 and seven- (604346) cortex hairpin glycosidases SWIP Fetal brain, prefrontal cortex, amygdale, Euteleostomi WD40 domain, SOCS domain (610091) olfactoty bulbspinal cord TECR Cerebellum peduncles, hypothalamus, Eukaryota 3-oxo-5-alpha-steroid 4-dehydrogenase (610057) prefrontal cortex X chromosome genes of cognition AGTR2 Medulla oblongata, pons, cingulate Euteleostomi Serpentine type 7TM GPCR (300034) cortex, temporal lobe, trigeminal ganglian TM4SF2 High expression in whole brain Euteleostomi Tetraspanin, extracellular domain or large (300096) extracellular loop(LEL) GDI1 High expression in whole brain Eukaryota GDP dissociation inhibitor (300104) PAK3 High expression in whole brain Amniota Protein kinase catalytic like domain and CRIB (300142) domain FACL4 Hypothalamus, fetal brain, superior Eukaryota 2 Lux E domain (ACSL4) cervical ganglian (300157) DLG3 Fetal brain Euteleostomi PDZ domain, Src homology 3, Guanylate kinase- (300189) like domain, PDZ-associated domain of NMDA receptors, MAGUK_N_PEST IL1RAPL superior cervical ganglian, dorsal root Euteleostomi Belongs to the interleukin-1 receptor family (300206) ganglian Contains 3 Ig-like C2-type (immunoglobulin- like) domains Contains 1 TIR domain ARHGEF6 Thalamus, hypothalamus, spinal cord Euteleostomi Calponin homology domain, SH3, RhoGEF (300267) domain, PH_DOMAIN KLF8/ZNF741 cingulate cortex, trigeminal ganglian Euteleostomi COG5048, but never assign to any domain (300286) family

Pakistan Journal of Medical Research, 2012 (January - March) 22 Comparative Analysis of Autosomal and X-linked Genes Involved in Nonspecific Cognitive Impairment

NLGN3 Fetal brain, cingulate cortex, cerebellum, Fungi/Metazoa Esterase_lipase (300336) thalamus, hypothalamus, prefrontal cortex, occipital lobe, globus paliodus, spinal cord NLGN4 High expression in whole brain Coelomata Esterase_lipase (300427) FTSJ1 ND Eukaryota NADB_Rossmann (300499) ZNF674 Cingulated cortex, trigeminal ganglian Eutheria KRAB (Kruppel-associated box) domain -A box, (300573) COG5048 ZDHHC15 ND Eukaryota DHHC zinc finger domain (300576) ZNF673 Amygdala, hypothalamus, olfactory Nil 1 KRAB domain (300585) bulb, trigeminal ganglian FMR2 Fetal brain Euteleostomi AF-4 proto-oncoprotein (309548) RLP10 ND Eukaryota ND (312173) ZNF41 Pons, cerebellum peduncle, trigeminal Eutheria KRAB (Kruppel-associated box) domain -A box, (314995) ganglian COG5048 ZNF81 Superior cervical ganglian, parietal lobe Eutheria KRAB (Kruppel-associated box) domain -A box, (314998) COG5049

Gene Expression and Localization Data expression profile (Table-2). Similarly, most of the Every autosomal gene shares the expression autosomal genes occupy the same subcellular localization profile with X linked genes e.g CC2D1A has significant as like X specific genes, for instance CC2D1A and FTSJ1 expression during fetal stage and in prefrontal cortex and are localize in nucleus (Table-2). cingulated cortex like NLGN3 which has the same

Table 2: Functional data of X-linked and autosomal nonspecific cognitive impairment from gene ontology database and BioGPS.

