Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 34-year-old gravida 2 para 1 (1001) mother was on prophylactic anticoagulation therapy because of pulmonary emboli postabdominal surgery. The pregnancy was terminated at 25 weeks' gestation after ultrasound examination showed a mild hydrocephalus and a cardiac structural defect. Congenital abnormalities of the delivered fetus included nasal hypoplasia, earfold atresia, bilobled lungs, coarctation of the aorta, ventricular septal defect, gastrochisis, and radiographic skeletal stippling. The radiological and physical findings were consistent with warfarin embryopathy.
Pediatr Pathol Mol Med
PMID:Warfarin embryopathy. 1469 24

Rodent models of polycystic kidney disease (PKD) have provided valuable insight into the cellular changes associated with cystogenesis in humans. The present study characterizes the morphology of renal and extrarenal pathology of autosomal recessive PKD induced by the wpk gene in Wistar rats. In wpk(-/-) rats, proximal tubule and collecting duct cysts develop in utero and eventually consume the kidney. Increased apoptosis, mitosis, and extracellular tenascin deposition parallel cyst development. Extrarenal pathology occurs in the immune system (thymic and splenic hypoplasia) and central nervous system (CNS; hypoplasia to agenesis of the corpus callosum with severe hydrocephalus). Severity of hydrocephalus varied inversely with size of the corpus callosum. In wpk(-/-) rats, the corpus callosum exhibits relatively few axons that cross the midline. This CNS pathology is similar to that described in three human renal cystic syndromes: orofaciodigital, genitopatellar, and cerebrorenal-digital syndromes. Collecting duct and ventricular ependymal cilia appear morphologically normal. To determine if rodent background strain and the presence of modifier genes affect severity of the disease, we crossed the Wistar-wpk rat with Brown Norway (BN) and Long Evan (LE) rats and found the degree of renal and cerebral pathology was diminished as evidenced by lower kidney weight as a percent of body weight and serum urea nitrogen concentration in cystic rats on LE or BN strains as well as less prominent cranial enlargement. Crosses with BN rats allowed us to localize the wpk gene on chromosome 5 very close to the D5Rat73 marker. The wpk gene lies within a chromosomal region known to harbor a PKD modifier locus. In summary, the types of renal and cerebral pathology seen in the Wistar wpk rat are a unique combination seen only in this rodent model.
Anat Rec A Discov Mol Cell Evol Biol 2004 Apr
PMID:Development of multiorgan pathology in the wpk rat model of polycystic kidney disease. 1505 65

Type XVIII collagen/endostatin is known to be crucial for the eye, as witnessed by severe eye defects in Knobloch syndrome patients with mutations in this collagen and in Col18a1(-/-) mice. We show here that in a specific C57BL background, 20% of the Col18a1(-/-) mice developed hydrocephalus, and dilation of the brain ventricles was observed by MRI in all of the mutant mice. Significant broadening was observed in the epithelial basement membrane (BM) of the choroid plexuses (CP), its width being 86.4+/-10.52 nm, compared with 61.4+/-6.05 nm in wild-type mice. The CP epithelial cell morphology was balloon-shaped rather than cuboidal, and the microvilli of the apical surface of the CP epithelium contained more vacuoles in the null mice than in the wild-type, as also did the CP epithelial cells, which is suggestive of alterations in cerebrospinal fluid production. Analysis of BMs elsewhere in the body revealed a broadened epidermal BM in the Col18a1(-/-) mice, but this did not result in any apparent functional deficiencies. Moreover, markedly broadened BMs were found in the atrioventricular valves of the heart and in the kidney tubules, whereas the glomerular mesangial matrix of the kidneys was expanded in the mutant mice and serum creatinine levels were elevated, indicating alterations in kidney filtration capacity. We thus suggest that type XVIII collagen is a structurally important constituent of BMs, and that its absence can result in a variety of phenotypic alterations.
Hum Mol Genet 2004 Sep 15
PMID:Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. 1525 16

