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PubMed2005

Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.

Adult↗
PubMed2006

Different activity regulation and subcellular localization of LIMK1 and LIMK2 during cell cycle transition.

LIM kinases (LIMK1 and LIMK2) regulate actin cytoskeletal reorganization through phosphorylating and inactivating cofilin, an actin-depolymerizing factor of actin filaments. Here, we describe a detailed analysis of the cell-cycle-dependent activity of LIMK2, and a subcellular localization of LIMK1 and LIMK2. The activity of LIMK2, distinct from LIMK1, toward cofilin phosphorylation did not change in the normal cell division cycle. In contrast, LIMK2 was hyperphosphorylated and its activity was markedly increased when HeLa cells were synchronized at mitosis with nocodazole treatment. Immunofluorescence analysis showed that LIMK1 was localized at cell-cell adhesion sites in interphase and prophase, redistributed to the spindle poles during prometaphase to anaphase, and accumulated at the cleavage furrow in telophase. In contrast, LIMK2 was diffusely localized in the cytoplasm during interphase, redistributed to the mitotic spindle, and finally to the spindle midzone during anaphase to telophase. These findings suggest that LIMK2 is activated in response to microtubule disruption, and that LIMK1 and LIMK2 may play different roles in regulating for the mitotic spindle organization, chromosome segregation, and cytokinesis during the cell division cycle.

Actin Depolymerizing Factors↗
PubMed2005

In-depth analysis of spatial cognition in Williams syndrome: A critical assessment of the role of the LIMK1 gene.

The LIM kinase1 protein (LIMK1) is thought to be involved in neuronal development and brain function. However, its role in spatial cognition in individuals with Williams syndrome (WS) is currently ambiguous, with conflicting reports on the cognitive phenotypes of individuals who do not have classic WS but harbour partial deletions including LIMK1. Two families with partial WS deletions have been described with deficits in visuospatial cognition (Frangiskakis, J. M., Ewart, A. K., Morris, C. A., Mervis, C. B., Bertrand, & J., Robinson, et al. (1996). LIM-kinase 1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell, 86, 59-69), in contrast to others with similar partial deletions who did not display spatial impairments (Tassabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M. J., Grant, J., & Dennis, N., et al. (1999). Williams syndrome: Use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. American Journal of Human Genetics, 64, 118-125). To determine the role of LIMK1 in the highly penetrant visuospatial deficits associated with classic WS, it is essential to investigate the discrepancies between the two studies. Previous research used a standardised task to measure spatial cognition, which may not pick up subtle impairments. We therefore undertook more extensive testing of the spatial cognition of two adults with partial genetic deletions in the WS critical region (LIMK1 and ELN only), who had not displayed spatial impairments in the previous study, and compared them to two high-functioning adults with WS matched on verbal ability. All participants completed a broad battery of 16 perceptual and constructive spatial tests, and the clear-cut spatial difficulties observed in the WS group were not found in the partial deletion group. These findings rule out the claim that the deletion of one copy of LIMK1 is alone sufficient to result in spatial impairment, but leave open the possibility that LIMK1 contributes to the WS cognitive deficits if deleted in combination with other genes within the WS deletion. We conclude that a deeper assessment of WS at the genetic level is required before the contribution of specific genes to phenotypic outcomes can be fully understood.

Adult↗
PubMed1998

Visualization and molecular analysis of actin assembly in living cells.

Actin filament assembly is critical for eukaryotic cell motility. Arp2/3 complex and capping protein (CP) regulate actin assembly in vitro. To understand how these proteins regulate the dynamics of actin filament assembly in a motile cell, we visualized their distribution in living fibroblasts using green flourescent protein (GFP) tagging. Both proteins were concentrated in motile regions at the cell periphery and at dynamic spots within the lamella. Actin assembly was required for the motility and dynamics of spots and for motility at the cell periphery. In permeabilized cells, rhodamine-actin assembled at the cell periphery and at spots, indicating that actin filament barbed ends were present at these locations. Inhibition of the Rho family GTPase rac1, and to a lesser extent cdc42 and RhoA, blocked motility at the cell periphery and the formation of spots. Increased expression of phosphatidylinositol 5-kinase promoted the movement of spots. Increased expression of LIM-kinase-1, which likely inactivates cofilin, decreased the frequency of moving spots and led to the formation of aggregates of GFP-CP. We conclude that spots, which appear as small projections on the surface by whole mount electron microscopy, represent sites of actin assembly where local and transient changes in the cortical actin cytoskeleton take place.

