Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Primary ciliary dyskinesia (PCD) is a genetically and phenotypically heterogeneous disorder, characterized by progressive development of bronchiectasis, inflammation, and features characteristic of chronic obstructive pulmonary disease. We report here that a murine mutation of the evolutionarily conserved adenylate kinase 7 (Ak7) gene results in animals presenting with pathological signs characteristic of PCD, including ultrastructural ciliary defects and decreased ciliary beat frequency in respiratory epithelium. The mutation is associated with hydrocephalus, abnormal spermatogenesis, mucus accumulation in paranasal passages, and a dramatic respiratory pathology upon allergen challenge. Ak7 appears to be a marker for cilia with (9 + 2) microtubular organization. This is suggested by its tissue specificity of expression and also the stringent conservation of Ak7 ortholog structure only in protozoans and metazoans possessing motile (9 + 2) cilia. Collectively, our results indicate an ancestral and crucial role of Ak7 in maintaining ciliary structure and function, and suggest that mutations of the human ortholog may underlie a subset of genetically uncharacterized PCD cases.
Am J Respir Cell Mol Biol 2009 Mar
PMID:Mutation of murine adenylate kinase 7 underlies a primary ciliary dyskinesia phenotype. 1877 31

Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1(+/-) mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu(+/-) mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu(+/-)Ptch1(+/-) mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu(+/-)Ptch1(+/-) compared to Sufu(+/-) female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu(+/-)Ptch1(+/-) compared to Ptch1(+/-) female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu(+/-)Ptch1(+/-) mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in approximately 20% of the Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) but not in Sufu(+/-) mice. Interestingly, most of the medulloblastomas from the Sufu(+/-)Ptch1(+/-) mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1(+/-) and Sufu(+/-)Ptch1(+/-) mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway.
Mol Carcinog 2009 May
PMID:Tumor suppressor gene co-operativity in compound Patched1 and suppressor of fused heterozygous mutant mice. 1878 8

Huntingtin (htt) is a 350 kDa protein of unknown function, with no homologies with other known proteins. Expansion of a polyglutamine stretch at the N-terminus of htt causes Huntington's disease (HD), a dominant neurodegenerative disorder. Although it is generally accepted that HD is caused primarily by a gain-of-function mechanism, recent studies suggest that loss-of-function may also be part of HD pathogenesis. Huntingtin is an essential protein in the mouse since inactivation of the mouse HD homolog (Hdh) gene results in early embryonic lethality. Huntingtin is widely expressed in embryogenesis, and associated with a number of interacting proteins suggesting that htt may be involved in several processes including morphogenesis, neurogenesis and neuronal survival. To further investigate the role of htt in these processes, we have inactivated the Hdh gene in Wnt1 cell lineages using the Cre-loxP system of recombination. Here we show that conditional inactivation of the Hdh gene in Wnt1 cell lineages results in congenital hydrocephalus, implicating huntingtin for the first time in the regulation of cerebral spinal fluid (CSF) homeostasis. Our results show that hydrocephalus in mice lacking htt in Wnt1 cell lineages is associated with increase in CSF production by the choroid plexus, and abnormal subcommissural organ.
Hum Mol Genet 2009 Jan 01
PMID:Congenital hydrocephalus associated with abnormal subcommissural organ in mice lacking huntingtin in Wnt1 cell lineages. 1883 63

In humans, OFD1 is mutated in oral-facial-digital type I syndrome leading to prenatal death in hemizygous males and dysmorphic faces and brain malformations, with polycystic kidneys presenting later in life in heterozygous females. To elucidate the function of Ofd1, we have studied its function during zebrafish embryonic development. In wild-type embryos, ofd1 mRNA is widely expressed and Ofd1-green fluorescent protein (GFP) fusion localizes to the centrosome/basal body. Disrupting Ofd1 using antisense morpholinos (MOs) led to bent body axes, hydrocephalus and oedema. Laterality was randomized in the brain, heart and viscera, likely a consequence of shorter cilia with disrupted axonemes and perturbed intravesicular fluid flow in Kupffer's vesicle. Embryos injected with ofd1 MOs also displayed convergent extension (CE) defects, which were enhanced by loss of Slb/Wnt11 or Tri/Vangl2, two proteins functioning in a non-canonical Wnt/Planar Cell Polarity (PCP) pathway. Pronephric glomerular midline fusion was compromised in vangl2 and ofd1 loss of function embryos and we suggest this anomaly may be a novel CE defect. Thus, Ofd1 is required for ciliary motility and function in zebrafish, supporting data showing that Ofd1 is essential for primary cilia function in mice. In addition, our data show that Ofd1 is important for CE during gastrulation, consistent with data linking primary cilia and non-canonical Wnt/PCP signalling.
Hum Mol Genet 2009 Jan 15
PMID:Convergent extension movements and ciliary function are mediated by ofd1, a zebrafish orthologue of the human oral-facial-digital type 1 syndrome gene. 1897 Dec 6

Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315-1325, 1998; Sheen et al. in 'Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69-76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in 'MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789-801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (alpha-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventricular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell adhesion and loss of neuroependymal integrity.
Hum Mol Genet 2009 Feb 01
PMID:Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia. 1899 16

The incidence of neural tube defects is higher in Turkey compared to that of developed countries. To prevent congenital malformations, understanding of the current status is necessary, which should be followed by public-based activities. We examined the incidence rate of neural tube defects (NTDs) in Afyonkarahisar. According to the records of the Department of Pediatrics, Zubeyde Hanim Hospital for Children's and Women's Health in Afyonkarahisar, the total number of births was 8631 during 2003 and 2004. Sixty-three babies with anomalies were identified in the early postnatal period. The incidence of neural tube defect based on records of hospitals in the city center was calculated as 3.58/1000, among which 9 (1.04%) of the malformed babies had spina bifida, 2 (0.23%) had encephalocele, 12 (1.39%) had anencephaly, and 8 (0.92%) had meningocele/meningomyelocele. In 32 of the 63 cases, there were also other malformations (cleft lip or clubfoot, hydrocephalus, foot abnormalities, etc.). We calculated the total incidence of NTDs, including live births, stillbirths and therapeutic abortions. Stillbirths referred to all fetal deaths after 24 weeks or longer gestation. In each case, the type of anomaly was determined. Thirty-one babies with an NTD were recorded among 8631 gestations (all live births, stillbirths and therapeutic abortions). The incidence of NTDs was found to be 35.9 per 10,000 live births in Afyonkarahisar. The incidence of spina bifida/anencephaly was 0.748 per 1000 newborns. Maternal illiteracy, maternal advanced age and residence in northern or eastern regions of Turkey were found to be risk factors for having a baby with an NTD. The incidence of NTDs is higher than in other European countries.
Genet Mol Res 2009 Feb 17
PMID:Incidence of neural tube defects in Afyonkarahisar, Western Turkey. 1928 82

The L1 cell adhesion molecule (L1CAM) is a protein encoded by a gene that has been localized to Xq28, is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules, and plays a role in CNS development and maturation. L1CAM is expressed in neurons and Schwann cells, where it is active in neurite overgrowth, adhesion fasciculation, migration, myelination, and axon guidance. Mutations within the gene have been associated with phenotypic changes that include hydrocephalus due to aqueductal stenosis, agenesis or hypoplasia of the corpus callosum and corticospinal tracts, mental retardation, spastic paraplegia, and adducted thumbs. Here, we present a 19-year-old primigravida Caucasian woman who was referred to us in the 27th week of the pregnancy because of fetal polyhydramnios and ventriculomegaly. Our evaluation identified a male fetus with hydrocephalus, ventriculomegaly, aqueductal stenosis, and polyhydramnios. An amniocentesis was performed, and isolated fetal DNA revealed a hemizygous G > C mutation in codon 2809 of exon 21 of the L1CAM gene. The patient was later tested and identified to be a carrier of the same mutation. The fetus was delivered during the 38th week. Neonatal physical examination revealed marked frontal bossing, contractures of the feet with rocker bottom appearance, and hyperactive reflexes with ankle and knee clonus. He died at 4 months of life.
Genet Test Mol Biomarkers 2009 Aug
PMID:Prenatal identification of a novel R937P L1CAM missense mutation. 1959 70