Motility of unicellular organisms occurred early in evolution with the emergence of cilia and flagella. In vertebrates, motile cilia are required for numerous functions such as clearance of the airways and determination of left-right body asymmetry. Ependymal cells lining the brain ventricles also carry motile cilia, but their biological function has remained obscure. Here, we show that ependymal cilia generate a laminar flow of cerebrospinal fluid through the cerebral aqueduct, which we term as 'ependymal flow'. The axonemal dynein heavy chain gene Mdnah5 is specifically expressed in ependymal cells, and is essential for ultrastructural and functional integrity of ependymal cilia. In Mdnah5-mutant mice, lack of ependymal flow causes closure of the aqueduct and subsequent formation of triventricular hydrocephalus during early postnatal brain development. The higher incidence of aqueduct stenosis and hydrocephalus formation in patients with ciliary defects proves the relevance of this novel mechanism in humans.
Hum Mol Genet 2004 Sep 15
PMID:Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation. 1526 78

cDNA rat stress microarrays were used to test the general hypothesis that atypical gene expression patterns exist in the brains of Hydrocephalic-Texas (H-Tx) compared to normal Sprague-Dawley (SD) rats on embryonic day 18. Sixty-two percent of the 216 target transcripts were detected in at least 2 of 3 replicates, with maximum mean fold change (MFC) ratios (H-Tx:SD) in Bcl-2-related ovarian killer protein (BOK, 3.07) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha, 0.04). Five (3.73%) of the 134 detected transcripts were elevated and 20 (17.2%) were suppressed more than twofold in H-Tx. MFC ratios for stress response, cytoskeleton-motility, and intracellular transducer-effector-modulator functional classifications were elevated, while MFC ratios for transcription and apoptosis groups were suppressed in H-Tx. K-means clustering revealed several patterns of gene expression with potential biological relevance in apoptosis, intracellular transducer-effector-modulator, metabolism, cell cycle, and stress response transcripts. Multiplex RT-PCR methodology, used to corroborate the cDNA data, captured four distinct temporal expression patterns on embryonic days 16-20 (E16-E20) for HSP27, DnaJ2, HSP47, HSP60, HSP70, HIP, HSP90A, and HSP90beta. The discovery of unique chaperone/heat shock expression profiles in the embryonic brains of H-Tx and SD rats is a powerful step towards the development of novel mechanistic hypotheses in the study of hydrocephalus disorders. This is the first study to associate early stress responses with the differential expression of chaperones/heat shock protein-related genes using the H-Tx model of congenital hydrocephalus.
Brain Res Mol Brain Res 2005 Aug 18
PMID:Differential expression of stress response genes in the H-Tx rat model of congenital hydrocephalus. 1596 63

The Drosophila Fused (Fu) kinase is an integral component of the Hedgehog (Hh) pathway that helps promote Hh-dependent gene transcription. Vertebrate homologues of Fu function in the Hh pathway in vitro, suggesting that Fu is evolutionarily conserved. We have generated fused (stk36) knockout mice to address the in vivo function of the mouse Fu (mFu) homologue. fused knockouts develop normally, being born in Mendelian ratios, but fail to thrive within 2 weeks, displaying profound growth retardation with communicating hydrocephalus and early mortality. The fused gene is expressed highly in ependymal cells and the choroid plexus, tissues involved in the production and circulation of cerebral spinal fluid (CSF), suggesting that loss of mFu disrupts CSF homeostasis. Similarly, fused is highly expressed in the nasal epithelium, where fused knockouts display bilateral suppurative rhinitis. No obvious defects were observed in the development of organs where Hh signaling is required (limbs, face, bones, etc.). Specification of neuronal cell fates by Hh in the neural tube was normal in fused knockouts, and induction of Hh target genes in numerous tissues is not affected by the loss of mFu. Furthermore, stimulation of fused knockout cerebellar granule cells to proliferate with Sonic Hh revealed no defect in Hh signal transmission. These results show that the mFu homologue is not required for Hh signaling during embryonic development but is required for proper postnatal development, possibly by regulating the CSF homeostasis or ciliary function.
Mol Cell Biol 2005 Aug
PMID:Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. 1605 17

UBP43/USP18 was described as a specific protease that removes conjugated ubiquitin-like modifier ISG15 from target proteins. The severe phenotype of UBP43(-/-) mice characterized by premature death, brain cell injury, and deregulated STAT1 signaling was ascribed to an enhanced conjugation of ISG15. In contrast, no phenotypic changes were detected in ISG15(-/-) mice. To verify the role of ISG15 in the phenotype of UBP43(-/-) mice, we employed mice deficient for both ISG15 and UBP43. Here, we show that the phenotype of UBP43(-/-) mice was not rescued by the absence of ISG15, as evident from unchanged mortality, neurological symptoms, and occurrence of hydrocephalus. Also, the reported hypersensitivity of UBP43(-/-) mice to an interferon inducer, poly(I . C), was ISG15 independent. Furthermore, no evidence for a role of ISG15 in the modulation of STAT1 signaling or in the resistance against lymphocytic choriomeningitis virus and vesicular stomatitis virus was found. Presented results clearly demonstrate that the phenotypic alterations of UBP43(-/-) mice are not caused by the lack of ISG15 deconjugation and must be due to another, non-ISG15-mediated molecular mechanism.
Mol Cell Biol 2005 Dec
PMID:Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice. 1631 24