Functional aspects of genes involved in NSCI Description of autosomal recessive NSCI Gene Molecular Function Biological Function Cellular Localization (Reference) PRSS1214 Serine-type endopeptidase activity, Zymogen activation Membrane, Dendrite Scavenger receptor activity Proteolysis Synaptic cleft, Terminal button of neurons, Synapse CRBN15 ATP dependent peptidase activity Proteolysis Membrane CC2D1A16 Signal transducer activity, Signal transducer activity, Nucleus, Nucleolus DNA binding DNA binding TUSC317 N-linked glycosylation Protein N-linked glycosylation via Mitochondrion, Asparagine Endoplasmic reticulum, Integral to membrane GRIK218 Extracellular-glutamate-gated ion channel Cellular calcium ion homeostasis, Pre and post synaptic activity, Glutamate signaling pathway, membrane, Integral to Kainate selective glutamate receptor activity, Synaptic transmission, membrane, Kainate Ion channel activity, PDZ domain binding, Regulation of long and short term selective glutamate Protein homodimerization activity neuronal synaptic plasticity, receptor complex, Regulation of synaptic transmission, Neuron apoptosis TRAPPC919 Signal transducer activity Cell differentiation Endoplasmic reticulum, Golgi complex ST3GAL20 N-acetyllactoseaminidine alpha 2, 3 Protein glycosylation Integral to membrane, sialtransferase activity Golgi complex MAN1B121 Mannosidase activity Protein folding, N-linked Endoplasmic reticulum, glycosylation, Metabolism Integral to membrane SWIP22 Protein binding Intra cellular signalling Intracellular TECR23 Oxidoreductase activity Triglyceride biosynthetic process Cytoplasm, Endoplasmic reticulum

Pakistan Journal of Medical Research, 2011 (January - March) 23 Muzammil Ahmad Khan, Naureen Aslam, Muhammad Ansar

Description of X-linked NSCI24 AGTR2 G-protein coupled receptor activity, Positive regulation of phosphoprotein Integral to plasma Protein binding phosphatase activity membrane, Negative regulation of nerve growth Neuropeptide Y factor receptor signaling pathway receptor, Protease G-protein coupled receptor signaling activated receptor, pathway. Brain development GPCR, rhodopsin-like Positive regulation of apoptosis Brain rennin-angiotensin system Regulation of systemic arterial blood pressure by circulatory rennin- angiotensin TM4SF2 Sodium:dicarboxylate symporter activity Dicarboxylic acid transport Integral to plasma membrane GDI1 GTPase activator activity, Regulation of GTPase activity Membrane fraction Rab GDP-dissociation inhibitor activity, Signal transduction Protein binding Regulation of transcription Protein transport PAK3 Protein serine/threonine kinase activity Protein amino acid phosphorylation Actin cytoskeleton Transferase activity SH3 domain binding Magnesium ion binding ATP binding FACL4 Magnesium ion binding Metabolic process Endoplasmic reticulum, Ligase activity Integral to membrane, ATP binding Mitochondrion Long-chain-fatty-acid-CoA ligase activity DLG3 Protein binding, Negative regulation of cell Cellular component Guanylate kinase activity proliferation IL1RAPL Transmembrane receptor activity, Learning or memory Integral to membrane Protein binding Innate immune response Protein amino acid phosphorylation Signal transduction ARHGEF6 GTPase activator activity Regulation of Rho protein signal Cytosol Rho guanyl-nucleotide exchange factor transduction activity KLF8/ZNF7 DNA binding, Regulation of transcription Intracellular, Nucleus 41 Zinc ion binding, Metal ion binding NLGN3 Protein binding Regulation of synaptic transmission Synapse, Integral to Regulation of respiratory gaseous membrane exchange by neurological process Visual learning and cell adhesion Regulation of inhibitory post synaptic membrane potential NLGN4 Protein homodimerization activity, Cell adhesion and cell-cell junction Integral to plasma Neurexin binding organization membrane, Cell surface Synapse organization FTSJ1 Methyltransferase activity, rRNA methyaltion and post Nucleus Nucleic acid binding, transcriptional modification Transferase activity ZNF674 DNA binding, Regulation of transcription Intracellular, Nucleus Metal ion binding, Zinc ion binding ZDHHC15 Metal ion binding, Synaptic vesicle maturation Integral to membrane Zinc ion binding, Establishment of protein localization Transferase activity, Protein palmitoylation Palmitoyltransferase activity ZNF673 Nucleic acid binding Regulation of transcription Intracellular FMR2 ND ND ND RLP10 Structural constituent of ribosome Translation Endoplasmic reticulum, Cytosolic large ribosomal subunit

Pakistan Journal of Medical Research, 2012 (January - March) 24 Comparative Analysis of Autosomal and X-linked Genes Involved in Nonspecific Cognitive Impairment

ZNF41 Metal ion binding, Regulation of transcription Intracellular, Nucleus Transcription factor activity, Zinc ion binding ZNF81 Transcription factor activity, Regulation of transcription Intracellular, Nucleus Metal ion binding, Zinc ion binding

