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Haploinsufficiency

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https://www.readbyqxmd.com/read/28636943/opa1-isoforms-in-the-hierarchical-organization-of-mitochondrial-functions
#1
Valentina Del Dotto, Prashant Mishra, Sara Vidoni, Mario Fogazza, Alessandra Maresca, Leonardo Caporali, J Michael McCaffery, Martina Cappelletti, Enrico Baruffini, Guy Lenaers, David Chan, Michela Rugolo, Valerio Carelli, Claudia Zanna
OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long and short forms, but it is unclear whether OPA1 functions are associated with specific isoforms and/or domains. To address this, we expressed each of the eight isoforms or different constructs of isoform 1 in Opa1(-/-) MEFs. We observed that any isoform could restore cristae structure, mtDNA abundance, and energetic efficiency independently of mitochondrial network morphology...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28630119/gata2-haploinsufficiency-accelerates-evi1-driven-leukemogenesis
#2
Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto
Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of the EVI1 gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the EVI1 gene reciprocally deprives this enhancer of one of the two GATA2 alleles, resulting in a loss of function genetic reduction in GATA2 abundance. As GATA2 haploinsufficiency is strongly associated with MDS and AML, here we asked whether EVI1 misexpression and GATA2 haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven EVI1 misexpression but in this case coupled to a Gata2 heterozygous germ-line deletion...
June 19, 2017: Blood
https://www.readbyqxmd.com/read/28616625/heterozygous-enos-deficient-mice-as-a-model-to-examine-the-effects-of-enos-haploinsufficiency-on-the-cerebral-circulation
#3
Sean P Didion
Nitric oxide derived from endothelial nitric oxide synthase (eNOS) has been shown to be a major mediator of endothelium-dependent responses in cerebral blood vessels. Loss of a single eNOS gene is not associated with any apparent negative consequences on endothelial function in most blood vessels. In contrast, we have recently demonstrated that heterozygous eNOS gene deficiency in combination with a high fat diet is associated with marked impairment of endothelial function. These findings provide an important example of eNOS haploinsufficiency and one that directly impacts the cerebral vasculature...
2017: Journal of Neurology & Neuromedicine
https://www.readbyqxmd.com/read/28614787/nell-1-induces-sca-1-mesenchymal-progenitor-cell-expansion-in-models-of-bone-maintenance-and-repair
#4
Aaron W James, Jia Shen, Rebecca Tsuei, Alan Nguyen, Kevork Khadarian, Carolyn A Meyers, Hsin Chuan Pan, Weiming Li, Jin H Kwak, Greg Asatrian, Cymbeline T Culiat, Min Lee, Kang Ting, Xinli Zhang, Chia Soo
NELL-1 is a secreted, osteogenic protein first discovered to control ossification of the cranial skeleton. Recently, NELL-1 has been implicated in bone maintenance. However, the cellular determinants of NELL-1's bone-forming effects are still unknown. Here, recombinant human NELL-1 (rhNELL-1) implantation was examined in a clinically relevant nonhuman primate lumbar spinal fusion model. Prolonged rhNELL-1 protein release was achieved using an apatite-coated β-tricalcium phosphate carrier, resulting in a local influx of stem cell antigen-1-positive (Sca-1+) mesenchymal progenitor cells (MPCs), and complete osseous fusion across all samples (100% spinal fusion rate)...
June 15, 2017: JCI Insight
https://www.readbyqxmd.com/read/28611040/%C3%AE-catenin-is-a-candidate-therapeutic-target-for-myeloid-neoplasms-with-del-5q
#5
Liping Li, Yue Sheng, Wenshu Li, Chao Hu, Nupur Mittal, Kaoru Tohyama, Amber Seba, Youyang Zhao, Howard Ozer, Tongyu Zhu, Zhijian Qian
Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the pre-leukemic stage of myeloid neoplasms with a -5/del(5q)...
June 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28608987/smarca4-inactivating-mutations-cause-concomitant-coffin-siris-syndrome-microphthalmia-and-small-cell-carcinoma-of-the-ovary-hypercalcemic-type
#6
Edoardo Errichiello, Noor Mustafa, Annalisa Vetro, Lucia Dora Notarangelo, Hugo de Jonge, Berardo Rinaldi, Debora Vergani, Sabrina Rita Giglio, Patrizia Morbini, Orsetta Zuffardi
SMARCA4 chromatin remodeling factor is mutated in 11% of Coffin-Siris syndrome (CSS) patients and in almost all small cell carcinoma of the ovary hypercalcemic type (SCCOHT) tumors. Missense mutations with gain-of-function or dominant-negative effects are associated with CSS, whereas inactivating mutations, leading to loss of SMARCA4 expression, have been exclusively found in SCCOHT. We applied whole exome sequencing to study a 15-year-old patient with mild CSS who concomitantly developed SCCOHT at age 13 years...