We report that the alternatively spliced isoforms of nonmuscle myosin heavy chain II-B (NHMC II-B) play distinct roles during mouse brain development. The B1-inserted isoform of NMHC II-B, which contains an insert of 10 amino acids near the ATP-binding region (loop 1) of the myosin heavy chain, is involved in normal migration of facial neurons. In contrast, the B2-inserted isoform, which contains an insert of 21 amino acids near the actin-binding region (loop 2), is important for postnatal development of cerebellar Purkinje cells. Deletion of the B1 alternative exon, together with reduced expression of myosin II-B, results in abnormal migration and consequent protrusion of facial neurons into the fourth ventricle. This protrusion is associated with the development of hydrocephalus. Restoring the amount of myosin II-B expression to wild-type levels prevents these defects, showing the importance of total myosin activity in facial neuron migration. In contrast, deletion of the B2 alternative exon results in abnormal development of cerebellar Purkinje cells. Cells lacking the B2-inserted isoform show reduced numbers of dendritic spines and branches. Some of the B2-ablated Purkinje cells are misplaced in the cerebellar molecular layer. All of the B2-ablated mice demonstrated impaired motor coordination.
Mol Biol Cell 2006 May
PMID:Function of the neuron-specific alternatively spliced isoforms of nonmuscle myosin II-B during mouse brain development. 1648 98

We describe the clinical course, as well as cytogenetic and molecular findings, of a 3-year-old obese boy with psychomotor retardation who exhibited two rare conditions: succinic semialdehyde dehydrogenase deficiency (SSADH deficiency, MIM 271980), a disorder of gamma-aminobutyric acid metabolism with a heterogeneous clinical spectrum, and partial Wilms' tumor, aniridia, genital abnormalities, and mental retardation (WAGR) syndrome, an association between Wilms' tumor, aniridia, genitourinary malformations, and mental retardation due to mutations involving the short arm of chromosome 11, particularly deletions at the chromosomal region 11p13 (MIM 194072). Diagnosis of SSADH deficiency in our patient was established by demonstration of absent enzyme activity in isolated leucocytes, and was associated with a novel missense mutation (c.587G>A; p.Gly196Asp) in the SSADH coding sequence. We further confirmed an incomplete WAGR syndrome in this boy [karyotype 46, XY, del (11) (p13p14.2)] with a normal WT1 (Wilms' tumor) gene and an absence of pathology in the genitourinary tract, but with obesity (WAGR syndrome with obesity, WAGRO syndrome). The patient also exhibited distinctive cerebral anomalies such as increased signals of the globi pallidi, internal hydrocephalus and cerebellar vermian atrophy. However, treatment options for this patient are limited, including supportive treatment, physiotherapy, special educational training, and vigabatrin. In summary, we report the first patient with the exceptional rare findings of both SSADH deficiency and partial WAGR/WAGRO syndrome.
Mol Genet Metab 2006 Jul
PMID:Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity. 1654 79

CDO is a cell surface immunoglobulin superfamily member that positively regulates myogenic differentiation in vitro and in vivo and signals to posttranslationally activate myogenic basic helix-loop-helix (bHLH) transcription factors. The Cdo gene is also expressed in the dorsal aspect and midline structures of the developing central nervous system, and mice lacking CDO on the C57BL/6 background display holoprosencephaly with approximately 80% penetrance, resulting in perinatal lethality. We report here that a fraction of Cdo-/- mice from this background have additional defects in brain development, including hydrocephalus and cortical thinning. Primary neural progenitor cultures from E14.5 Cdo-/- mutants display reduced proliferation, which may underlie the thinning. The cortical preplate and cortices of mutant animals also show reduced staining for beta-tubulin III, indicating defective neuronal differentiation. CDO levels are strongly increased in cultured C17.2 neuronal precursor cells stimulated to differentiate; modulation of CDO levels in these cells by overexpression or interfering RNA approaches enhances or diminishes differentiation, respectively. Cotransfection of CDO enhances the activity of the neurogenic bHLH factor, neurogenin1, in reporter assays and enhances heterodimerization of neurogenin1 and E47. These results indicate that CDO promotes neuronal differentiation and support the hypothesis that CDO coordinates differentiation of multiple cell lineages by regulating the activity of tissue-specific bHLH factors.
Mol Cell Biol 2006 May
PMID:Cortical thinning and hydrocephalus in mice lacking the immunoglobulin superfamily member CDO. 1664 72


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