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‣ Increased noise as an effect of haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 in vitro

Kemkemer, Ralf; Schrank, Stephanie; Vogel, Walther; Gruler, Hans; Kaufmann, Dieter
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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In human diseases related to tumor-suppressor genes, it is suggested that only the complete loss of the protein results in specific symptoms such as tumor formation, whereas simple reduction of protein quantity to 50%, called haploinsufficiency, essentially does not affect cellular behavior. Using a model of gene expression, it was presumed that haploinsufficiency is related to an increased noise in gene expression also in vivo [Cook, D. L., Gerber, A. N. & Tapscott, S. J. (1998) Proc. Natl. Acad. Sci. USA 95, 15641–15646]. Here, we demonstrate that haploinsufficiency of the tumor-suppressor gene neurofibromatosis type 1 (NF1) results in an increased variation of dendrite formation in cultured NF1 melanocytes. These morphological differences between NF1 and control melanocytes can be described by a mathematical model in which the cell is considered to be a self-organized automaton. The model describes the adjustment of the cells to a set point and includes a noise term that allows for stochastic processes. It describes the experimental data of control and NF1 melanocytes. In the cells haploinsufficient for NF1 we found an altered signal-to-noise ratio detectable as increased variation in dendrite formation in two of three investigated morphological parameters. We also suggest that in vivo NF1 haploinsufficiency results in an increased noise in cellular regulation and that this effect of haploinsufficiency may be found also in other tumor suppressors.

‣ Functional interactions between alternatively spliced forms of Pax6 in crystallin gene regulation and in haploinsufficiency

Chauhan, Bharesh K.; Yang, Ying; Cveklová, Květa; Cvekl, Aleš
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Pax6 is essential for development of the eye, olfactory system, brain and pancreas. Haploinsufficiency of Pax6 causes abnormal eye development. Two forms of Pax6 protein, PAX6 and PAX6(5a), differ in a 14 amino acid insertion encoded by an alternatively spliced exon 5a in the N-terminal DNA-binding paired domain (PD), and they are simultaneously expressed. Here, we show that PAX6 and PAX6(5a) together synergistically activate transcription from promoters recognized by Pax6 PD and PD5a, but not by their homeodomain. This synergism promotes activation of transcription by c-Maf and MafA on the αB-crystallin promoter, and is required for transcriptional co-activation by RARβ/RXRβ and PAX6/PAX6(5a) on the γF-crystallin promoter. To determine the role of this synergism in haploinsufficiency, we tested four human missense (G18W, R26G, G64V and R128C) and one nonsense (R317X) mutants, with reporters driven by Pax6 PD consensus binding sites and the αB-crystallin promoter. The simultaneous activity of Pax6 proteins [PAX6, mutated PAX6, PAX6(5a) and mutated PAX6(5a)] modeling haploinsufficiency yielded results not predicted by properties of individual PAX6 or PAX6(5a). Taken together, these results indicate that complex ocular phenotypes due to Pax6 haploinsufficiency originate...

‣ Phenotypes in Three Pedigrees with Autosomal Dominant Obesity Caused by Haploinsufficiency Mutations in the Melanocortin-4 Receptor Gene

Sina, Mani; Hinney, Anke; Ziegler, Andreas; Neupert, Tanja; Mayer, Hermann; Siegfried, Wolfgang; Blum, Werner F.; Remschmidt, Helmut; Hebebrand, Johannes
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Recently, haploinsufficiency mutations in the melanocortin-4 receptor gene (MC4-R) were detected which were assumed to lead to the phenotype of extreme obesity. Previously, we detected three obese carriers among 306 index patients. Here we describe the detection of one haploinsufficiency carrier in an additional study group of 186 obese individuals. We subsequently genotyped and phenotyped 43 family members of these four index patients, two of whom were second-degree cousins. A total of 19 carriers were identified. Extreme obesity was the predominating phenotype. However, moderate obesity occurred in three of the carriers. No other specific phenotypic abnormalities were detected. Female haploinsufficiency carriers were heavier than male carriers in the respective families, a finding similar to findings in MC4-R–knockout mice. In conclusion, our data fully support the etiologic role of MC4-R haploinsufficiency mutations in obesity.

