A novel de novo 1.1 Mb duplication of 17q21.33 associated with cognitive impairment and other anomalies

Zahir, Farah; Langlois, Sylvie; Gall, Kim; Eydoux, Patrice; Marra, Marco A.; Friedman, Jan M.

doi:10.1002/ajmg.a.32827

Cited by 15 publications

(11 citation statements)

References 32 publications

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“…Mutations in genes encoding proteins in the integrin α3β1-Arg signaling axis have been linked to human disorders in brain development. For example, chromosomal microdeletions involving integrinα3 and duplications of integrinα3 coding regions have been found in patients with intellectual disability (Zahir et al, 2009; Preiksaitiene et al, 2012). Likewise, microdeletions involving genes for integrin β1 (Megarbane et al, 2001; Talkowski et al, 2012), Arg (Scarbrough et al, 1988; Takano et al, 1997; Chaabouni et al, 2006), p190 (James et al, 1996; Leal et al, 2009), and Rho-family GTPases(Newey et al, 2005; Benarroch, 2007) have all been identified in cases of intellectual disability that have been associated with developmental disorders.…”

Section: Discussionmentioning

confidence: 99%

Integrin α3 Is Required for Late Postnatal Stability of Dendrite Arbors, Dendritic Spines and Synapses, and Mouse Behavior

2013

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Most dendrite branches and a large fraction of dendritic spines in the adult rodent forebrain are stable for extended periods of time. Destabilization of these structures compromises brain function and is a major contributing factor to psychiatric and neurodegenerative diseases. Integrins are a class of transmembrane extracellular matrix receptors that function as αβ heterodimersand activate signaling cascades regulating the actin cytoskeleton. Here we identify integrin α3 as a key mediator of neuronal stability. Dendrites, dendritic spines, and synapses develop normally in mice with selective loss of integrin α3 in excitatory forebrain neurons, reaching their mature sizes and densities through post-natal day 21 (P21). However, by P42 integrin α3 mutant mice exhibit significant reductions in hippocampal dendrite arbor size and complexity, loss of dendritic spine and synapse densities, and impairments in hippocampus-dependent behavior. Furthermore, gene-dosage experiments demonstrate that integrin α3 interacts functionally with the Arg nonreceptor tyrosine kinase to activate p190RhoGAP (p190), which inhibits RhoA GTPase and regulates hippocampal dendrite and synapse stability and mouse behavior. Together our data support a fundamental role for integrin α3 in regulating dendrite arbor stability, synapse maintenance, and proper hippocampal function. In addition, these results provide a biochemical and structural explanation for the defects in LTP, learning, and memory previously reported in mice lacking integrin α3.

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Section: Discussionmentioning

confidence: 99%

Integrin α3 Is Required for Late Postnatal Stability of Dendrite Arbors, Dendritic Spines and Synapses, and Mouse Behavior

2013

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“…Several studies have previously pointed out CACNA1G implication in patient phenotypes. Zahir et al [] and Preiksaitiene et al [] proposed that CACNA1G overexpression or haploinsufficiency was responsible for intellectual disability in patients harboring respectively a de novo 1.1 Mb duplication or 1.8 Mb deletion on 17q21.33. Another patient reported in the DECIPHER database (ID 255632), presenting with intellectual disability and dysmorphic features, had a de novo 1.92 Mb deletion that affected 37 genes including CACNA1G gene (Fig.…”

Section: Discussionmentioning

confidence: 99%

Osteogenesis imperfecta, tricho‐dento‐osseous syndrome and intellectual disability: A familial case with 17q21.33‐q22 (COL1A1 and DLX3) deletion and 7q32.3‐q33 duplication resulting from a reciprocal interchromosomal insertion

Harbuz

Bilan

Couet

et al. 2013

American J of Med Genetics Pt A

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We report on a 22-year-old woman with features of osteogenesis imperfecta (OI), tricho-dento-osseous (TDO) syndrome and intellectual disability. Whole genome oligonucleotide microarray analysis revealed a copy number gain of 3 Mb in 7q32.3-q33 and a loss of 3.4 Mb in 17q21.33-q22. FISH analysis showed that the third copy of 7q32 was inserted into the long arm of one chromosome 17, exactly in the region 17q21.33-q22 that was deleted. The maternal uncle presented with clinical features similar to the proposita and had the same chromosomal anomalies. The mother of the proposita and two other family members were balanced carriers of this rearrangement, interpreted as an interchromosomal reciprocal insertion. Reciprocal insertion/four-break rearrangement is a very rare chromosomal event. The deleted region on chromosome 17 contains 39 genes, including COL1A1 and DLX3 involved in OI and TDO syndrome respectively. The CACNA1G gene on the deleted segment of chromosome 17 may be a good candidate gene to explain the intellectual impairment. © 2013 Wiley Periodicals, Inc.

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“…Of note, one case with Klippel-Feil anomaly had a translocation involving chromosome band 17q23 (26), which is close to the human hemp orthologous locus at 17q21.3. In addition, several patients with unrelated skeletal abnormalities were shown to bear chromosomal aberrations involving 17q21.3 (28)(29)(30). Therefore, it would be intriguing to investigate whether human hemp expression is affected in patients with Klippel-Feil anomaly and patients with skeletal abnormalities carrying chromosomal aberrations involving 17q21.3.…”

Section: Discussionmentioning

confidence: 99%

Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation

Honda

Takubo

Oda

et al. 2011

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

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To clarify the molecular pathways governing hematopoietic stem cell (HSC) development, we screened a fetal liver (FL) HSC cDNA library and identified a unique gene, hematopoietic expressed mammalian polycomb ( hemp ), encoding a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To investigate its biological role, we generated mice lacking Hemp ( hemp −/− ). Hemp −/− mice exhibited a variety of skeletal malformations and died soon after birth. In the FL, hemp was preferentially expressed in the HSC and early progenitor cell fractions, and analyses of fetal hematopoiesis revealed that the number of FL mononuclear cells, including HSCs, was reduced markedly in hemp −/− embryos, especially during early development. In addition, colony-forming and competitive repopulation assays demonstrated that the proliferative and reconstitution abilities of hemp −/− FL HSCs were significantly impaired. Microarray analysis revealed alterations in the expression levels of several genes implicated in hematopoietic development and differentiation in hemp −/− FL HSCs. These results demonstrate that Hemp, an mbt-containing protein, plays essential roles in HSC function and skeletal formation. It is also hypothesized that Hemp might be involved in certain congenital diseases, such as Klippel-Feil anomaly.

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A novel de novo 1.1 Mb duplication of 17q21.33 associated with cognitive impairment and other anomalies

Cited by 15 publications

References 32 publications

Integrin α3 Is Required for Late Postnatal Stability of Dendrite Arbors, Dendritic Spines and Synapses, and Mouse Behavior

Integrin α3 Is Required for Late Postnatal Stability of Dendrite Arbors, Dendritic Spines and Synapses, and Mouse Behavior

Osteogenesis imperfecta, tricho‐dento‐osseous syndrome and intellectual disability: A familial case with 17q21.33‐q22 (COL1A1 and DLX3) deletion and 7q32.3‐q33 duplication resulting from a reciprocal interchromosomal insertion

Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation

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