June 13, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28604966/-detection-of-a-patient-with-ring-chromosome-15-by-low-coverage-massively-parallel-copy-number-variation-sequencing
#7
Qiong Pan, Li Zhang, Fengting Zhang, Xin Jin, Yue Hu, Liyan Zhu, Longfei Cheng, Qigang Zhang, Ying Ning
OBJECTIVE: To explore the genetic cause for a child with developmental delay. METHODS: The karotypes of the child and her parents were analyzed with G-banding analysis. Their genome DNA was analyzed with low-coverage massively parallel copy number variation sequencing (CNV-seq) and verified by single nucleotide polymorphism array (SNP-array). RESULTS: The karyotype of the child was ascertained as 46,XX,r(15)(p13q26.3), while both parents showed a normal karyotype...
June 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28600463/aldehydes-promote-brca2-haploinsufficiency-and-genomic-instability
#8
(no author information available yet)
Inherited BRCA2 mutations promote genome instability via aldehyde-induced BRCA2 degradation.
June 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28600438/human-rela-haploinsufficiency-results-in-autosomal-dominant-chronic-mucocutaneous-ulceration
#9
Yousef R Badran, Fatma Dedeoglu, Juan Manuel Leyva Castillo, Wayne Bainter, Toshiro K Ohsumi, Athos Bousvaros, Jeffrey D Goldsmith, Raif S Geha, Janet Chou
The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency...
June 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28600059/molecular-genetic-characterization-of-a-prenatally-detected-de-novo-interstitial-deletion-of-chromosome-2q-2q31-1-q32-1-encompassing-hoxd13-znf385b-and-znf804a-associated-with-syndactyly-and-increased-first-trimester-nuchal-translucency
#10
Chih-Ping Chen, Chen-Ju Lin, Yen-Ni Chen, Schu-Rern Chern, Shin-Wen Chen, Shih-Ting Lai, Peih-Shan Wu, Li-Feng Chen, Wayseen Wang
OBJECTIVE: We present prenatal diagnosis and molecular genetic characterization of a de novo interstitial deletion of 2q (2q31.1-q32.1) and discuss the genotype-phenotype correlation. CASE REPORT: A 34-year-old, primigravid woman was referred to the hospital at 20 weeks of gestation for genetic counseling because of a prenatally detected de novo interstitial deletion of chromosome 2q (2q31.1-q32.1). She underwent amniocentesis at 17 weeks of gestation because of advanced maternal age and an increased first-trimester nuchal translucency (NT) thickness of 3...
June 2017: Taiwanese Journal of Obstetrics & Gynecology
https://www.readbyqxmd.com/read/28599093/clinical-and-molecular-cytogenetic-characterization-of-four-unrelated-patients-carrying-2p14-microdeletions
#11
Marie-Laure Mathieu, Caroline Demily, Sandra Chantot-Bastaraud, Alexandra Afenjar, Cyril Mignot, Joris Andrieux, Marion Gerard, Jaume Catala-Mora, Pierre Simon Jouk, Audrey Labalme, Patrick Edery, Damien Sanlaville, Massimiliano Rossi
We report the clinical and molecular cytogenetic characterization of four unrelated patients from France and Spain, carrying 2p14 microdeletions and presenting with intellectual disability and dysmorphisms. 2p14 microdeletions are very rare. Seven patients have been reported so far harboring deletions including 2p14p15 and encompassing OTX1, whose haploinsufficiency is frequently associated with genitourinary defects. To date, only one patient has been reported carrying a more proximal 2p14 microdeletion which does not include OTX1...
June 9, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28596562/characterizing-haploinsufficiency-of-shell-gene-to-improve-fruit-form-prediction-in-introgressive-hybrids-of-oil-palm
#12
Chee-Keng Teh, Siti Dalila Muaz, Praveena Tangaya, Po-Yee Fong, Ai-Ling Ong, Sean Mayes, Fook-Tim Chew, Harikrishna Kulaveerasingam, David Appleton
The fundamental trait in selective breeding of oil palm (Eleais guineensis Jacq.) is the shell thickness surrounding the kernel. The monogenic shell thickness is inversely correlated to mesocarp thickness, where the crude palm oil accumulates. Commercial thin-shelled tenera derived from thick-shelled dura × shell-less pisifera generally contain 30% higher oil per bunch. Two mutations, sh (MPOB) (M1) and sh (AVROS) (M2) in the SHELL gene - a type II MADS-box transcription factor mainly present in AVROS and Nigerian origins, were reported to be responsible for different fruit forms...
June 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28596252/success-in-bone-marrow-failure-novel-therapeutic-directions-based-on-the-immune-environment-of-myelodysplastic-syndromes
#13
REVIEW
Alyssa H Cull, Michael J Rauh
Myelodysplastic syndromes (MDS) are clonal neoplasms of aging that are associated with BM failure, related cytopenias, fatigue, susceptibility to infections, bruising, bleeding, a shortened lifespan, and a propensity for leukemic transformation. Most frail, elderly patients are not candidates for curative allogeneic BM transplantations and instead receive expectant management, supportive blood transfusions, or empirical, nontargeted therapy. It has been known for some time that MDS arises in an abnormal BM immune environment; however, connections have only recently been established with recurring MDS-associated mutations...