‣ Mechanisms of Haploinsufficiency Revealed by Genome-Wide Profiling in Yeast

Deutschbauer, Adam M.; Jaramillo, Daniel F.; Proctor, Michael; Kumm, Jochen; Hillenmeyer, Maureen E.; Davis, Ronald W.; Nislow, Corey; Giaever, Guri
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /04/2005 Português
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Haploinsufficiency is defined as a dominant phenotype in diploid organisms that are heterozygous for a loss-of-function allele. Despite its relevance to human disease, neither the extent of haploinsufficiency nor its precise molecular mechanisms are well understood. We used the complete set of Saccharomyces cerevisiae heterozygous deletion strains to survey the genome for haploinsufficiency via fitness profiling in rich (YPD) and minimal media to identify all genes that confer a haploinsufficient growth defect. This assay revealed that ∼3% of all ∼5900 genes tested are haploinsufficient for growth in YPD. This class of genes is functionally enriched for metabolic processes carried out by molecular complexes such as the ribosome. Much of the haploinsufficiency in YPD is alleviated by slowing the growth rate of each strain in minimal media, suggesting that certain gene products are rate limiting for growth only in YPD. Overall, our results suggest that the primary mechanism of haploinsufficiency in yeast is due to insufficient protein production. We discuss the relevance of our findings in yeast to human haploinsufficiency disorders.

‣ NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects

Lu, Weining; Quintero-Rivera, Fabiola; Fan, Yanli; Alkuraya, Fowzan S; Donovan, Diana J; Xi, Qiongchao; Turbe-Doan, Annick; Li, Qing-Gang; Campbell, Craig G; Shanske, Alan L; Sherr, Elliott H; Ahmad, Ayesha; Peters, Roxana; Rilliet, Benedict; Parvex, Palo
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia−/− knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia+/− and Nfia−/− phenotypes now reveals that...

‣ Integrated Genomic Analysis Implicates Haploinsufficiency of Multiple Chromosome 5q31.2 Genes in De Novo Myelodysplastic Syndromes Pathogenesis

Graubert, Timothy A.; Payton, Michelle A.; Shao, Jin; Walgren, Richard A.; Monahan, Ryan S.; Frater, John L.; Walshauser, Mark A.; Martin, Mike G.; Kasai, Yumi; Walter, Matthew J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 25/02/2009 Português
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Deletions spanning chromosome 5q31.2 are among the most common recurring cytogenetic abnormalities detectable in myelodysplastic syndromes (MDS). Prior genomic studies have suggested that haploinsufficiency of multiple 5q31.2 genes may contribute to MDS pathogenesis. However, this hypothesis has never been formally tested. Therefore, we designed this study to systematically and comprehensively evaluate all 28 chromosome 5q31.2 genes and directly test whether haploinsufficiency of a single 5q31.2 gene may result from a heterozygous nucleotide mutation or microdeletion. We selected paired tumor (bone marrow) and germline (skin) DNA samples from 46 de novo MDS patients (37 without a cytogenetic 5q31.2 deletion) and performed total exonic gene resequencing (479 amplicons) and array comparative genomic hybridization (CGH). We found no somatic nucleotide changes in the 46 MDS samples, and no cytogenetically silent 5q31.2 deletions in 20/20 samples analyzed by array CGH. Twelve novel single nucleotide polymorphisms were discovered. The mRNA levels of 7 genes in the commonly deleted interval were reduced by 50% in CD34+ cells from del(5q) MDS samples, and no gene showed complete loss of expression. Taken together, these data show that small deletions and/or point mutations in individual 5q31.2 genes are not common events in MDS...