Actin Cytoskeleton↗
PubMed2006

CRIPak, a novel endogenous Pak1 inhibitor.

p21-activated protein kinase 1 (Pak1) plays an important role in several cellular processes, including cytoskeleton reorganization, promotion of the cell survival, and the estrogen receptor (ER) signaling. Pak1 expression and activity is deregulated in a number of cancers. Pak1 is activated by a variety of physiological signals; however, less is known about the negative regulators of Pak1. Here, we report a negative regulator of Pak1. By performing a yeast two-hybrid screen of a mammary gland library, we identified cysteine-rich inhibitor of Pak1 (CRIPak) as a novel Pak1-interacting protein. We found that CRIPak is an intronless gene that localized to chromosome 4p16.3. It contains 13 zinc-finger domains and has three trypsin inhibitor-like, cysteine-rich domains and is widely expressed in a number of human cells and tissues. We further found that CRIPak interacted with Pak1 through the N-terminal regulatory domain and inhibited Pak1 kinase in both in vitro and in vivo assays. CRIPak inhibited Pak1-mediated LIM kinase activation and enhancement of ER transactivation. Conversely, selective inhibition of the endogenous CRIPak resulted in an increased Pak1 activity, and consequently, increased cytoskeleton remodeling and Pak1-mediated ER transactivation activity. The hormonal stimulation of cells enhanced CRIPak expression and promoted its colocalization with ER in the nuclear compartment. Our findings suggest that CRIPak is a novel negative regulator of the Pak1 and has a role in the modulation of Pak1-mediated ER transactivation in breast cancer cells.

Amino Acid Sequence↗
PubMed2003

Bikunin target genes in ovarian cancer cells identified by microarray analysis.

Bikunin, a Kunitz-type protease inhibitor, could potentially suppress tumor cell invasion and metastasis. Our previous study revealed that overexpression of bikunin in a human ovarian cancer cell line, HRA, resulted in a down-regulation in uPA and uPAR gene expression. For identifying the full repertoire of bikunin-regulated genes, a cDNA microarray hybridization screening was conducted using mRNA from bikunin-treated or bikunin-transfected HRA cells. A number of bikunin-regulated genes were identified, and their regulation was confirmed by Northern blot analysis. Our screen identified 11 bikunin-stimulated genes and 29 bikunin-repressed genes. The identified genes can indeed be classified into distinct subsets. These include transcriptional regulators, oncogenes/tumor suppressor genes, signaling molecules, growth/cell cycle, invasion/metastasis, cytokines, apoptosis, ion channels, extracellular matrix proteins, as well as some proteases. This screen identified suppression of several genes such as CDC-like kinase, LIM domain binding, Ets domain transcription factor, Rho GTPase-activating protein, tyrosine phosphorylation-regulated kinase, hyaluronan-binding protein, matriptase, and pregnancy-associated plasma protein-A (PAPP-A), which have previously been implicated in enhancing tumor promotion. Northern blot analysis confirmed that several genes including matriptase and PAPP-A were down-regulated by bikunin by approximately 9-fold. Further, genetic inhibition of matriptase or PAPP-A could lead to diminished invasion. These results show that bikunin alters the pattern of gene expression in HRA cells leading to a block in cell invasion.

Cell Movement↗
PubMed2001

Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility.

Transformation by oncogenic Ras requires the function of the Rho family GTPases. We find that Ras-transformed cells have elevated levels of RhoA-GTP, which functions to inhibit the expression of the cell cycle inhibitor p21/Waf1. These high levels of Rho-GTP are not a direct consequence of Ras signalling but are selected for in response to sustained ERK-MAP kinase signalling. While the elevated levels of Rho-GTP control the level of p21/Waf, they no longer regulate the formation of actin stress fibres in transformed cells. We show that the sustained ERK-MAP kinase signalling resulting from transformation by oncogenic Ras down-regulates ROCK1 and Rho-kinase, two Rho effectors required for actin stress fibre formation. The repression of Rho- dependent stress fibre formation by ERK-MAP kinase signalling contributes to the increased motility of Ras-transformed fibroblasts. Overexpression of the ROCK target LIM kinase restores actin stress fibres and inhibits the motility of Ras-transformed fibroblasts. We propose a model in which Ras and Rho signalling pathways cross-talk to promote signalling pathways favouring transformation.

