Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033377 (prolapse)
 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mutation in the EFEMP1 gene causes Malattia Leventinese, an inherited macular degenerative disease with strong similarities to age-related macular degeneration. EFEMP1 encodes fibulin-3, an extracellular matrix protein of unknown function. To investigate its biological role, the murine Efemp1 gene was inactivated through targeted disruption. Efemp1(-/-) mice exhibited reduced reproductivity, and displayed an early onset of aging-associated phenotypes including reduced lifespan, decreased body mass, lordokyphosis, reduced hair growth, and generalized fat, muscle and organ atrophy. However, these mice appeared to have normal wound healing ability. Efemp1(-/-) mice on a C57BL/6 genetic background developed multiple large hernias including inguinal hernias, pelvic prolapse and protrusions of the xiphoid process. In contrast, Efemp1(-/-) mice on a BALB/c background rarely had any forms of hernias, indicating the presence of modifiers for fibulin-3's function in different mouse strains. Histological analysis revealed a marked reduction of elastic fibers in fascia, a thin layer of connective tissue maintaining and protecting structures throughout the body. No apparent macular degeneration associated defects were found in Efemp1(-/-) mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration. These data demonstrate that fibulin-3 plays an important role in maintaining the integrity of fascia connective tissues and regulates aging.
Hum Mol Genet 2007 Dec 15
PMID:Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice. 1787 5

We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.
Mol Genet Metab 2008 Feb
PMID:Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin. 1805 10

Failure of ligamentous support of the genital tract to resist intra-abdominal pressure is a plausible underlying mechanism for the development of pelvic organ prolapse, but the nature of the molecular response of pelvic tissue support remains unknown. We hypothesized that the expression of genes coding for proteins involved in maintaining the cellular and extracellular integrity would be altered as a result of mechanical stretch. Therefore, cDNA microarrays were used to examine the difference in transcriptional profile in RNA of primary culture fibroblasts subjected to mechanical stretch and those that remained static. Out of 34 mechano-responsive genes identified (P < 0.05), four were coding for regulation of actin cytoskeleton remodelling, and its interaction with the extracellular matrix proteins; these are phosphatidyl inositol-4-phosphate 5-kinase (PIP5K1C), the human signal-induced proliferation associated gene-1 (SIPA-1), TNFRSF1A-associated via death domain (TRADD) and deoxyribonuclease 1-like 1 (DNase 1-L1). The transcriptosomal changes led us to investigate the phenotypic consequences of stretch, levormeloxifene and estradiol (E(2)) on the cytoskeleton of cultured fibroblasts. The percentage of cells with abnormal F-actin configuration was significantly higher in fibroblasts subjected to stretch compared with the static model (P < 0.0001). Levormeloxifene caused similar significant alterations in actin morphology of the static fibroblasts. The use of E(2) did not reverse the process or protect the cells from the effect of stretch, but significantly increased the rate of fibroblast proliferation, suggestive of a role in healing process. Mechanical stretch and/or levormeloxifene disturb the fibroblasts ability to maintain the cytoskeleton architecture and we speculate that they may disrupt ligamentous integrity and result in clinical prolapse.
Mol Hum Reprod 2008 Feb
PMID:Changes in transcription profile and cytoskeleton morphology in pelvic ligament fibroblasts in response to stretch: the effects of estradiol and levormeloxifene. 1818 56

Diverging results have been published concerning collagen metabolism in uterovaginal prolapse (UP). We have investigated collagen turnover in urogenital tissue in urologically healthy women with (UP patients) and without UP or any history of UP (controls). Markers of collagen turnover, carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of procollagen III (PIIINP) and carboxy-terminal telopeptide of type I collagen (ICTP) were assayed in urogenital tissue homogenates and serum. Tissue and serum concentrations of collagen turnover markers were related to UP and to menopausal/estrogen status. UP patients were significantly older than the controls. UP patients had significantly higher tissue PICP and PIIINP and significantly lower tissue ICTP levels than the controls, but the difference in ICTP disappeared after matching for menopausal/estrogen status and age. There were no associations between tissue collagen turnover markers on the one hand and menopausal/estrogen status or age on the other. The higher tissue concentrations of PICP and especially PIIINP in tissue from women with UP compared to controls, suggest an increased collagen breakdown in UP. This pattern differs from that in stress urinary incontinent women without UP, where tissue levels of collagen turnover markers are low, indicating reduced collagen breakdown.
Mol Hum Reprod 2008 Mar
PMID:Markers of collagen synthesis and degradation in urogenital tissue and serum from women with and without uterovaginal prolapse. 1823 Jun 25