‣ Haploinsufficiency of DNA Damage Response Genes and their Potential Influence in Human Genomic Disorders

O’Driscoll, Mark
Fonte: Bentham Science Publishers Ltd. Publicador: Bentham Science Publishers Ltd.
Tipo: Artigo de Revista Científica
Publicado em /05/2008 Português
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Genomic disorders are a clinically diverse group of conditions caused by gain, loss or re-orientation of a genomic region containing dosage-sensitive genes. One class of genomic disorder is caused by hemizygous deletions resulting in haploinsufficiency of a single or, more usually, several genes. For example, the heterozygous contiguous gene deletion on chromosome 22q11.2 causing DiGeorge syndrome involves at least 20-30 genes. Determining how the copy number variation (CNV) affects human variation and contributes to the aetiology and progression of various genomic disorders represents important questions for the future. Here, I will discuss the functional significance of one form of CNV, haploinsufficiency (i.e. loss of a gene copy), of DNA damage response components and its association with certain genomic disorders. There is increasing evidence that haploinsufficiency for certain genes encoding key players in the cells response to DNA damage, particularly those of the Ataxia Telangiectasia and Rad3-related (ATR)-pathway, has a functional impact. I will review this evidence and present examples of some well known clinically similar genomic disorders that have recently been shown to be defective in the ATR-dependent DNA damage response. Finally...

‣ Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences

Mohan, S; Baylink, D J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/2005 Português
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Although it is well established that there is considerable inter-individual variation in the circulating levels of IGF-I in normal, healthy individuals and that a genetic component contributes substantially to this variation, the direct evidence that inter-individual variation in IGF-I contributes to differences in peak bone mineral density (BMD) is lacking. To examine if differences in IGF-I expression could contribute to peak BMD differences, we measured skeletal changes at days 23 (prepubertal), 31 (pubertal) and 56 (postpubertal) in mice with haploinsufficiency of IGF-I (+/−) and corresponding control mice (+/+). Mice (MF1/DBA) heterozygous for the IGF-I knockout allele were bred to generate +/+ and +/− mice (n=18–20 per group). Serum IGF-I was decreased by 23% (P<0·001) in mice with IGF-I haploinsufficiency (+/−) group at day 56 compared with the control (+/+) group. Femoral bone mineral content and BMD, as determined by dual energy X-ray absorptiometry, were reduced by 20% (P<0·001) and 12% respectively in the IGF-I (+/−) group at day 56 compared with the control group. The peripheral quantitative computed tomography measurements at the femoral mid-diaphysis revealed that periosteal circumference (7%, P<0·01) and total volumetric BMD (5%...

‣ Characterising and Predicting Haploinsufficiency in the Human Genome

Huang, Ni; Lee, Insuk; Marcotte, Edward M.; Hurles, Matthew E.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Haploinsufficiency, wherein a single functional copy of a gene is insufficient to maintain normal function, is a major cause of dominant disease. Human disease studies have identified several hundred haploinsufficient (HI) genes. We have compiled a map of 1,079 haplosufficient (HS) genes by systematic identification of genes unambiguously and repeatedly compromised by copy number variation among 8,458 apparently healthy individuals and contrasted the genomic, evolutionary, functional, and network properties between these HS genes and known HI genes. We found that HI genes are typically longer and have more conserved coding sequences and promoters than HS genes. HI genes exhibit higher levels of expression during early development and greater tissue specificity. Moreover, within a probabilistic human functional interaction network HI genes have more interaction partners and greater network proximity to other known HI genes. We built a predictive model on the basis of these differences and annotated 12,443 genes with their predicted probability of being haploinsufficient. We validated these predictions of haploinsufficiency by demonstrating that genes with a high predicted probability of exhibiting haploinsufficiency are enriched among genes implicated in human dominant diseases and among genes causing abnormal phenotypes in heterozygous knockout mice. We have transformed these gene-based haploinsufficiency predictions into haploinsufficiency scores for genic deletions...

‣ Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3ε haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration

Jafar-Nejad, Paymaan; Ward, Christopher S.; Richman, Ronald; Orr, Harry T.; Zoghbi, Huda Y.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1154Q/+ mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1’s small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions...

