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1.
Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6
《American journal of human genetics》2015,97(4):535-545
Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6. 相似文献
2.
Meike Hoffmeister Carola Prelle Philipp Küchler Igor Kovacevic Markus Moser Werner Müller-Esterl Stefanie Oess 《PloS one》2014,9(12)
Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans. 相似文献
3.
Unique Alterations of an Ultraconserved Non-Coding Element in the 3'UTR of ZIC2 in Holoprosencephaly
E Roessler P Hu SK Hong K Srivastava B Carrington R Sood H Petrykowska L Elnitski LA Ribeiro A Richieri-Costa B Feldman WF Odenwald M Muenke 《PloS one》2012,7(7):e39026
Coding region alterations of ZIC2 are the second most common type of mutation in holoprosencephaly (HPE). Here we use several complementary bioinformatic approaches to identify ultraconserved cis-regulatory sequences potentially driving the expression of human ZIC2. We demonstrate that an 804 bp element in the 3' untranslated region (3'UTR) is highly conserved across the evolutionary history of vertebrates from fish to humans. Furthermore, we show that while genetic variation of this element is unexpectedly common among holoprosencephaly subjects (6/528 or >1%), it is not present in control individuals. Two of six proband-unique variants are de novo, supporting their pathogenic involvement in HPE outcomes. These findings support a general recommendation that the identification and analysis of key ultraconserved elements should be incorporated into the genetic risk assessment of holoprosencephaly cases. 相似文献
4.
Evidence of a link between demographic rates and species habitat suitability from post release movements in a reinforced bird population
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Anne‐Christine Monnet Loïc A. Hardouin Alexandre Robert Yves Hingrat Frédéric Jiguet 《Oikos》2015,124(8):1089-1097
Despite the increasing use of species distribution models for predicting current or future animal distribution, only a few studies have linked the gradient of habitat suitability (HS) to demographic parameters. While such approaches can improve the reliability of models, they can help to better predict the response of species to changes in HS over space and time, as induced by ongoing global change. Here, we tested whether the spatial variation in HS along the individual movement path is related to survival, using extensive tracking data collected from captive‐bred individuals translocated to reinforce the wild populations of houbara bustard. We first modelled and mapped the HS from presence data of wild individuals using niche models in a consensus framework. We further analysed survival of released individuals using capture–recapture modelling and its links to HS, as the trend in suitability from the release sites along movements. We found that the survival of released individuals was related to changes in HS along their movements. For instance, individuals which moved to sites of lower HS than their release sites have lower survival probabilities than the others, independently of the HS of the release sites and daily movement rate. Our results provide an empirical support of the relationship between HS and survival, a major fitness component. 相似文献
5.
Mariëlle Alders Lihadh Al-Gazali Isabelle Cordeiro Bruno Dallapiccola Livia Garavelli Beyhan Tuysuz Faranak Salehi Martin A. Haagmans Olaf R. Mook Charles B. Majoie Marcel M. Mannens Raoul C. Hennekam 《Human genetics》2014,133(9):1161-1167
The Hennekam lymphangiectasia–lymphedema syndrome is a genetically heterogeneous disorder. It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases. We used homozygosity mapping and whole-exome sequencing in the original HS family with multiple affected individuals in whom no CCBE1 mutation had been detected, and identified a homozygous mutation in the FAT4 gene. Subsequent targeted mutation analysis of FAT4 in a cohort of 24 CCBE1 mutation-negative Hennekam syndrome patients identified homozygous or compound heterozygous mutations in four additional families. Mutations in FAT4 have been previously associated with Van Maldergem syndrome. Detailed clinical comparison between van Maldergem syndrome and Hennekam syndrome patients shows that there is a substantial overlap in phenotype, especially in facial appearance. We conclude that Hennekam syndrome can be caused by mutations in FAT4 and be allelic to Van Maldergem syndrome. 相似文献
