Triangular tibia with fibular aplasia associated with a microdeletion on 2q11.2 encompassing <i>LAF4</i>

Steichen-Gersdorf, Elisabeth; Gaßner, Ingmar; Superti‐Furga, Andrea; Ullmann, Reinhard; Stricker, Sigmar; Klopocki, Eva; Mundlos, Stefan

doi:10.1111/j.1399-0004.2008.01050.x

Cited by 32 publications

(51 citation statements)

References 19 publications

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“…In order to confirm the effectiveness of this genetic tool to generate mouse models, we aimed at reproducing a human disease-associated SV of unknown pathogenicity (Steichen-Gersdorf et al, 2008). The SV had occurred de novo, but its functional relevance remained unclear.…”

Section: A 353 Kb Intragenic Deletion Of Laf4 Recapitulates a Human Mmentioning

confidence: 99%

Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice

et al. 2015

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Structural variations (SVs) contribute to the variability of our genome and are often associated with disease. Their study in model systems was hampered until now by labor-intensive genetic targeting procedures and multiple mouse crossing steps. Here we present the use of CRISPR/Cas for the fast (10 weeks) and efficient generation of SVs in mice. We specifically produced deletions, inversions, and also duplications at six different genomic loci ranging from 1.1 kb to 1.6 Mb with efficiencies up to 42%. After PCR-based selection, clones were successfully used to create mice via aggregation. To test the practicability of the method, we reproduced a human 500 kb disease-associated deletion and were able to recapitulate the human phenotype in mice. Furthermore, we evaluated the regulatory potential of a large genomic interval by deleting a 1.5 Mb fragment. The method presented permits rapid in vivo modeling of genomic rearrangements.

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Section: A 353 Kb Intragenic Deletion Of Laf4 Recapitulates a Human Mmentioning

confidence: 99%

Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice

et al. 2015

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“…Given the degree of sequence conservation within the ALF family (Bitoun and Davies, 2005), this study also potentially bears important implications for other disorders of the CNS such as mental retardation to which both LAF4 and FMR2 have been linked (Gécz et al, 1997;Steichen-Gersdorf et al, 2008). Increasing evidence indeed suggests that the IGF-1 pathway plays an important role in cognitive function, especially in learning and memory.…”

Section: Discussionmentioning

confidence: 88%

AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development

Bitoun¹,

Finelli²,

Oliver³

et al. 2009

J. Neurosci.

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Deregulation of the insulin-like growth factor 1 (IGF-1) signaling pathway is a recurrent finding in mouse models and human patients with cerebellar ataxia and thus represents a common pathological cascade in neuronal cell death that may be targeted for therapy. We have previously identified a point mutation in AF4, a transcription cofactor of RNA polymerase II elongation and chromatin remodeling, that causes progressive and highly specific Purkinje cell (PC) death in the ataxic mouse mutant robotic, leading to the accumulation of AF4 in PCs. Here we confirm that the spatiotemporal pattern of PC degeneration in the robotic cerebellum correlates with the specific profile of AF4 upregulation. To identify the underlying molecular pathways, we performed microarray gene expression analysis of PCs obtained by laser capture microdissection (LCM) at the onset of degeneration. Igf-1 was significantly downregulated in robotic PCs compared with wild-type controls before and throughout the degenerative process. Consistently, we observed a decrease in the activation of downstream signaling molecules including type 1 IGF receptor (IGF-1R) and the extracellular signal-regulated kinase (ERK) 1 and ERK2. Chromatin immunoprecipitation confirmed that Igf-1 is a direct and the first validated target of the AF4 transcriptional regulatory complex, and treatment of presymptomatic robotic mice with IGF-1 indeed markedly delayed the progression of PC death. This study demonstrates that small changes in the levels of a single transcriptional cofactor can deleteriously affect normal cerebellum function and opens new avenues of research for the manipulation of the IGF-1 pathway in the treatment of cerebellar ataxia in humans.

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“…The Fmr2 KO mouse, which efficiently recapitulates the human phenotype with impaired learning and memory performance, also shows increased long-term potentiation (LTP) in the hippocampus where Fmr2 is highly expressed, indicating that FMR2 likely regulates neuronal synaptic activity in cognitive function by buffering the LTP response [52,53]. Loss of LAF4 gene expression through chromosomal deletion of region 2q11.2 has recently been described in a patient with delayed psychomotor development who also presented with malformation of the urogenital tract and skeletal abnormalities of the lower legs, similar to those found in Nievergelt syndrome [54]. The strong expression of LAF4 in the subventricular zone during embryonic cortical differentiation had predicted a major role in early stages of cortex development.…”

Section: Functional Disruption Of Other Alf Family Proteins In Disordmentioning

confidence: 84%

The Robotic Mouse: Understanding the Role of AF4, a Cofactor of Transcriptional Elongation and Chromatin Remodelling, in Purkinje Cell Function

Bitoun

Davies

2009

Cerebellum

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Neurological disorders represent a large share of the disease burden worldwide, and the incidence of age-related forms will continue to rise with life expectancy. Gene targeting has been and will remain a valuable approach to the generation of clinically relevant mouse models from which to elucidate the underlying molecular basis. However, as the aetiology of the majority of these conditions is still unknown, a reverse approach based on large-scale random chemical mutagenesis is now being used in an attempt to identify new genes and associated signalling pathways that control neuronal cell death and survival. Here, we review the characterisation of a novel model of autosomal dominant cerebellar ataxia which shows general growth retardation and develops adult-onset region-specific Purkinje cell loss as well as cataracts and defects in early T-cell maturation. We have previously established that the mutated protein Af4, which is a member of the AF4/LAF4/FMR2 (ALF) family of transcription cofactors frequently translocated in childhood leukaemia, undergoes slower proteasomal turnover through the ubiquitin pathway and abnormally accumulates in Purkinje cells of the cerebellum. We have also shown that Af4 functions as part of a large multiprotein complex that stimulates RNA polymerase II elongation and mediates chromatin remodelling during transcription. With the forthcoming identification of the gene targets that trigger Purkinje cell death in the robotic cerebellum, and the functional conservation among the ALF proteins, the robotic mouse promises to deliver important insights into the pathogenesis of human ataxia, but also of mental retardation to which FMR2 and LAF4 have been linked.

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Triangular tibia with fibular aplasia associated with a microdeletion on 2q11.2 encompassing LAF4

Cited by 32 publications

References 19 publications

Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice

Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice

AF4 Is a Critical Regulator of the IGF-1 Signaling Pathway during Purkinje Cell Development

The Robotic Mouse: Understanding the Role of AF4, a Cofactor of Transcriptional Elongation and Chromatin Remodelling, in Purkinje Cell Function

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