June 8, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28595573/a-novel-kcnq1-nonsense-variant-in-the-isoform-specific-first-exon-causes-both-jervell-and-lange-nielsen-syndrome-1-and-long-qt-syndrome-1-a-case-report
#14
Motoi Nishimura, Marehiko Ueda, Ryota Ebata, Emi Utsuno, Takuma Ishii, Kazuyuki Matsushita, Osamu Ohara, Naoki Shimojo, Yoshio Kobayashi, Fumio Nomura
BACKGROUND: According to previous KCNQ1 (potassium channel, voltage gated, KQT-like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS...
June 8, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28589569/identification-of-novel-bcl11a-variants-in-patients-with-epileptic-encephalopathy-expanding-the-phenotypic-spectrum
#15
Michiko Yoshida, Mitsuko Nakashima, Tohru Okanishi, Sotaro Kanai, Ayataka Fujimoto, Kazuya Itomi, Masafumi Morimoto, Hirotomo Saitsu, Mitsuhiro Kato, Naomichi Matsumoto, Tomohiro Chiyonobu
BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified two novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p...
June 6, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28588821/coupling-clinical-exome-sequencing-with-functional-characterization-studies-to-diagnose-a-patient-with-familial-mediterranean-fever-and-med13l-haploinsufficiency-syndromes
#16
Sureni V Mullegama, Phillip Jensik, Chen Li, Naghmeh Dorrani, Sibel Kantarci, Bruce Blumberg, Wayne W Grody, Samuel P Strom
Clinicians should consider that clinical exome sequencing provides the unique potential to disentangle complex phenotypes into multiple genetic etiologies. Further, functional studies on variants of uncertain significance are necessary to arrive at an accurate diagnosis for the patient.
June 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28588437/molecular-characterization-of-koolen-de-vries-syndrome-in-two-girls-with-idiopathic-intellectual-disability-from-central-brazil
#17
Gustavo R Nascimento, Irene P Pinto, Aldaires V de Melo, Damiana M da Cruz, Cristiano L Ribeiro, Claudio C da Silva, Aparecido D da Cruz, Lysa B Minasi
Koolen de Vries syndrome (KDVS; MIM 610443) is a genomic disorder caused by a recurrent microdeletion derived from nonallelic homologous recombination mediated by flanking segmental duplications. Clinical manifestations of this syndrome are characterized by intellectual disability, hypotonia, a friendly behavior, distinctive facial features, and epilepsy. Herein, we report a case of 2 girls who revealed global developmental delay, mild facial dysmorphisms, friendly behavior, and epileptic seizure with a de novo 17q21...
May 2017: Molecular Syndromology
https://www.readbyqxmd.com/read/28586040/low-expression-of-pinx1-is-associated-with-malignant-behavior-in-basal-like-breast-cancer
#18
Yu-Zhen Feng, Qing-Yan Zhang, Mei-Ting Fu, Zhen-Fei Zhang, Min Wei, Jue-Yu Zhou, Rong Shi
Human Pinx1 protein, associated with shelterin proteins, is widely revealed as a haploinsufficient tumor suppressor. Growing evidence has manifested the deregulation of PinX1 in distinct cancers. Nonetheless, the loss status of PinX1 and its diagnostic, prognostic and clinicopathological significance in Basal-like breast cancer are still unclear. In the present study, the PinX1 expression levels of breast cancer tissues were investigated by qRT-PCR and immunoblotting assays. Then immunohistochemistry (IHC) was performed to detect PinX1 expression on a tissue microarray...
June 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28582318/recent-advances-in-childhood-vasculitis
#19
Seza Ozen, Nazire Pinar Acar-Ozen
PURPOSE OF REVIEW: The review aims to summarize the recent findings in vasculitis that may have an impact in our understanding or management of these diseases. RECENT FINDINGS: We are learning more about monogenic diseases that closely mimic the pediatric vasculitides. Deficiency of adenosine deaminase 2 can present with a polyarteritis nodosa (PAN)-like picture and should be included in the differential of all pediatric cases of PAN with a family history or in cases with early stroke, or in cases resistant to conventional therapy...
June 2, 2017: Current Opinion in Rheumatology
https://www.readbyqxmd.com/read/28579578/the-t-box-transcription-factor-3-in-development-and-cancer
#20
Tarryn Willmer, Aretha Cooper, Jade Peres, Rehana Omar, Sharon Prince
T-box factors comprise an archaic family of evolutionary conserved transcription factors that regulate patterns of gene expression essential for embryonic development. The T-box transcription factor 3 (TBX3), a member of this family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal dominant disorder, ulnar-mammary syndrome. Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes...
June 4, 2017: Bioscience Trends
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