It was hypothesized that the processes contributing to pelvic organ prolapse (POP) may be identified by transcriptional profiling of pelvic connective tissue in conjunction with light microscopy. In order to test this, we performed a frequency-matched case-control study of women undergoing hysterectomy for POP and controls. Total RNA, extracted from uterosacral and round ligament samples used to generate labeled cRNA, was hybridized to microarrays and analyzed for the expression of 32 878 genes. Significance Analysis of Microarrays (Stanford University, CA, USA) identified differentially expressed genes used for ontoanalysis. Quantitative PCR (qPCR) confirmed results. Light microscopy confirmed the tissue type and assessed inflammatory infiltration. The analysis of 34 arrays revealed 249 differentially expressed genes with fold changes (FC) larger than 1.5 and false discovery rates < or =5.2%. Immunity and defense was the most significant biological process differentially expressed in POP. qPCR confirmed the elevated steady-state mRNA levels for four genes: interleukin-6 (FC 9.8), thrombospondin 1 (FC 3.5) and prostaglandin-endoperoxide synthase 2 (FC 2.4) and activating transcription factor 3 (FC 2.6). Light microscopy showed all the samples were composed of fibromuscular connective tissue with no inflammatory infiltrates. In conclusion, genes enriched for 'immunity and defense' contribute to POP independent of inflammatory infiltrates.
Mol Hum Reprod 2009 Jan
PMID:Gene expression profile in pelvic organ prolapse. 1905 8

An autopsy of a 44-year-old Japanese woman with mitochondrial cytopathy confirmed the presence of chronic progressive external ophthalmoplegia (CPEO). Immunohistochemistry using antimitochondrial antibody was performed to observe the ultrastructure of the skeletal muscle and renal tissues. The patient was born of consanguineous parents, developed normally, and was of average intelligence. At 22 years of age, the patient noticed hearing loss, and subsequently, over time, developed a progressive generalized muscle weakness, which included limitation of eye movement and ptosis. At age 41, a muscle biopsy was performed using the modified Gomori trichrome method and demonstrated the presence of ragged red fibers. After the evaluation of her results in conjunction with her clinical course, she was diagnosed with CPEO. Renal insufficiency was discovered at age 30, and the patient died at the age of 44 of respiratory failure caused by respiratory muscle weakness and pneumonia. The autopsy revealed fiber size variation within the skeletal muscle, and an antimitochondrial antibody analysis demonstrated the accumulation of mitochondria between the bundles of myofibrils, as well as in subsarcolemmal locations. Ultrastructurally, abnormal mitochondria with disoriented cristae and paracrystalline inclusions were seen. Although no remarkable histological changes were noted in the kidneys, tubular epithelial cells exhibited accumulated abnormal mitochondria, similar to those seen in the skeletal muscle. Because mitochondrial diseases can affect other energy-dependent organs in addition to the skeletal muscle, immunohistochemical examinations employing an antimitochondrial antibody are useful for obtaining further ultrastructural observations that can assist in making a distinct diagnosis of this systemic disorder.
Med Mol Morphol 2008 Dec
PMID:An autopsy case of chronic progressive external ophthalmoplegia with renal insufficiency. 1910 14

WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities and mental retardation) and Potocki-Shaffer syndrome are rare contiguous gene deletion syndromes caused by deletions of the 11p14-p12 chromosome region.We present a patient with mental retardation, unilateral cataract, bilateral ptosis, genital abnormalities, seizures and a dysmorphic face. Cytogenetic analysis showed a deletion on 11p that was further characterized using FISH and MLPA analyses. The deletion (11p13-p12) located in the area between the deletions associated with the WAGR and Potocki-Shaffer syndromes had a maximum size of 8.5 Mb and encompasses 44 genes. Deletion of WT1 explains the genital abnormalities observed. As PAX6 was intact the cataract observed cannot be explained by a deletion of this gene. Seizures have been described in Potocki-Shaffer syndrome while mental retardation has been described in both WAGR and Potocki-Shaffer syndrome. Characterization of this patient contributes further to elucidate the function of the genes in the 11p14-p12 chromosome region.
Mol Cytogenet 2009 Feb 17
PMID:11p Microdeletion including WT1 but not PAX6, presenting with cataract, mental retardation, genital abnormalities and seizures: a case report. 1922 35