alpha-SNAP is an essential component of the protein machinery responsible for membrane fusion events in different cell types. The hyh (hydrocephalus with hop gait) mouse carries a missense mutation in Napa gene that results in a point mutation (M105I) in alpha-SNAP protein. Homozygous animals for the mutant allele have been identified by the clinical and/or neuropathological phenotype, or by direct sequencing of PCR products. The aims of the present study were (i) to develop a high-throughput technique to genotype hyh mice, (ii) to correlate genotype-phenotype, and (iii) to analyze the earliest pathological changes of hyh mutant mice. As no restriction sites are affected by the hyh mutation, we resolved this problem by creating a BspHI restriction site with a modified (mismatch) polymerase chain reaction (PCR) primer in wild-type allele. This artificially created restriction site (ACRS)-PCR technique is a simple, rapid and reliable method to genotype hyh mice in a day-work procedure. Biochemical and histological analysis of genotyped hyh embryos at different developmental stages allowed us to identify and characterize the earliest brain pathological changes of the hyh phenotype, including the first signs of neuroepithelial disruption and neuronal ectopia. In addition, genotype-phenotype analysis of 327 animals confirmed that (i) hyh is a single-gene autosomal recessive disorder, and (ii) the disorder has 100% penetrance (i.e., the mutation was only present in affected mice). The genotyping method described here enhances the potentiality of hyh mouse as a unique in vivo model to study the role of membrane trafficking in different developmental and physiological processes.
Mol Cell Probes 2009 Dec
PMID:A simple PCR-based genotyping method for M105I mutation of alpha-SNAP enhances the study of early pathological changes in hyh phenotype. 1961 40

Studies of primary ciliary dyskinesia (PCD) have been hampered by the lack of a suitable animal model because disruption of essential ciliary genes in mice results in a high incidence of lethal hydrocephalus. To develop a viable mouse model for long-term studies of PCD, we have generated a transgenic mouse line in which two conserved exons of the mouse intermediate dynein chain gene, Dnaic1, are flanked by loxP sites (Dnaic1(flox/flox)). Dnaic1 is the murine homolog of human DNAI1, which is mutated in approximately 10% of human PCD cases. These mice have been crossed with mice expressing a tamoxifen-inducible Cre recombinase (CreER). Treatment of adult Dnaic1(flox/flox)/CreER(+/-) mice with tamoxifen results in an almost complete deletion of Dnaic1 with no evidence of hydrocephalus. Treated animals have reduced levels of full-length Dnaic1 mRNA, and electron micrographs of cilia demonstrate a loss of outer dynein arm structures. In treated Dnaic1(flox/flox)/CreER(+/-) animals, mucociliary clearance (MCC) was reduced over time. After approximately 3 months, no MCC was observed in the nasopharynx, whereas in the trachea, MCC was observed for up to 6 months, likely reflecting a difference in the turnover of ciliated cells in these tissues. All treated animals developed severe rhinosinusitis, demonstrating the importance of MCC to the health of the upper airways. However, no evidence of lung disease was observed up to 11 months after Dnaic1 deletion, suggesting that other mechanisms are able to compensate for the lack of MCC in the lower airways of mice. This model will be useful for the study of the pathogenesis and treatment of PCD.
Am J Respir Cell Mol Biol 2010 Jul
PMID:Conditional deletion of dnaic1 in a murine model of primary ciliary dyskinesia causes chronic rhinosinusitis. 1967 6

Dysfunction of primary cilia is associated with tissue-specific or syndromic disorders. RPGR is a ciliary protein, mutations in which can lead to retinitis pigmentosa (RP), cone-rod degeneration, respiratory infections and hearing disorders. Though RPGR is implicated in ciliary transport, the pathogenicity of RPGR mutations and the mechanism of underlying phenotypic heterogeneity are still unclear. Here we have utilized genetic rescue studies in zebrafish to elucidate the effect of human disease-associated mutations on its function. We show that rpgr is expressed predominantly in the retina, brain and gut of zebrafish. In the retina, RPGR primarily localizes to the sensory cilium of photoreceptors. Antisense morpholino (MO)-mediated knockdown of rpgr function in zebrafish results in reduced length of Kupffer's vesicle (KV) cilia and is associated with ciliary anomalies including shortened body-axis, kinked tail, hydrocephaly and edema but does not affect retinal development. These phenotypes can be rescued by wild-type (WT) human RPGR. Several of the RPGR mutants can also reverse the MO-induced phenotype, suggesting their potential hypomorphic function. Notably, selected RPGR mutations observed in XLRP (T99N, E589X) or syndromic RP (T124fs, K190fs and L280fs) do not completely rescue the rpgr-MO phenotype, indicating a more deleterious effect of the mutation on the function of RPGR. We propose that RPGR is involved in cilia-dependent cascades during development in zebrafish. Our studies provide evidence for a heterogenic effect of the disease-causing mutations on the function of RPGR.
Hum Mol Genet 2010 Jan 01
PMID:Human retinopathy-associated ciliary protein retinitis pigmentosa GTPase regulator mediates cilia-dependent vertebrate development. 1981 19


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