Animals↗
PubMed2006

Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling.

Cyclin D1 is overexpressed in human tumors, correlating with cellular metastasis, and is induced by activating Rho GTPases. Herein, cyclin D1-deficient mouse embryo fibroblasts (MEFs) exhibited increased adhesion and decreased motility compared with wild-type MEFs. Retroviral transduction of cyclin D1 reversed these phenotypes. Mutational analysis of cyclin D1 demonstrated that its effects on cellular adhesion and migration were independent of the pRb and p160 coactivator binding domains. Genomewide expression arrays identified a subset of genes regulated by cyclin D1, including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1). cyclin D1(-/-) cells showed increased Rho GTP and ROCKII activity and signaling, with increased phosphorylation of LIM kinase, cofilin (Ser3), and myosin light chain 2 (Thr18/Ser19). Cyclin D1 repressed ROCKII and TSP-1 expression, and the migratory defect of cyclin D1(-/-) cells was reversed by ROCK inhibition or TSP-1 immunoneutralizing antibodies. cyclin E knockin to the cyclin D1(-/-) MEFs rescued the DNA synthesis defect of cyclin D1(-/-) MEFs but did not rescue either the migration defect or the abundance of ROCKII. Cyclin D1 promotes cellular motility through inhibiting ROCK signaling and repressing the metastasis suppressor TSP-1.

Animals↗
PubMed2003

Phosphoinositide 3-kinase-mediated activation of cofilin phosphatase Slingshot and its role for insulin-induced membrane protrusion.

Cofilin plays an essential role in actin filament dynamics and membrane protrusion in motile cells. Cofilin is inactivated by phosphorylation at Ser-3 by LIM kinase and reactivated by dephosphorylation by cofilin-phosphatase Slingshot (SSH). Although cofilin is dephosphorylated in response to various extracellular stimuli, signaling pathways regulating SSH activation and cofilin dephosphorylation have remained to be elucidated. Here we show that insulin stimulates the phosphatase activity of Slingshot-1L (SSH1L) and cofilin dephosphorylation in cultured cells, in a manner dependent on phosphoinositide 3-kinase (PI3K) activity. Consistent with this, the level of Ser-3-phosphorylated cofilin is increased in PTEN (phosphatase and tensin homolog deleted in chromosome 10)-overexpressing cells and decreased in PTEN-deficient cells. Insulin induced the accumulation of SSH1L and active Akt (a downstream effector of PI3K), together with a PI3K product phosphatidylinositol 3,4,5-trisphosphate, onto membrane protrusions. Cofilin, but not Ser-3-phosphorylated cofilin, accumulated in membrane protrusions in insulin-stimulated cells, indicating that cofilin is dephosphorylated in these areas. Finally, suppression of SSH1L expression by RNA interference abolished insulin-induced cofilin dephosphorylation and the membrane protrusion. These findings suggest that SSH1L is activated downstream of PI3K and plays a critical role in insulin-induced membrane protrusion by dephosphorylating and activating cofilin.

Actin Depolymerizing Factors↗
PubMed2006

Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling.

The conserved polarity complex, comprising the partitioning-defective (Par) proteins Par3 and Par6, and the atypical protein kinase C, functions in various cell-polarization events and asymmetric cell divisions. However, little is known about whether and how external stimuli-induced signals may regulate Par3 function in epithelial cell polarity. Here, we found that Par3 was tyrosine phosphorylated through phosphoproteomic profiling of pervanadate-induced phosphotyrosine proteins. We also demonstrated that the tyrosine phosphorylation event induced by multiple growth factors including epidermal growth factor (EGF) was dependent on activation of Src family kinase (SFK) members c-Src and c-Yes. The tyrosine residue 1127 (Y1127) of Par3 was identified as the major EGF-induced phosphorylation site. Moreover, we found that Y1127 phosphorylation reduced the association of Par3 with LIM kinase 2 (LIMK2), thus enabling LIMK2 to regulate cofilin phosphorylation dynamics. Substitution of Y1127 for phenylalanine impaired the EGF-induced Par3 and LIMK2 dissociation and delayed epithelial tight junction (TJ) assembly considerably. Collectively, these data suggest a novel, phosphotyrosine-dependent fine-tuning mechanism of Par3 in epithelial TJ assembly controlled by the EGF receptor-SFK signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2002

The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway.

