Molecular and Comparative Genetics of Mental Retardation

Corresponding author: Linda L. Restifo, 611 Gould-Simpson Bldg., 1040 E. 4th St., University of Arizona, Tucson, AZ 85721-0077., llr{at}neurobio.arizona.edu (E-mail)

Communicating editor: R. S. HAWLEY

Affecting 1–3% of the population, mental retardation (MR) poses significant challenges for clinicians and scientists. Understanding the biology of MR is complicated by the extraordinary heterogeneity of genetic MR disorders. Detailed analyses of >1000 Online Mendelian Inheritance in Man (OMIM) database entries and literature searches through September 2003 revealed 282 molecularly identified MR genes. We estimate that hundreds more MR genes remain to be identified. A novel test, in which we distributed unmapped MR disorders proportionately across the autosomes, failed to eliminate the well-known X-chromosome overrepresentation of MR genes and candidate genes. This evidence argues against ascertainment bias as the main cause of the skewed distribution. On the basis of a synthesis of clinical and laboratory data, we developed a biological functions classification scheme for MR genes. Metabolic pathways, signaling pathways, and transcription are the most common functions, but numerous other aspects of neuronal and glial biology are controlled by MR genes as well. Using protein sequence and domain-organization comparisons, we found a striking conservation of MR genes and genetic pathways across the 700 million years that separate Homo sapiens and Drosophila melanogaster. Eighty-seven percent have one or more fruit fly homologs and 76% have at least one candidate functional ortholog. We propose that D. melanogaster can be used in a systematic manner to study MR and possibly to develop bioassays for therapeutic drug discovery. We selected 42 Drosophila orthologs as most likely to reveal molecular and cellular mechanisms of nervous system development or plasticity relevant to MR.

This article has been cited by other articles:

				H. L. Kim and Y. Satta Population Genetic Analysis of the N-Acylsphingosine Amidohydrolase Gene Associated With Mental Activity in Humans Genetics, March 1, 2008; 178(3): 1505 - 1515. [Abstract] [Full Text] [PDF]

				R. Batista-Brito, R. Machold, C. Klein, and G. Fishell Gene Expression in Cortical Interneuron Precursors is Prescient of their Mature Function Cereb Cortex, February 3, 2008; (2008) bhm258v1. [Abstract] [Full Text] [PDF]

				G. B. Call, J. M. Olson, J. Chen, N. Villarasa, K. T. Ngo, A. M. Yabroff, S. Cokus, M. Pellegrini, E. Bibikova, C. Bui, et al. Genomewide Clonal Analysis of Lethal Mutations in the Drosophila melanogaster Eye: Comparison of the X Chromosome and Autosomes Genetics, October 1, 2007; 177(2): 689 - 697. [Abstract] [Full Text] [PDF]

				T. Preat, J.-L. Da Lage, L. Colleaux, G. Didelot, F. Molinari, P. Tchenio, E. Milhiet, A. Munnich, and M.-L. Cariou Response to Comment on "Tequila, a Neurotrypsin Ortholog, Regulates Long-Term Memory Formation in Drosophila" Science, June 22, 2007; 316(5832): 1698c - 1698c. [Abstract] [Full Text] [PDF]

				S. M Sisodiya, P. J Thompson, A. Need, S. E Harris, M. E Weale, S. E Wilkie, M. Michaelides, S. L Free, N. Walley, C. Gumbs, et al. Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation J. Med. Genet., June 1, 2007; 44(6): 373 - 380. [Abstract] [Full Text] [PDF]

				H. Augustin, Y. Grosjean, K. Chen, Q. Sheng, and D. E. Featherstone Nonvesicular Release of Glutamate by Glial xCT Transporters Suppresses Glutamate Receptor Clustering In Vivo J. Neurosci., January 3, 2007; 27(1): 111 - 123. [Abstract] [Full Text] [PDF]

				P. Saccucci, C. Arpino, R. Rizzo, A. Gagliano, A. Volzone, C. Lalli, C. Galasso, and P. Curatolo Association of Adenosine Deaminase Polymorphism With Mild Mental Retardation J Child Neurol, September 1, 2006; 21(9): 753 - 756. [Abstract] [PDF]

				R. Kraft, M. M. Escobar, M. L. Narro, J. L. Kurtis, A. Efrat, K. Barnard, and L. L. Restifo Phenotypes of Drosophila Brain Neurons in Primary Culture Reveal a Role for Fascin in Neurite Shape and Trajectory. J. Neurosci., August 23, 2006; 26(34): 8734 - 8747. [Abstract] [Full Text] [PDF]

				G. Didelot, F. Molinari, P. Tchenio, D. Comas, E. Milhiet, A. Munnich, L. Colleaux, and T. Preat Tequila, a neurotrypsin ortholog, regulates long-term memory formation in Drosophila. Science, August 11, 2006; 313(5788): 851 - 853. [Abstract] [Full Text] [PDF]

				X. Sun, T. Morozova, and M. Sonnenfeld Glial and Neuronal Functions of the Drosophila Homolog of the Human SWI/SNF Gene ATR-X (DATR-X) and the jing Zinc-Finger Gene Specify the Lateral Positioning of Longitudinal Glia and Axons Genetics, July 1, 2006; 173(3): 1397 - 1415. [Abstract] [Full Text] [PDF]

				Y. Sun, F. Zhang, J. Gao, X. Gao, T. Guo, K. Zhang, Y. Shi, Z. Zheng, W. Tang, Y. Zheng, et al. Positive association between POU1F1 and mental retardation in young females in the Chinese Han population Hum. Mol. Genet., April 1, 2006; 15(7): 1237 - 1243. [Abstract] [Full Text] [PDF]

				S. Vaynman and F. Gomez-Pinilla License to Run: Exercise Impacts Functional Plasticity in the Intact and Injured Central Nervous System by Using Neurotrophins Neurorehabil Neural Repair, December 1, 2005; 19(4): 283 - 295. [Abstract] [PDF]

				D. B. Bailey Jr, D. Skinner, and S. F. Warren Newborn Screening for Developmental Disabilities: Reframing Presumptive Benefit Am J Public Health, November 1, 2005; 95(11): 1889 - 1893. [Abstract] [Full Text] [PDF]

				R. Plomin and K. Asbury Nature and Nurture: Genetic and Environmental Influences on Behavior The ANNALS of the American Academy of Political and Social Science, July 1, 2005; 600(1): 86 - 98. [Abstract] [PDF]

				L. M. Butcher, E. Meaburn, J. Knight, P. C. Sham, L. C. Schalkwyk, I. W. Craig, and R. Plomin SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children Hum. Mol. Genet., May 15, 2005; 14(10): 1315 - 1325. [Abstract] [Full Text] [PDF]

				M. Pinter, D. D. Lent, and N. J. Strausfeld Memory consolidation and gene expression in Periplaneta americana Learn. Mem., January 1, 2005; 12(1): 30 - 38. [Abstract] [Full Text] [PDF]

				C. I. Michel, R. Kraft, and L. L. Restifo Defective Neuronal Development in the Mushroom Bodies of Drosophila Fragile X Mental Retardation 1 Mutants J. Neurosci., June 23, 2004; 24(25): 5798 - 5809. [Abstract] [Full Text] [PDF]