An 8.9 Mb 19p13 duplication associated with precocious puberty and a sporadic 3.9 Mb 2q23.3q24.1 deletion containing NR4A2 in mentally retarded members of a family with an intrachromosomal 19p-into-19q between-arm insertion

Lybæk, Helle; Ørstavik, Karen Helene; Prescott, Trine; Hovland, Randi; Breilid, Harald; Stansberg, Carl Trygve; Steen, Vidar M.; Houge, Gunnar

doi:10.1038/ejhg.2008.261

Cited by 34 publications

(43 citation statements)

References 16 publications

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“…5). However, while RhoGEFs and RhoGTPases have been implicated in mental retardation, also when haploinsufficient [Lybaek et al, 2008[Lybaek et al, , 2009Nadif Kasri and Van Aelst, 2008], this has, as far as we know, not been shown for RapGEFs. Quite recently patients with overlapping but mostly larger 2q31.1 deletions have been described [Svensson et al, 2007;Mitter et al, manuscript in preparation].…”

Section: Discussionmentioning

confidence: 99%

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of <i>LRFN5</i> Expression

et al. 2010

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In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient’s autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint.

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Section: Discussionmentioning

confidence: 99%

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of <i>LRFN5</i> Expression

et al. 2010

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“…Besides a link to cancer progression, FMNL2 could also be involved in diseases of the nervous system. A sporadic 3.9 Mb deletion in gene locus 2q23.3 of an infant caused severe mental retardation, early onset of puberty, reduced stature and hand anomalies 104 . This locus encompasses five genes including fmnl2 .…”

Section: Fmnlmentioning

confidence: 99%

“…This locus encompasses five genes including fmnl2 . As a possible reason for these symptoms a morphological change of the dendritic spines based on disturbances of the actin cytoskeleton has been proposed 104 . Like the other two FMNL proteins, also FMNL3 seems to participate in the proliferation of malignant tumor cells 105 …”

Section: Fmnlmentioning

confidence: 99%

Formins as effector proteins of Rho GTPases

2014

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Formin proteins were recognized as effectors of Rho GTPases some 15 years ago. They contribute to different cellular actin cytoskeleton structures by their ability to polymerize straight actin filaments at the barbed end. While not all formins necessarily interact with Rho GTPases, a subgroup of mammalian formins, termed Diaphanous-related formins or DRFs, were shown to be activated by small GTPases of the Rho superfamily. DRFs are autoinhibited in the resting state by an N- to C-terminal interaction that renders the central actin polymerization domain inactive. Upon the interaction with a GTP-bound Rho, Rac, or Cdc42 GTPase, the C-terminal autoregulation domain is displaced from its N-terminal recognition site and the formin becomes active to polymerize actin filaments. In this review we discuss the current knowledge on the structure, activation, and function of formin-GTPase interactions for the mammalian formin families Dia, Daam, FMNL, and FHOD. We describe both direct and indirect interactions of formins with GTPases, which lead to formin activation and cytoskeletal rearrangements. The multifaceted function of formins as effector proteins of Rho GTPases thus reflects the diversity of the actin cytoskeleton in cells.

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“…A recessive mutation of metastasis suppressor 1-like (MTSS1L) caused neurodegeneration in a consanguineous family (Alazami et al, 2015). FMNL2 was one of the essential genes deleted in a severely mentally retarded patient (Lybaek et al, 2009). Frameshift mutations of inositol polyphosphate-4-phosphatase type I (INPP4A) caused neuronal loss and seizures in both a patient and the weeble mutant mouse line that arose spontaneously (Nystuen et al, 2001;Sheffer et al, 2015).…”

Section: Substrates and Phosphorylation Consensus Sequences Of Tnikmentioning

confidence: 99%

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK

Wang

Amato

Rubitski

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Traf2-and Nck-interacting kinase (TNIK) is a serine/threonine kinase highly expressed in the brain and enriched in the postsynaptic density of glutamatergic synapses in the mammalian brain. Accumulating genetic evidence and functional data have implicated TNIK as a risk factor for psychiatric disorders. However, the endogenous substrates of TNIK in neurons are unknown. Here, we describe a novel selective small molecule inhibitor of the TNIK kinase family. Using this inhibitor, we report the identification of endogenous neuronal TNIK substrates by immunoprecipitation with a phosphomotif antibody followed by mass spectrometry. Phosphorylation consensus sequences were defined by phosphopeptide sequence analysis. Among the identified substrates were members of the delta-catenin family including p120-catenin, d-catenin, and armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), each of which is linked to psychiatric or neurologic disorders. Using p120-catenin as a representative substrate, we show TNIK-induced p120-catenin phosphorylation in cells requires intact kinase activity and phosphorylation of TNIK at T181 and T187 in the activation loop. Addition of the small molecule TNIK inhibitor or knocking down TNIK by two shRNAs reduced endogenous p120-catenin phosphorylation in cells. Together, using a TNIK inhibitor and phosphomotif antibody, we identify endogenous substrates of TNIK in neurons, define consensus sequences for TNIK, and suggest signaling pathways by which TNIK influences synaptic development and function linked to psychiatric and neurologic disorders.

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An 8.9 Mb 19p13 duplication associated with precocious puberty and a sporadic 3.9 Mb 2q23.3q24.1 deletion containing NR4A2 in mentally retarded members of a family with an intrachromosomal 19p-into-19q between-arm insertion

Cited by 34 publications

References 16 publications

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of <i>LRFN5</i> Expression

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of <i>LRFN5</i> Expression

Formins as effector proteins of Rho GTPases

Identification of Phosphorylation Consensus Sequences and Endogenous Neuronal Substrates of the Psychiatric Risk Kinase TNIK

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