X-linked myoclonic epilepsy with spasticity and intellectual disability

Scheffer, Ingrid E.; Wallace, Robyn H.; Phillips, Fiona; Hewson, Peter; Reardon, Katrina; Parasivam, Gayathri; Strømme, Petter; Berkovic, Samuel F.; Gécz, Jozef; Mulley, John C.

doi:10.1212/wnl.59.3.348

Cited by 86 publications

(63 citation statements)

References 36 publications

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“…The interactions within the Leu 26 network may account for the observed co-variance of the participating residues among the diverse homeodomain family members. Our observations may also explain the dysfunctional phenotype associated with a P26L mutation in the human ARX homeodomain, which is found in cases of rare X-linked myoclonic epilepsy (13,14). These results provide further structural insights into the determinants of stability and functional specificity for this highly conserved domain.…”

supporting

confidence: 53%

“…The importance of position 26 and its network of interacting residues is highlighted further by a recently discovered mutation, P26L, in the human ARX domain that is associated with myoclonic epilepsy (13,14). This mutation is distinctive, first because the majority of disease-causing mutations in homeodomains are associated with DNA-binding residues rather than core residues, such as Pro 26 .…”

Section: A Special Interaction Between Water and Trpmentioning

confidence: 99%

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Crystal Structures of Engrailed Homeodomain Mutants

Stollar¹,

Mayor

Lovell³

et al. 2003

Journal of Biological Chemistry

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We report the crystal structures and biophysical characterization of two stabilized mutants of the Drosophila Engrailed homeodomain that have been engineered to minimize electrostatic repulsion. Four independent copies of each mutant occupy the crystal lattice, and comparison of these structures illustrates variation that can be partly ascribed to networks of correlated conformational adjustments. Central to one network is leucine 26 (Leu 26 ), which occupies alternatively two side chain rotameric conformations (-gauche and trans) and different positions within the hydrophobic core. Similar sets of conformational substates are observed in other Engrailed structures and in another homeodomain. The pattern of structural adjustments can account for NMR relaxation data and sequence co-variation networks in the wider homeodomain family. It may also explain the dysfunction associated with a P26L mutation in the human ARX homeodomain protein. Finally, we observe a novel dipolar interaction between a conserved tryptophan and a water molecule positioned along the normal to the indole ring. This interaction may explain the distinctive fluorescent properties of the homeodomain family.The homeodomain is a simple fold common to many different DNA-binding proteins from diverse eukaryotes. The domain is found in transcription factors that regulate a variety of genes and so control key processes ranging from early developmental decision to homeostasis and general "housekeeping" (1-3).The homeodomain fold comprises three helices, connected by a flexible loop and a ␤-turn, and has a small hydrophobic core that is remarkably well conserved (4). The side chains in this conserved core appear to be well packed, which is a hallmark of stable folds. However, homeodomain folds generally have poorer stabilities in comparison with other proteins of similar size (5-8). The termini of homeodomains are disordered in solution (9 -11) and structures of free-and DNA-bound forms illustrate that DNA binding is accompanied by a structural condensation of the termini (12). Possibly, the homeodomain core also undergoes subtle structural changes upon DNA binding. Thus, the homeodomain would appear to mold to the surface of specific DNA by induced fit. Despite the wealth of current stereochemical and functional data for homeodomains, the basis for their comparatively low stability and its relationship, if any, to their induced fit remains to be established.Sequence co-variance analysis of homeodomains highlights several strongly correlated residue pairs that form conserved interactions and that may affect stability and DNA binding (4). One pair identified was the surface residues 17 and 52, which forms, in the majority of cases, a salt bridge. However, in the transcriptional repressor Engrailed from Drosophila, two lysines are instead found in these positions. We have substituted lysine 52 for glutamate, to mimic the conserved Glu 17 -Arg 52 salt bridge, and for alanine, to relieve the repulsion of the clustered positive charges. Standard equilibrium ...

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supporting

confidence: 53%

Section: A Special Interaction Between Water and Trpmentioning

confidence: 99%

Crystal Structures of Engrailed Homeodomain Mutants

Stollar¹,

Mayor

Lovell³

et al. 2003

Journal of Biological Chemistry

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“…Recently, genetic investigations of X-linked mental retardation (XLMR) disorders have identified aristalessrelated homeobox (ARX ) as the causative gene in X-linked infantile spasms, Partington syndrome, and in certain families with nonsyndromic XLMR (Bienvenu et al, 2002;Scheffer et al, 2002;Strømme et al, 2002a,b). More severe mutations in ARX, resulting in premature termination of the protein, have been reported in X-linked lissencephaly with abnormal genitalia (XLAG) (Dobyns et al, 1999;Kitamura et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Friocourt¹,

Kanatani²,

Tabata³

et al. 2008

J. Neurosci.

118

106

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The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to knock down or overexpress ARX. We show here that targeted inhibition of ARX causes cortical progenitor cells to exit the cell cycle prematurely and impairs their migration toward the cortical plate. In contrast, ARX overexpression increases the length of the cell cycle. In addition, we report that RNA interferencemediated inactivation of ARX prevents cells from acquiring multipolar morphology in the subventricular and intermediate zones, resulting in decreased neuronal motility. In contrast, ARX overexpression appears to promote the development of tangentially oriented processes of cells in the subventricular and intermediate zones and affects radial migration of pyramidal neurons. We also demonstrate that the level of ARX expression is important for tangential migration of GABA-containing interneurons, because both inactivation and overexpression of the gene impair their migration from the ganglionic eminence. However, our data suggest that ARX is not directly involved in GABAergic cell fate specification. Overall, these results identify multiple and distinct cell-autonomous roles for ARX in corticogenesis.

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“…However in MRX, only 15 genes are known to be involved accounting for less than one-fifth of all MRX. [1][2][3][4][5][6] The recent observations that RSK2, MECP2, and ARX play a role in both syndromic and non-syndromic forms of XLMR, [7][8][9][10] suggest that a molecular basis to strictly separate these two forms is not always present. In addition, careful clinical re-examination of patients with an OPHN1 gene mutation has revealed distinctive phenotypic hallmarks, such as cerebellar hypoplasia, in patients who were previously classified as nonsyndromic.…”

mentioning

confidence: 99%