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F Frezzato C Gattazzo V Martini V Trimarco A Teramo S Carraro A Cabrelle E Ave M Facco R Zambello E Tibaldi AM Brunati G Semenzato L Trentin 《PloS one》2012,7(6):e39902
In B-Chronic Lymphocytic Leukemia (B-CLL) kinase Lyn is overexpressed, active, abnormally distributed, and part of a cytosolic complex involving hematopoietic lineage cell-specific protein 1 (HS1). These aberrant properties of Lyn could partially explain leukemic cells' defective apoptosis, directly or through its substrates, for example, HS1 that has been associated to apoptosis in different cell types. To verify the hypothesis of HS1 involvement in Lyn-mediated leukemic cell survival, we investigated HS1 protein in 71 untreated B-CLL patients and 26 healthy controls. We found HS1 overexpressed in leukemic as compared to normal B lymphocytes (1.38±0.54 vs 0.86±0.29, p<0.01), and when HS1 levels were correlated to clinical parameters we found a higher expression of HS1 in poor-prognosis patients. Moreover, HS1 levels significantly decreased in ex vivo leukemic cells of patients responding to a fludarabine-containing regimen. We also observed that HS1 is partially localized in the nucleus of neoplastic B cells. All these data add new information on HS1 study, hypothesizing a pivotal role of HS1 in Lyn-mediated modulation of leukemic cells' survival and focusing, one more time, the attention on the BCR-Lyn axis as a putative target for new therapeutic strategies in this disorder. 相似文献
8.
De Schepper S Boucneau J Lambert J Messiaen L Naeyaert JM 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》2005,18(1):13-24
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, affecting approximately 1 in 3500 individuals. The most commonly seen tumors in NF1 patients are the (sub)cutaneous neurofibromas. However, individuals with NF1 typically present in childhood with well-defined pigmentary defects, including cafe-au-lait macules (CALMs), intertriginous freckling and iris Lisch nodules. NF1 is considered a neurocristopathy, primarily affecting tissues derived from the neural crest. Since the pigment producing melanocyte originates in the neural crest, the presence of (hyper)pigmentary lesions in the NF1 phenotype because of changes in melanocyte cell growth and differentiation is to be expected. We want to discuss the pigmentary cutaneous manifestations of NF1 represented by CALMs and intertriginous freckles and the pigmentary non-cutaneous manifestations represented by iris Lisch nodules. Several hypotheses have been suggested in explaining the poorly understood etiopathogenesis of CALMs. Whether other pigmentary manifestations might share similar etiopathogenic mechanisms remains obscure. Additional attention will be drawn to a readily seen phenomenon in NF1: hyperpigmentation overlying (plexiform) neurofibromas, which could suggest common etiopathogenetic-environmental cues or mechanisms underlying CALMs and neurofibromas. Finally, we want to address the relationship between malignant melanoma and NF1. 相似文献
9.
Sofie De Schepper Joachim Boucneau Jo Lambert Ludwine Messiaen Jean‐Marie Naeyaert 《Pigment cell & melanoma research》2005,18(1):13-24
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, affecting approximately 1 in 3500 individuals. The most commonly seen tumors in NF1 patients are the (sub)cutaneous neurofibromas. However, individuals with NF1 typically present in childhood with well‐defined pigmentary defects, including café‐au‐lait macules (CALMs), intertriginous freckling and iris Lisch nodules. NF1 is considered a neurocristopathy, primarily affecting tissues derived from the neural crest. Since the pigment producing melanocyte originates in the neural crest, the presence of (hyper)pigmentary lesions in the NF1 phenotype because of changes in melanocyte cell growth and differentiation is to be expected. We want to discuss the pigmentary cutaneous manifestations of NF1 represented by CALMs and intertriginous freckles and the pigmentary non‐cutaneous manifestations represented by iris Lisch nodules. Several hypotheses have been suggested in explaining the poorly understood etiopathogenesis of CALMs. Whether other pigmentary manifestations might share similar etiopathogenic mechanisms remains obscure. Additional attention will be drawn to a readily seen phenomenon in NF1: hyperpigmentation overlying (plexiform) neurofibromas, which could suggest common etiopathogenetic‐environmental cues or mechanisms underlying CALMs and neurofibromas. Finally, we want to address the relationship between malignant melanoma and NF1. 相似文献
10.
