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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators of developmental processes such as regional specification, patterning, migration and differentiation. In both mouse and humans, the developing forebrain is marked by distinct boundaries of homeobox gene expression at different developmental time points. These genes regulate the patterning of the forebrain along the dorsal/ventral and rostral/caudal axes and are also essential for the differentiation of specific neuronal subtypes. Inhibitory interneurons that arise from the ganglionic eminences and migrate tangentially to the neocortex and hippocampus are dramatically affected by mutations in several homeobox genes. In this review, we discuss the identification, expression patterns, loss- and/or gain-of-function models, and confirmed transcriptional targets for a set of homeobox genes required for the correct development of the forebrain in the mouse. In humans, mutations of homeobox genes expressed in the forebrain have been shown to result in mental retardation, epilepsy or movement disorders. The number of homeobox genes currently linked to human nervous system disease is surprisingly low, perhaps reflecting the essential functions of these genes throughout embryogenesis or the degree of functional redundancy during central nervous system development.
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PMID:Homeobox genes in vertebrate forebrain development and disease. 1824 Dec 23

ARX (the aristaless-related homeobox gene) is a transcription factor that participates in the development of GABAergic and cholinergic neurons in the forebrain. Many ARX mutations have been identified in X-linked lissencephaly and mental retardation with epilepsy, and thus ARX is considered to be a causal gene for the two syndromes although the neurobiological functions of each mutation remain unclear. We attempted to elucidate the causal relationships between individual ARX mutations and disease phenotypes by generating a series of mutant mice. We generated three types of mice with knocked-in ARX mutations associated with X-linked lissencephaly (P353R) and mental retardation [P353L and 333ins(GCG)7]. Mice with the P355R mutation (equivalent to the human 353 position) that died after birth were significantly different in Arx transcript/protein amounts, GABAergic and cholinergic neuronal development, brain morphology and lifespan from mice with P355L and 330ins(GCG)7 but considerably similar to Arx-deficient mice with truncated ARX mutation in lissencephaly. Mice with the 330ins(GCG)7 mutation showed severe seizures and impaired learning performance, whereas mice with the P355L mutation exhibited mild seizures and only slightly impaired learning performance. Both types of mutant mice exhibited the mutation-specific lesser presence of GABAergic and cholinergic neurons in the striatum, medial septum and ventral forebrain nuclei when compared with wild-type mice. Present findings that reveal a causal relationship between ARX mutations and the pleiotropic phenotype in mice, suggest that the ARX-related syndrome, including lissencephaly or mental retardation, is caused by only the concerned ARX mutations without the involvement of other genetic factors.
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PMID:Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. 1960 12


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