Functional Homology Acknowledgement Most of the autosomal genes have their functional homolog on X chromosome and more or less Muzammil Ahmad Khan was sponsored by share the common functional aspect like post Higher Education Commission of Pakistan as an translational modification, signal transduction, regulation indigenous Ph.D. scholar and currently serving on HEC of synaptic transmission etc. For instance, CC2D1A, IPFP program at GCBB, Gomal University D.I.Khan. TRAPPC9 (on autosome) and AGTR2, GDI1 (on X chromosome) are involved in signal transduction and in References some case they share the common pathway (Table-2). 1. Garshasbi M, Motazacker MM, Kahrizi K, Behjati Discussion F, Abedini SS, Nieh SE, et al. SNP array-based homozygosity mapping reveals MCPH1 deletion in family The comparative analytical discussion is mainly with autosomal recessive mental retardation and mild concerned with the future direction of nonsyndromic microcephaly. Hum Genet 2006; 118:708–15. 2. American Psychiatric Association Diagnostic and cognitive dysfunction and identification of their genetic th players. When we analyzed the functional data it was Statistical Manual of Mental Disorders. 4 ed. Text revision (2000). Washington: American Psychiatric observed that almost every functional aspect of Association. autosomal genes were present in X linked genes but still 3. WHO. The ICD-10 classiﬁ cation of mental and behavioral there are varieties of functional characteristics of X disorders. WHO: 1992 linked genes which need to be explored in autosomal 4. Uyguner O, Kayserili H, Li Y, Karaman B, Nürnberg genes (Table-2). Analyzing the paralogous genes of G, Hennies H, et al. A new locus for autosomal recessive cognitive impairment, some autosomal genes showed non-syndromic mental retardation maps to 1p21.1–p13.3. their paralogs on other autosomes and was involved in Clin Genet. 2007; 71:212–9. MR, e.g. CC2D1A and CC2D2A (both on autosomes). So 5. Lisik MZ, Sieron AL. X-linked mental retardation. Med extending the assumption of X chromosome evolution Sci Monit. 2008; 14:221-9. from autosome we can assume that paralog of X-linked 6. Humeau Y, Gambino F, Chelly J, Vitale N. X-linked genes must be on autosome and should be involved in the mental retardation: focus on synaptic function and plasticity. J Neurochem. 2009; 109:1-14. same disorder; like ARHGEF6 (X chromosome) has its 7. The Gene Ontology Consortium. Gene ontology: tool for paralog ARHGEF3 and ARHGEF4 on autosome; the unification of biology. Nat Genet 2000 25: 25-9. similarly NLGN3, NLGN4 on X-chromosome has paralog [searched on July 2011] Available from URL: NLGN1 and NLGN2 on autosome. This paralogous http://www.geneontology.org/. relationship might be helpful in exploring more 8. Chunlei Wu, Camilo Orozco, Jason Boyer, Marc autosomal genes by using X-linked gene data. Protein- Leglise, James Goodale, Serge Batalov, et al. BioGPS: an Protein interaction data has revealed some X linked gene extensible and customizable portal for querying and showing interaction with autosomal gene e.g. DLG3 with organizing gene annotation resources. Genome GRIK2. Thus by pooling up the protein interactor idea Biol 2009 10:R130. [searched on July 2011] Available and paralogous gene idea, disease gene identification can from URL: http://biogps.gnf.org/#goto=welcome. be done with high significance. Moreover, the functional 9. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. data can be utilized for establishment of bioinformatics Genome Res 2002; 12: 996-1006. Available from URL: based software for candidate genes identification in http://genome.ucsc.edu/. which developer can utilize both set of genes as training 10. Stelzer G, Dalah I, Iny Stein T, Satanower Y, Rosen N, set because of sharing expression profile, evolutionary Nativ N et al. In-silico Human Genomics with GeneCards. conservation data, molecular pathway, biological Human Genomics 2011 5:709-17. {version 3 [searched on processes, protein domain sharing and thus ultimately July 2011] Available from URL: will help in exploring new genetic entities in molecular http://www.genecards.org/. biology of nervous system. 11. Shah SP, Huang Y, Xu T, Yuen MM, Ling J, Ouellette BF. Atlas - a data warehouse for integrative bioinformatics. BMC Bioinformatics 2005 21:6:34.[searched on August 2011] Available from URL: http://www.ncbi.nlm.nih.gov/homologene/.

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