High-throughput methods for measuring heparanase activity and screening potential antimetastatic and anti-inflammatory agents 总被引:2,自引:0,他引:2
Huang KS Holmgren J Reik L Lucas-McGady D Roberts J Liu CM Levin W 《Analytical biochemistry》2004,333(2):389-398
Heparanase plays an important role in the degradation of the extracellular matrix. It is implicated in inflammation, tumor angiogenesis and metastasis. We have developed two high-throughput methods for measuring heparanase activity and screening potential inhibitors. The first method involves coating fibroblast growth factor (FGF) on microtiter plates and capturing fluorescein isothiocyanate (FITC)-labeled heparin sulfate (HS), which is used as a substrate for heparanase digestion. Labeled HS fragments are released into the medium and quantitated by fluorescence intensity measurement. We have implemented this assay method into a Zeiss uHTS system and screened compound libraries for heparanase inhibitors. The second method involves labeling HS with biotin followed by FITC to generate a dual-labeled HS. The labeled material is bound to streptavidin-coated plates and used as a substrate for heparanase digestion. Both methods are sensitive and easily applicable to robotic systems. In addition, we have labeled both HS and biotin-HS with Eu-chelate, a fluorophore that exhibits long decay fluorescence. Assays using Eu-labeled HS and Eu-labeled biotin-HS have been developed and show higher sensitivity than those using FITC-labeled material. Furthermore, assays using Eu-chelate HS (or biotin-HS) should eliminate the interference of fluorescence compounds. 相似文献
11.
NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway 总被引:1,自引:0,他引:1
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McDaniell R Warthen DM Sanchez-Lara PA Pai A Krantz ID Piccoli DA Spinner NB 《American journal of human genetics》2006,79(1):169-173
Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease. 相似文献
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Ulla Lng Hugh Ramsay Kathryn Yates Juha Veijola David Gyllenberg Mary C. Clarke Finbarr P. Leacy Mika Gissler Ian Kelleher 《World psychiatry》2022,21(3):436
Current strategies to predict psychosis identify only a small proportion of individuals at risk. Additional strategies are needed to increase capacity for prediction and prevention of serious mental illness, ideally during childhood and adolescence. One possible approach would be to investigate systems in which psychosis risk factors are concentrated during childhood. One notable such system is represented by Child and Adolescent Mental Health Services (CAMHS). Although psychotic disorders are uncommon in CAMHS, many risk factors for psychosis are highly prevalent in young people who enter this system. We hypothesized, therefore, that youth attending CAMHS would be a high‐risk group for psychosis if followed into adulthood and, furthermore, that CAMHS systems would capture a substantial proportion of future psychosis cases. We constructed a total population cohort study of all Finns born in 1987 (N=55,875), linking together extensive register data on health care contacts from birth through age 28 years. We identified all individuals diagnosed with a psychotic or bipolar disorder by age 28 (N=1,785). The risk of psychosis/bipolar disorder by age 28 years was 1.8% for individuals who had not attended CAMHS during childhood or adolescence, whereas it was 12.8% for those with a history of any outpatient CAMHS contact (odds ratio, OR=7.9, 95% CI: 7.2‐8.7). Furthermore, the risk of psychosis/bipolar disorder by age 28 years was 2.3% for individuals without a history of inpatient CAMHS admission, whereas it was 24.0% for those with a history of inpatient CAMHS admission (OR=13.3, 95% CI: 11.9‐14.9), and 36.5% for those with a history of inpatient CAMHS admission in adolescence (age 13‐17 years) (OR=24.2, 95% CI: 21.2‐27.6). Individuals who attended CAMHS but received no mental disorder diagnosis had an equally high risk of subsequently developing a psychosis/bipolar disorder as individuals who did receive a diagnosis (OR=0.9, 99.5% CI: 0.7‐1.1). Compared to other CAMHS attendees, individuals who developed psychosis or bipolar disorder were more likely to have had an initial CAMHS diagnosis of depressive or other mood disorder (OR=2.3, 99.5% CI: 1.6‐3.0) and disruptive behaviour disorder (OR=1.7, 99.5% CI: 1.2‐2.5). Of all psychosis/bipolar diagnoses by age 28 years, 50.2% occurred in individuals who had, at some point in childhood or adolescence, attended CAMHS, indicating that CAMHS represent not only a high‐risk but also a high‐capacity system for prediction of psychosis/bipolar disorder. These findings suggest an enormous, untapped potential for large‐scale psychosis/bipolar disorder prediction and prevention research within existing specialist CAMHS. 相似文献
14.
Matteo Nicola Dario Di Minno Rosario Peluso Salvatore Iervolino Roberta Lupoli Anna Russolillo Giovanni Tarantino Raffaele Scarpa 《Arthritis research & therapy》2012,14(5):R211
Introduction
We prospectively evaluated whether hepatic steatosis (HS) and the presence of carotid plaques (CPs) impacts on achieving minimal disease activity (MDA) in psoriatic arthritis (PsA) patients starting tumor necrosis factor (TNF)-α blockers treatment.Methods
Before starting treatment with TNF-α blockers, consecutive PsA subjects with an active disease were evaluated for the presence of the metabolic syndrome (MetS), HS and CPs. The incidence of MDA was evaluated 12 and 24 months later.Results
Among 270 PsA subjects, 91 (33.7%) exhibited the MetS, 58 (21.5%) CPs and 76 (28.1%) HS. At the 12-month follow-up, 98 (36.3%) individuals achieved MDA. Compared with those who did, a higher prevalence of the MetS, HS and CPs was found in subjects who did not achieve the MDA (P always < 0.001). After adjusting for the MetS and for all the other demographic/clinical characteristics analyzed, the presence of HS and CPs at baseline independently predicted the risk of not achieving MDA (Hazard Ratio: 1.91, 95% confidence interval (CI): 1.04 to 3.38, P = 0.035 and Hazard Ratio: 3.21, 95%CI: 1.64 to 6.29, P = 0.001, respectively). Separate Kaplan-Meier survival models confirmed this (Log-Rank: 12.894, P < 0.001 and Log-Rank: 12.849, P < 0.001, respectively). Compared with those without, progressively increasing Hazard Ratios of not achieving MDA were found in those with HS, CPs or HS + CPs at baseline. Moreover, the presence of HS and/or CPs predicted the risk of relapse during the additional 12-month follow-up (Hazard Ratio: 2.85, 95%CI: 1.27 to 6.37, P = 0.011 and Hazard Ratio: 3.17, 95%CI: 1.57 to 6.41, P = 0.001 respectively).Conclusions
HS and/or CPs at baseline are negative predictors of achieving and maintaining MDA. 相似文献15.
Eva Fucikova Piet J. Drent Nadine Smits & Kees van Oers 《Ethology : formerly Zeitschrift fur Tierpsychologie》2009,115(4):366-374
Interest in personality is growing in a wide range of disciplines, but only in a few systems it is possible to assess the survival value of personality. Field studies looking at the relationship between personality and survival value early in life are greatly hampered by the fact that personality can at present only be assessed after individuals become independent from their parents. In passerines, for example, this is often after a period of intensive selection for the survival on fledglings. The main aim of this study is therefore to develop a method to measure personality before this period of selection. For this purpose, we developed the handling stress (HS) test. We measured HS in 14-d-old great tit nestlings by counting the number of breast movements (breath rate) in four subsequent 15-s bouts for 1 min; before and after they were socially isolated from their siblings for 15 min. To calculate the repeatability of HS, we repeated the test 6 mo later. To assess the relationship between HS and exploratory behaviour, we correlated the outcome of both tests. We ran tests both on birds of lines selected for extreme personality and on wild birds from a natural population. We found that birds selected for fast exploration reacted more to HS compared with birds selected for slow exploration and that HS was repeatable in different life phases. We confirmed this by finding an increase in the HS with increasing exploratory scores in wild birds. These results show that we can use the HS test as a measurement of personality, making it a potential tool for studying the relationship between personality and survival value early in life. 相似文献
16.
The Smad transcriptional corepressor TGIF recruits mSin3. 总被引:15,自引:0,他引:15
D Wotton P S Knoepfler C D Laherty R N Eisenman J Massagué 《Cell growth & differentiation》2001,12(9):457-463
17.
A new assay was developed to measure the N-deacetylase activity of the glucosaminyl N-deacetylase/N-sulfotransferases (NDSTs), which are key enzymes in sulfation of heparan sulfate (HS)/heparin. The assay is based on the recognition of NDST-generated N-unsubstituted glucosamine units in Escherichia coli K5 capsular polysaccharide or in HSs by monoclonal antibody JM-403. Substrate specificity and potential product inhibition of the NDST isoforms 1 and 2 were analyzed by comparing lysates of human 293 kidney cells stably transfected with mouse NDST-1 or -2. We found HSs to be excellent substrates for both NDST enzymes. Both NDST-1 and -2 N-deacetylate heparan sulfate from human aorta ( approximately 0.6 sulfate groups/disaccharide) with comparable high efficiency, apparent Km values of 0.35 and 0.76 microM (calculation based on [HexA]) being lower (representing a higher affinity) than those for K5 polysaccharide (13.3 and 4.7 microM, respectively). Comparison of various HS preparations and the unsulfated K5 polysaccharide as substrates indicate that both NDST-1 and -2 can differentially N-sulfate polysaccharides already modified to some extent by various other enzymes involved in HS/heparin synthesis. Both enzymes were equally inhibited by N-sulfated sequences (>or=6 sugar residues) present in N-sulfated K5, N-deacetylated N-resulfated HS, and heparin. Our primary findings were confirmed in the conventional N-deacetylase assay measuring the release of 3H-acetate of radiolabeled K5 or HS as substrates. We furthermore showed that NDST N-deacetylase activity in crude cell/tissue lysates can be partially blocked by endogenous HS/heparin. We speculate that in HS biosynthesis, some NDST variants initiate HS modification/sulfation reactions, whereas other (or the same) NDST isoforms later on fill in or extend already modified HS sequences. 相似文献
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Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by variable clinical manifestations including branchial fistulae, preauricular pits, ear malformations, hearing impairment, and renal anomalies. BOR is caused by mutations in the genes EYA1 and SIX1. A Danish BOR family with five affected individuals in three generations was analyzed for mutations in all 17 exons of EYA1 using direct sequencing of polymerase chain reaction (PCR) amplified genomic DNA. A novel splice-site mutation (IVS9+1 G>C) was detected in all affected family members but not in unaffected family members or in 96 controls. We conclude that this mutation is causing BOR in the family, most likely as a result of haploinsufficiency or an abnormal protein product caused by aberrant splicing of EYA1 mRNA. 相似文献
20.
K. Zerres H. Schüler U. Gembruch R. Bald M. Hansmann G. Schwanitz 《Human genetics》1992,89(3):301-304
Summary Choroid plexus cysts were diagnosed in 25 out of 823 fetuses with prenatally diagnosed abnormalities (growth retardation/malformations). Among these, 5 revealed a chromosomal disorder (4 cases with trisomy 18 and one case with a translocation trisomy 21). Additional abnormalities, such as growth retardation, holoprosencephaly, hydrocephalus and club foot, were found in 6 out of the 20 fetuses with no chromosomal abnormality. All fetuses with a chromosomal disorder revealed further typical prenatally recognizable abnormalities. Our observation indicates that prenatally diagnosed choroid plexus cysts should be considered as an indication for prenatal chromosomal diagnosis, although the risk of there being an underlying chromosomal disorder is low in cases with no additional abnormalities. 相似文献