Few studies are performed on the sustainability of the pelvic floor extracellular matrix important for preventing development of pelvic organ prolapse (POP). Collagens I and III, the elastin-associated proteins fibrillin-1 and fibulin-5 and the small leucine-rich repeat proteoglycans (SLRPs) decorin, lumican and fibromodulin are involved in giving the tissue its mechanical properties. Para-urethral biopsies were obtained from 15 women, 6 pre- and 9 post-menopausal, with POP. Real-time reverse transcription-polymerase chain reaction and immunohistochemistry for collagen I, collagen III, fibrillin-1, fibulin-5, decorin, lumican and fibromodulin were performed and compared with 14 controls, 8 pre- and 6 post-menopausal. Statistical comparisons controlled for age changes in gene expressions. A 16-fold decrease in decorin mRNA expression, P = 0.0001, and 8-fold in lumican mRNA expression, P = 0.001, were discovered in premenopausal POP compared with matched controls. In all women with POP, there were lower gene expressions of fibromodulin, P = 0.004, and fibulin-5, P = 0.001, compared with all controls. All proteins were detectable by immunohistochemistry, showing a weaker staining for decorin in premenopausal POP. For the first time, we show substantially decreased gene signal for production of SLRPs, regulators of collagen fiber assembly and impairment in elastic fiber assembly by down-regulation of fibulin-5 in POP.
Mol Hum Reprod 2009 Apr
PMID:Gene expressions of small leucine-rich repeat proteoglycans and fibulin-5 are decreased in pelvic organ prolapse. 1925 63

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant syndrome of eyelid malformations with (type I) or without (type II) associated premature ovarian failure. Multiple mutations in the exon and the putative core promoter region of FOXL2 gene encoding a putative forkhead transcription factor have been linked to this disease. To examine whether FOXL2 gene mutations contribute to BPES in the Chinese patient population, we screened 33 patients from 18 Chinese families with BPES of unknown types, together with 57 healthy individuals, including 27 relatives of the affected families. Genomic DNA was extracted from the participants' peripheral blood leukocytes, and amplified by polymerase chain reaction for various regions of the FOXL2 gene, followed by sequencing analysis. Ten mutations in the FOXL2 gene were detected: four were previously reported (g.1041_1042insC, g.1366_1367insT, g.909_938dup30, and g.900_929dup30), and six were novel ones (g.406T>A, g.-14G>A, g.1108_1109insC, g.2577C>T, g.1987C>A, and g.1002C>G). Among them, mutations in the coding region for the polyalanine tract, as well as novel mutations in the core promoter, the 3'-UTR, and in the forkhead domain were identified. Our results expanded the spectrum of FOXL2 mutations in BPES and provided additional valuable genetic information for this rare disease.
Genet Test Mol Biomarkers 2009 Apr
PMID:Mutations of the transcription factor FOXL2 gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. 1937 Dec 27

Mutations in FOXL2 gene are responsible for blepharophimosis ptosis epicanthus inversus and telecanthus syndrome (BPES). The BPES syndrome is a rare autosomal dominant genetic disease characterized by eyelid malformations associated with premature ovarian failure (BPES type I) or not (BPES type II). The human FOXL2 protein (376 aa) contains a 100 amino-acid DNA-binding forkhead domain (residues 52-152) and a polyalanine tract (residues 221-234). In the present study, we report the molecular investigation of four affected members with BPES syndrome in a Tunisian consanguineous family. To identify the causative mutation, we performed a direct sequencing of the FOXL2 gene. The sequence analysis of the coding exon revealed a novel frameshift mutation g.1113 dup C, c.876 dup C, p.P292 Fs. The mutation is located downstream of the polyalanine tract and causes the protein extension to 532 aa. This study reports for the first time a novel frameshift mutation in two-generation consanguineous Tunisian family with BPES. Our results expand the spectrum of FOXL2 mutations.
Genet Test Mol Biomarkers 2010 Feb
PMID:Identification of a novel mutation in FOXL2 gene that leads to blepharophimosis ptosis epicanthus inversus and telecanthus syndrome in a Tunisian consanguineous family. 1992 10


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