‣ Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice

Alvarado, David M.; McCall, Kevin; Aferol, Hyuliya; Silva, Matthew J.; Garbow, Joel R.; Spees, William M.; Patel, Tarpit; Siegel, Marilyn; Dobbs, Matthew B.; Gurnett, Christina A.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Clubfoot affects 1 in 1000 live births, although little is known about its genetic or developmental basis. We recently identified a missense mutation in the PITX1 bicoid homeodomain transcription factor in a family with a spectrum of lower extremity abnormalities, including clubfoot. Because the E130K mutation reduced PITX1 activity, we hypothesized that PITX1 haploinsufficiency could also cause clubfoot. Using copy number analysis, we identified a 241 kb chromosome 5q31 microdeletion involving PITX1 in a patient with isolated familial clubfoot. The PITX1 deletion segregated with autosomal dominant clubfoot over three generations. To study the role of PITX1 haploinsufficiency in clubfoot pathogenesis, we began to breed Pitx1 knockout mice. Although Pitx1+/− mice were previously reported to be normal, clubfoot was observed in 20 of 225 Pitx1+/− mice, resulting in an 8.9% penetrance. Clubfoot was unilateral in 16 of the 20 affected Pitx1+/− mice, with the right and left limbs equally affected, in contrast to right-sided predominant hindlimb abnormalities previously noted with complete loss of Pitx1. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1−/− E12.5 hindlimb buds compared with the wild-type...

‣ Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis

Yamada, Hiroshi Y; Yao, Yixin; Wang, Xiaoxing; Zhang, Yuting; Huang, Ying; Dai, Wei; Rao, Chinthalapally V
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
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Chromosome instability (CIN) is found in 85% of colorectal cancers. Defects in mitotic processes are implicated in high CIN and may be critical events in colorectal tumorigenesis. Shugoshin-1 (SGO1) aids in the maintenance of chromosome cohesion and prevents premature chromosome separation and CIN. In addition, integrity of the centrosome may be compromised due to the deficiency of Cohesin and Sgo1 through the disengagement of centrioles. We report here the generation and characterization of SGO1-mutant mice and show that haploinsufficiency of SGO1 leads to enhanced colonic tumorigenesis. Complete disruption of SGO1 results in embryonic lethality, whereas SGO1+/− mice are viable and fertile. Haploinsufficiency of SGO1 results in genomic instability manifested as missegregation of chromosomes and formation of extra centrosomal foci in both murine embryonic fibroblasts and adult bone marrow cells. Enhanced CIN observed in SGO1-deficient mice resulted in an increase in formation of aberrant crypt foci (ACF) and accelerated development of tumors after exposure to azoxymethane (AOM), a colon carcinogen. Together, these results suggest that haploinsufficiency of SGO1 causes enhanced CIN, colonic preneoplastic lesions and tumorigenesis in mice. SGO1 is essential for the suppression of CIN and tumor formation.

‣ Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice

Welch, John S.; Klco, Jeffery M.; Varghese, Nobish; Nagarajan, Rakesh; Ley, Timothy J.
Fonte: American Society of Hematology Publicador: American Society of Hematology
Tipo: Artigo de Revista Científica
Publicado em 24/02/2011 Português
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RARA (retinoic acid receptor alpha) haploinsufficiency is an invariable consequence of t(15;17)(q22;q21) translocations in acute promyelocytic leukemia (APL). Retinoids and RARA activity have been implicated in hematopoietic self-renewal and neutrophil maturation. We and others therefore predicted that RARA haploinsufficiency would contribute to APL pathogenesis. To test this hypothesis, we crossed Rara+/− mice with mice expressing PML (promyelocytic leukemia)-RARA from the cathepsin G locus (mCG-PR). We found that Rara haploinsufficiency cooperated with PML-RARA, but only modestly influenced the preleukemic and leukemic phenotype. Bone marrow from mCG-PR+/− × Rara+/− mice had decreased numbers of mature myeloid cells, increased ex vivo myeloid cell proliferation, and increased competitive advantage after transplantation. Rara haploinsufficiency did not alter mCG-PR–dependent leukemic latency or penetrance, but did influence the distribution of leukemic cells; leukemia in mCG-PR+/− × Rara+/− mice presented more commonly with low to normal white blood cell counts and with myeloid infiltration of lymph nodes. APL cells from these mice were responsive to all-trans retinoic acid and had virtually no differences in expression profiling compared with tumors arising in mCG-PR+/− × Rara+/+ mice. These data show that Rara haploinsufficiency (like Pml haploinsufficiency and RARA-PML) can cooperate with PML-RARA to influence the pathogenesis of APL in mice...