The cytoskeletal changes that alter cellular morphogenesis and motility depend upon a complex interplay among molecules that regulate actin, myosin, and other cytoskeletal components. The Rho family of GTP binding proteins are important upstream mediators of cytoskeletal organization. Gem and Rad are members of another family of small GTP binding proteins (the Rad, Gem, and Kir family) for which biochemical functions have been mostly unknown. Here we show that Gem and Rad interface with the Rho pathway through association with the Rho effectors, Rho kinase (ROK) alpha and beta. Gem binds ROKbeta independently of RhoA in the ROKbeta coiled-coil region adjacent to the Rho binding domain. Expression of Gem inhibited ROKbeta-mediated phosphorylation of myosin light chain and myosin phosphatase, but not LIM kinase, suggesting that Gem acts by modifying the substrate specificity of ROKbeta. Gem or Rad expression led to cell flattening and neurite extension in N1E-115 neuroblastoma cells. In interference assays, Gem opposed ROKbeta- and Rad opposed ROKalpha-mediated cell rounding and neurite retraction. Gem did not oppose cell rounding initiated by ROKbeta containing a deletion of the Gem binding region, demonstrating that Gem binding to ROKbeta is required for the effects observed. In epithelial or fibroblastic cells, Gem or Rad expression resulted in stress fiber and focal adhesion disassembly. In addition, Gem reverted the anchorage-independent growth and invasiveness of Dbl-transformed fibroblasts. These results identify physiological roles for Gem and Rad in cytoskeletal regulation mediated by ROK.

3T3 Cells↗
PubMed1997

Xenopus LIM motif-containing protein kinase, Xlimk1, is expressed in the developing head structure of the embryo.

The LIM double zinc finger motif locates in several developmentally functioning and cytoskeletal proteins, and is considered to act as a specific motif for protein-protein interactions. LIM kinase (LIMK) is a novel protein kinase containing two LIM motifs at the N-terminal, the function of which has yet to be clearly defined. In this study, we cloned a cDNA encoding Xenopus counterpart of human LIMK1 gene by RT-PCR mediated cloning, and designated in Xlimk1. Xlimk1 is highly homologous to mammalian LIMK1 in each structural domain, particularly in LIM and protein kinase domains. In Northern blot analysis, two distinct Xlimk1 transcripts of 9.0 Kb and 3.7 Kb were present in early cleavage stages of the embryo. Both mRNA species were subsequently decreased at the gastrula stages. The 9.0 Kb of Xlimk1 mRNA again appeared in late neurula stage, then the expression level gradually increased in later stages of the embryo. Whole-mount in situ hybridization analysis showed the localization of Xlimk1 transcripts in the animal half of the blastula embryo. In post-neurula stages, specific signals for Xlimk1 were predominant in the anterior (head) region of the embryo, including developing brain, hyoid and branchial arches, and anlagen of sensory organs. These results indicate that Xlimk1 may play an important role in neural development and formation of anterior (head) structures in the Xenopus embryo.

Amino Acid Sequence↗
PubMed2006

Connective tissue growth factor/CCN2 stimulates actin disassembly through Akt/protein kinase B-mediated phosphorylation and cytoplasmic translocation of p27(Kip-1).

