Characterisation and expression of a large, 13.7 kb FMR2 isoform.

Gécz, Jozef; Mulley, John C.

doi:10.1038/sj.ejhg.5200279

Cited by 14 publications

(8 citation statements)

References 18 publications

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“…There remained the remote possibility that a large gene spanning the 805-kb distance between DXS8091 and DXS1193 and extending beyond each marker into each critical region might be involved in both diseases (see Fig, C). FMR2, the gene responsible for the FRAXE form of fragile-X mental retardation, 22 occupies 520 kb of this region and encompasses DXS8091 in its first intron, but it does not extend as far as DXS1193 located 285 kb beyond its telomeric end. FMR2 is therefore outside the XMEA critical region and is not a candidate gene for this disease.…”

Section: Discussionmentioning

confidence: 99%

Benzodiazepine receptor binding in Huntington's disease: [11C]Flumazenil uptake measured using positron emission tomography

et al. 2000

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We used positron emission tomography and [11C]flumazenil to analyze the benzodiazepine receptor binding in symptomatic and asymptomatic carriers of the Huntington's disease gene. We found an inverse relationship between [11C]flumazenil and [11C]raclopride binding in the putamen of symptomatic patients, and interpret this result as GABA receptor upregulation. We used positron emission tomography and [11C]flumazenil to analyze the benzodiazepine receptor binding in symptomatic and asymptomatic carriers of the Huntington's disease gene. We found an inverse relationship between [11C]flumazenil and [11C]raclopride binding in the putamen of symptomatic patients, and interpret this result as GABA receptor upregulation. Ann Neurol 2000;47:644–648

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Section: Discussionmentioning

confidence: 99%

Benzodiazepine receptor binding in Huntington's disease: [11C]Flumazenil uptake measured using positron emission tomography

et al. 2000

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“…Lobe II of the cerebellum is shown. tional modifications or alternative splicing, as is the case for FMR2 (22). It is most likely, however, that the smaller band corresponds to a degradation product of the 183-kDa full-length Af4 protein.…”

Section: Figmentioning

confidence: 95%

Mediation of Af4 protein function in the cerebellum by Siah proteins

Oliver

Bitoun

Clark

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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We have established that the gene AF4, which had long been recognized as disrupted in childhood leukemia, also plays a role in the CNS. Af4 is mutated in the robotic mouse that is characterized by ataxia and Purkinje cell loss. To determine the molecular basis of this mutation, we carried out a yeast two-hybrid screen and show that Af4 binds the E3 ubiquitin ligases Drosophila seven in absentia (sina) homologues (Siah)-1a and Siah-2 in the brain. Siah-1a and Af4 are expressed in Purkinje cells and colocalize in the nucleus of human embryonic kidney 293T and P19 cells. In vitro binding assays and coimmunoprecipitation reveal a significant reduction in affinity between Siah-1a and robotic mutant Af4 compared with wild-type, which correlates with the almost complete abolition of mutant Af4 degradation by Siah-1a. These data strongly suggest that an accumulation of mutant Af4 occurs in the robotic mouse due to a reduction in its normal turnover by the proteasome. A significant increase in the transcriptional activity of mutant Af4 relative to wild-type was obtained in mammalian cells, suggesting that the activity of Af4 is controlled through Siahmediated degradation. Another member of the Af4 family, Fmr2, which is involved in mental handicap in humans, binds Siah proteins in a similar manner. These results provide evidence that a common regulatory mechanism exists that controls levels of the Af4͞Fmr2 protein family. The robotic mouse thus provides a unique opportunity to understand how these proteins play a role in disorders as diverse as leukemia, mental retardation, and neurodegenerative disease.

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“…Like LAF4, AF4 and AF5Q31 are known to form fusion proteins with MLL [7], [8], whereas FMR2 is silenced in FRAXE (mental retardation, X-linked, associated with fragile site) intellectual disability and is not implicated in ALL [9], [10]. While a mouse Fmr2 null mutant does show some subtle behavioral and electrophysiological deficits related to synaptic plasticity [11], gene knockouts of Af4 and Af5q31 have not revealed a great deal regarding the normal molecular function of AFF proteins [12], [13] and no Laf4 mutants have been reported to date.…”

Section: Introductionmentioning

confidence: 99%

Laf4/Aff3, a Gene Involved in Intellectual Disability, Is Required for Cellular Migration in the Mouse Cerebral Cortex

et al. 2014

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Members of the AFF (AF4/FMR2) family of putative transcription factors are involved in infant acute leukaemia and intellectual disability (ID), although very little is known about their transcriptional targets. For example, deletion of human lymphoid nuclear protein related to AF4/AFF member 3 (LAF4/AFF3) is known to cause severe neurodevelopmental defects, and silencing of the gene is also associated with ID at the folate-sensitive fragile site (FSFS) FRA2A; yet the normal function of this gene in the nervous system is unclear. The aim of this study was to further investigate the function of Laf4 in the brain by focusing on its role in the cortex. By manipulating expression levels in organotypic slices, we demonstrate here that Laf4 is required for normal cellular migration in the developing cortex and have subsequently identified Mdga2, an important structural protein in neurodevelopment, as a target of Laf4 transcriptional activity. Furthermore, we show that the migration deficit caused by loss of Laf4 can be partially rescued by Mdga2 over-expression, revealing an important functional relationship between these genes. Our study demonstrates the key transcriptional role of Laf4 during early brain development and reveals a novel function for the gene in the process of cortical cell migration relevant to the haploinsufficiency and silencing observed in human neurodevelopmental disorders.

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Characterisation and expression of a large, 13.7 kb FMR2 isoform.

Cited by 14 publications

References 18 publications

Benzodiazepine receptor binding in Huntington's disease: [11C]Flumazenil uptake measured using positron emission tomography

Benzodiazepine receptor binding in Huntington's disease: [11C]Flumazenil uptake measured using positron emission tomography

Mediation of Af4 protein function in the cerebellum by Siah proteins

Laf4/Aff3, a Gene Involved in Intellectual Disability, Is Required for Cellular Migration in the Mouse Cerebral Cortex

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