‣ Engineered Zinc-Finger Proteins Can Compensate Genetic Haploinsufficiency by Transcriptional Activation of the Wild-Type Allele: Application to Willams-Beuren Syndrome and Supravalvular Aortic Stenosis

Zhang, Pei; Huang, Angela; Morales-Ruiz, Manuel; Starcher, Barry C.; Huang, Yan; Sessa, William C.; Niklason, Laura E.; Giordano, Frank J.
Fonte: Mary Ann Liebert, Inc. Publicador: Mary Ann Liebert, Inc.
Tipo: Artigo de Revista Científica
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Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibility of using engineered zinc-finger protein transcription factors (ZFPs) to achieve compensatory expression of haploinsufficient genes by inducing augmented expression from the remaining wild-type allele. For complex genes with multiple splice variants, this approach could have distinct advantages over cDNA-based gene replacement strategies. Targeting the elastin gene, we show that transcriptional activation by engineered ZFPs can induce compensatory expression from the wild-type allele in the setting of classic WBS and SVAS genetic mutations, increase elastin expression in wild-type cells, induce expression of the major elastin splice variants, and recapitulate their natural stoichiometry. Further, we establish that transcriptional activation of the mutant allele in SVAS does not overcome nonsense-mediated decay, and thus ZFP-mediated transcriptional activation is not likely to induce production of a mutant protein, a crucial consideration. Finally...

‣ Endoglin Haploinsufficiency Promotes Fibroblast Accumulation during Wound Healing through Akt Activation

Pericacho, Miguel; Velasco, Soraya; Prieto, Marta; Llano, Elena; López-Novoa, José M.; Rodríguez-Barbero, Alicia
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 17/01/2013 Português
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Accurate regulation of dermal fibroblast function plays a crucial role in wound healing. Many fibrotic diseases are characterized by a failure to conclude normal tissue repair and the persistence of fibroblasts inside lesions. In the present study we demonstrate that endoglin haploinsufficiency promotes fibroblast accumulation during wound healing. Moreover, scars from endoglin-heterozygous (Eng+/−) mice show persisting fibroblasts 12 days after wounding, which could lead to a fibrotic scar. Endoglin haploinsufficiency results in increased proliferation and migration of primary cultured murine dermal fibroblasts (MDFs). Moreover, Eng+/− MDF have diminished responses to apoptotic signals compared with control cells. Altogether, these modifications could explain the augmented presence of fibroblasts in Eng+/− mice wounds. We demonstrate that endoglin expression regulates Akt phosphorylation and that PI3K inhibition abolishes the differences in proliferation between endoglin haploinsufficient and control cells. Finally, persistent fibroblasts in Eng+/− mice wound co-localize with a greater degree of Akt phosphorylation. Thus, endoglin haploinsufficiency seems to promote fibroblast accumulation during wound healing through the activation of the PI3K/Akt pathway. These studies open new non-Smad signaling pathway for endoglin regulating fibroblast cell function during wound healing...

‣ Characterization and Prediction of Haploinsufficiency Using Systems-Level Gene Properties in Yeast

Norris, Matthew; Lovell, Simon; Delneri, Daniela
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em 01/11/2013 Português
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Variation in gene copy number can significantly affect organism fitness. When one allele is missing in a diploid, the phenotype can be compromised because of haploinsufficiency. In this work, we identified associations between Saccharomyces cerevisiae gene properties and genome-scale haploinsufficiency phenotypes from previous work. We compared the haploinsufficiency profiles against 23 gene properties and found that genes with higher level of connectivity (degree) in a protein–protein interaction network, higher genetic interaction degree, greater gene sequence conservation, and higher protein expression were significantly more likely to be haploinsufficient. Additionally, haploinsufficiency showed negative relationships with cell cycle regulation and promoter sequence conservation.