Connective tissue growth factor (CTGF/CCN2) is a 38-kDa secreted protein, a prototypic member of the CCN family, which is up-regulated in many diseases, including atherosclerosis, pulmonary fibrosis, and diabetic nephropathy. We previously showed that CTGF can cause actin disassembly with concurrent down-regulation of the small GTPase Rho A and proposed an integrated signaling network connecting focal adhesion dissolution and actin disassembly with cell polarization and migration. Here, we further delineate the role of CTGF in cell migration and actin disassembly in human mesangial cells, a primary target in the development of renal glomerulosclerosis. The functional response of mesangial cells to treatment with CTGF was associated with the phosphorylation of Akt/protein kinase B (PKB) and resultant phosphorylation of a number of Akt/PKB substrates. Two of these substrates were identified as FKHR and p27(Kip-1). CTGF stimulated the phosphorylation and cytoplasmic translocation of p27(Kip-1) on serine 10. Addition of the PI-3 kinase inhibitor LY294002 abrogated this response; moreover, addition of the Akt/PKB inhibitor interleukin (IL)-6-hydroxymethyl-chiro-inositol-2(R)-2-methyl-3-O-octadecylcarbonate prevented p27(Kip-1) phosphorylation in response to CTGF. Immunocytochemistry revealed that serine 10 phosphorylated p27(Kip-1) colocalized with the ends of actin filaments in cells treated with CTGF. Further investigation of other Akt/PKB sites on p27(Kip-1), revealed that phosphorylation on threonine 157 was necessary for CTGF mediated p27(Kip-1) cytoplasmic localization; mutation of the threonine 157 site prevented cytoplasmic localization, protected against actin disassembly and inhibited cell migration. CTGF also stimulated an increased association between Rho A and p27(Kip-1). Interestingly, this resulted in an increase in phosphorylation of LIM kinase and subsequent phosphorylation of cofilin, suggesting that CTGF mediated p27(Kip-1) activation results in uncoupling of the Rho A/LIM kinase/cofilin pathway. Confirming the central role of Akt/PKB, CTGF-stimulated actin depolymerization only in wild-type mouse embryonic fibroblasts (MEFs) compared to Akt-1/3 (PKB alpha/gamma) knockout MEFs. These data reveal important mechanistic insights into how CTGF may contribute to mesangial cell dysfunction in the diabetic milieu and sheds new light on the proposed role of p27(Kip-1) as a mediator of actin rearrangement.

Actins↗
PubMed2005

Rho-associated protein kinase inhibitor, Y-27632, induces alterations in adhesion, contraction and motility in cultured human trabecular meshwork cells.

We investigated the roles of Rho-associated protein kinase (ROCK) in regulating activities such as adhesion, contraction and migration in cultured human trabecular meshwork (TM) cells. Human TM cells in culture were treated with Y-27632, a specific ROCK inhibitor. Trypan blue exclusion test and TUNEL staining showed little or no direct toxicity of Y-27632 on TM cells. By MTT assay, Y-27632 did not significantly affect the proliferation of TM cells. The cell adhesion assay showed that Y-27632 promoted the cell adhesiveness to both fibronectin and collagen type I in a dose-dependent manner. Collagen gel contraction activity of TM cells was significantly inhibited by the treatment of Y-27632 in a dose-dependent manner. The addition of Y-27632 accelerated motility of TM cells in wound healing assay. Phosphorylated LIM kinase 2 and cofilin, related to actin bundling and integrin clustering, were dephosphorylated (activated) by Y-27632. In conclusion, Y-27632 elicits profound effects on TM cell activities including adhesion, gel contraction, and cell motility. These Y-27632-induced changes of TM cells may be relevance to the physiology of the aqueous outflow system.

Amides↗
PubMed2002

Characterization and purification of truncated human Rho-kinase II expressed in Sf-21 cells.

Rho-kinase II (ROCK-II) is a serine/threonine kinase that is involved in regulation of smooth muscle contraction and has been shown to contribute to the early stages of axon formation in neurons and the regulation of the neuronal cytoskeleton. Much of what is known about Rho-kinase function comes from cell-biological studies, whereas a paucity of biochemical characterization exists for the enzyme. In an effort to characterize ROCK-II biochemically we have cloned a truncated form of human ROCK-II comprising amino acids 1-543 and overexpressed it in Sf-21 cells. Utilizing the Sf-21/baculovirus expression system we isolated milligram quantities of ROCK-II (1-543) and purified the enzyme to near homogeneity. Optimal expression conditions revealed that infection of Sf-21 cells at a multiplicity of infection of 10 for 72h yielded maximal protein expression. Expression of ROCK-II (1-543) as an N-terminal Flag fusion protein allowed a single-step purification yielding greater than 90% homogeneous protein as assessed by SDS-PAGE. Enzyme activity was linear over a range of enzyme concentrations and times. Capture of phosphorylated, biotinylated peptides on streptavidin membrane allowed assessment of peptide substrate preference and measurement of steady-state rate constants. The data indicated that an 11-mer peptide containing Ser235/Ser236 of the S6 ribosomal protein and a 12-mer peptide containing Thr508 of LIM kinase were preferred substrates for ROCK-II (1-543). Finally, staurosporine had an IC(50) value 215-fold more potent than that of the ROCK inhibitor Y-27632. Collectively these data lay the foundation for the beginning of a biochemical characterization for this enzyme and provide methodology for more detailed biochemical, biophysical, and kinetic analysis.

Animals↗
PubMed2004

Nuclear accumulation of globular actin as a cellular senescence marker.

We evaluated the nuclear actin accumulation as a new marker of cellular senescence, using human diploid fibroblast (HDF), chondrocyte primary cultures, Mv1Lu epithelial cells, and Huh7 cancer cells. Nuclear accumulation of globular actin (G-actin) and dephosphorylated cofilin was highly significant in the senescent HDF cells, accompanied with inhibition of LIM kinase (LIMK) -1 activity. When nuclear export of the actin was induced by 12-O-tetradecanoylphorbol-13-acetate, DNA synthesis of the senescent cells increased significantly, accompanied with changes of morphologic and biochemical profiles, such as increased RB protein phosphorylation and decreased expressions of p21(WAF1), cytoplasmic p-extracellular signal-regulated kinase 1/2, and caveolins 1 and 2. Significance of these findings was strengthened additionally by the fact that nuclear actin export of young HDF cells was inhibited by the treatment with leptomycin B and mutant cofilin transfection, whose LIMK-1 phosphorylation site was lost, and the old cell phenotypes were duplicated with nuclear actin accumulation, suggesting that nuclear actin accumulation was accompanied with G1 arrest during cellular senescence. The aforementioned changes were observed not only in the replicative senescence but also in the senescence induced by treatment of HDF cells, Mv1Lu, primary culture of human chondrocytes, or Huh7 cells with H-ras virus infection, hydroxyurea, deferoxamine, or H(2)O(2). Nuclear actin accumulation was much more sensitive and an earlier event than the well-known, senescence-associated beta-galactosidase activity.

Actin Depolymerizing Factors↗
PubMed1998

A novel human gene FKBP6 is deleted in Williams syndrome.

Williams syndrome (WS) is a developmental disorder caused by haploinsufficiency of genes at 7q11.23. We have shown that hemizygosity of elastin is responsible for one feature of WS, supravalvular aortic stenosis. We have also implicated LIM-kinase 1 hemizygosity as a contributing factor to impaired visual-spatial constructive cognition in WS. Here we identify and characterize a novel gene, FKBP6, within the common WS deletion region. FKBP6 shows homology to the FK-506 binding protein (FKBP) class of immunophilins. FKBP6 has a putative N-terminal FK-506 binding and peptidylproyl isomerase (rotamase) domain and, like known high-molecular-weight FKBPs, an imperfect C-terminal tetratricopeptide repeat domain. FKBP6 is expressed in testis, heart, skeletal muscle, liver, and kidney. FKBP6 consists of nine exons and is completely contained within a 35-kb cosmid clone. Fluorescence in situ hybridization experiments show that FKBP6 gene is deleted in 40/40 WS individuals. Hemizygous deletion of FKBP6 may contribute to certain defects such as hypercalcemia and growth delay in WS.

Amino Acid Sequence↗
PubMed2006

The neurobiology of Williams syndrome: cascading influences of visual system impairment?

Williams syndrome (WS) is characterized by a unique pattern of cognitive, behavioral, and neurobiological findings that stem from a microdeletion of genes on chromosome 7. Visuospatial ability is particularly affected in WS and neurobiological studies of WS demonstrate atypical function and structure in posterior parietal, thalamic, and cerebellar regions that are important for performing space-based actions. This review summarizes the neurobiological findings in WS, and, based on these findings, we suggest that people with WS have a primary impairment in neural systems that support the performance of space-based actions. We also examine the question of whether impaired development of visual systems could affect the development of atypical social-emotional and language function in people with WS. Finally, we propose developmental explanations for the visual system impairments in WS. While hemizygosity for the transcription factor II-I gene family probably affects the development of visual systems, we also suggest that Lim-kinase 1 hemizygosity exacerbates the impairments in performing space-based actions.

Brain↗