‣ Different Skeletal Phenotypes in a Mother and Two Daughters with Short Stature Homeobox-Containing Haploinsufficiency

Nagasaki, Keisuke; Kikuchi, Toru; Uchiyama, Makoto
Fonte: The Japanese Society for Pediatric Endocrinology Publicador: The Japanese Society for Pediatric Endocrinology
Tipo: Artigo de Revista Científica
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Haploinsufficiency of the short stature homeobox-containing (SHOX) gene causes Turner skeletal features such as short metacarpals, cubitus valgus, and Madelung deformity. We report the clinical findings of a Japanese family consisting of two daughters with SHOX haploinsufficiency (46, X, del(X) (p.22.3)) and their mother with 45,X [9]/ 46, X, del(X) (p22.3) [11] karyotype. Physical and auxological examinations revealed a mesomelic appearance, cubitus valgus, a short neck and short stature in the daughters, but on the other hand, only a short neck and short stature in the mother. Radiological studies indicated markedly curved radii in the daughters, but only mild curvature of the radii in the mother. Regular menstruation had taken place since the age of 12 yr in the elder daughter, but the mother had irregular menstruation and she had received fertility treatment for pregnancy. The different skeletal phenotypes of the mother and her daughters with SHOX haploinsufficiency might be due to the mild gonadal estrogen deficiency found in the mother, which was caused by mosaic Turner syndrome, and the phenotypic variability of SHOX haploinsufficiency.

‣ SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure

Prasad, Vikram; Lorenz, John N.; Lasko, Valerie M.; Nieman, Michelle L.; Huang, Wei; Wang, Yigang; Wieczorek, David W.; Shull, Gary E.
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
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Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), cause Darier disease in humans, a skin condition involving keratinocytes. Cardiac function appears to be unimpaired in Darier disease patients, with no evidence that SERCA2 haploinsufficiency itself causes heart disease. However, SERCA2 deficiency is widely considered a contributing factor in heart failure. We therefore analyzed Atp2a2 heterozygous mice to determine whether SERCA2 haploinsufficiency can exacerbate specific heart disease conditions. Despite reduced SERCA2a levels in heart, Atp2a2 heterozygous mice resembled humans in exhibiting normal cardiac physiology. When subjected to hypothyroidism or crossed with a transgenic model of reduced myofibrillar Ca2+-sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca2+-sensitivity, SERCA2 haploinsufficiency caused rapid onset of hypertrophy, decompensation, and death. These effects were associated with reduced expression of the antiapoptotic Hax1, increased levels of the proapoptotic genes Chop and Casp12, and evidence of perturbations in energy metabolism. These data reveal myofibrillar Ca2+-sensitivity to be an important determinant of the cardiac effects of SERCA2 haploinsufficiency and raise the possibility that Darier disease patients are more susceptible to heart failure under certain conditions.

‣ Analysis of haploinsufficiency in women carrying germline mutations in the BRCA1 gene: Different mutations, different phenotypes ?

Vaclová, Tereza
Fonte: Universidade Autônoma de Madrid Publicador: Universidade Autônoma de Madrid
Tipo: Tese de Doutorado
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Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 30-01-2015; BRCA1 germline mutations are associated with significantly increased lifetime risk of developing breast and ovarian cancers. However, taking into account considerable differences in disease manifestation among mutation carriers, it is probable that various BRCA1 mutations lead to formation of distinct phenotypes and haploinsufficiency effects and that both type and location of the mutation could play an important role in cancer initiation. PARP inhibitors are currently one of the most promising agents for treatment of tumors deficient in BRCA1 or BRCA2. However, cancer patients carrying germline mutation in BRCA1/2 genes show a big variability in the responses to PARP inhibitors in clinical trials. Thus, we were interested in investigating whether and how BRCA1 mutation type influences the response of cells to PARP inhibitors We used a panel of lymphoblastoid cell lines (LCLs) derived either from heterozygous BRCA1 mutation carriers or non-carriers in order to study haploinsufficiency effects of various mutation types (truncating vs missense). LCLs carrying truncating mutations showed significantly lower BRCA1 mRNA and protein levels and higher levels of gamma-H2AX than control cells or LCLs harboring missense mutation...

‣ Genetic and Biochemical Evidence That Haploinsufficiency of the Nf1 Tumor Suppressor Gene Modulates Melanocyte and Mast Cell Fates in Vivo

Ingram, David A.; Yang, Feng-Chun; Travers, Jeffrey B.; Wenning, Mary Jo; Hiatt, Kelly; New, Sheryl; Hood, Antoinette; Shannon, Kevin; Williams, David A.; Clapp, D. Wade
Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 03/01/2000 Português
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Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's “two hit” model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1−/− murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W41 mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor...