共查询到20条相似文献,搜索用时 15 毫秒
1.
Georgia Vasileiou Silvia Vergarajauregui Sabine Endele Bernt Popp Christian Büttner Arif B. Ekici Marion Gerard Nuria C. Bramswig Beate Albrecht Jill Clayton-Smith Jenny Morton Susan Tomkins Karen Low Astrid Weber Maren Wenzel Janine Altmüller Yun Li Bernd Wollnik André Reis 《American journal of human genetics》2018,102(3):468-479
2.
Mohammed?A. Aldahmesh Arif?O. Khan Hisham Alkuraya Nouran Adly Shamsa Anazi Ahmed?A. Al-Saleh Jawahir?Y. Mohamed Hadia Hijazi Sarita Prabakaran Marlene Tacke Abdullah Al-Khrashi Mais Hashem Thomas Reinheckel Abdullah Assiri Fowzan?S. Alkuraya 《American journal of human genetics》2013,93(2):313-320
Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-β activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-β in cells from affected individuals, the latter being consistent with available data on the role of TGF-β in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-β signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes. 相似文献
3.
Stephen?R.F. Twigg Jennifer Forecki Jacqueline?A.C. Goos Ivy?C.A. Richardson A.?Jeannette?M. Hoogeboom Ans?M.W. van?den?Ouweland Sigrid?M.A. Swagemakers Maarten?H. Lequin Daniel Van?Antwerp Simon?J. McGowan Isabelle Westbury Kerry?A. Miller Steven?A. Wall WGS Consortium Peter?J. van?der?Spek Irene?M.J. Mathijssen Erwin Pauws Christa?S. Merzdorf Andrew?O.M. Wilkie 《American journal of human genetics》2015,97(3):378-388
4.
Jie Sun Yuxia Wang Yisui Xia Ye Xu Tao Ouyang Jinfeng Li Tianfeng Wang Zhaoqing Fan Tie Fan Benyao Lin Huiqiang Lou Yuntao Xie 《PLoS genetics》2015,11(5)
The genetic cause for approximately 80% of familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset familial breast cancer patients without BRCA1/2 mutations (diagnosed with breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in DNA double-strand break repair and it plays an important role in the maintenance of genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated familial breast cancer patients. In total, we found three nonsense mutations leading to a truncated protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential breast cancer susceptibility gene and that mutations in this gene contribute to familial breast cancer development. 相似文献
5.
Esther Meyer Neil V. Morgan Shanaz Pasha Fatimah Rahman Bettina Bessières Mohamed T. Yacoubi Tamas Marton Richard C. Trembath Phillip Cox Eamonn R. Maher 《American journal of human genetics》2010,86(3):471-654
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome, is an autosomal-recessively inherited prenatal lethal disorder characterized by hydranencephaly; brain stem, basal ganglia, and spinal cord diffuse clastic ischemic lesions with calcifications; glomeruloid vasculopathy of the central nervous system and retinal vessels; and a fetal akinesia deformation sequence (FADS) with muscular neurogenic atrophy. To identify the molecular basis for Fowler syndrome, we performed autozygosity mapping studies in three consanguineous families. The results of SNP microarrays and microsatellite marker genotyping demonstrated linkage to chromosome 14q24.3. Direct sequencing of candidate genes within the target interval revealed five different germline mutations in FLVCR2 in five families with Fowler syndrome. FLVCR2 encodes a transmembrane transporter of the major facilitator superfamily (MFS) hypothesized to be involved in regulation of growth, calcium exchange, and homeostasis. This is the first gene to be associated with Fowler syndrome, and this finding provides a basis for further studies to elucidate the pathogenetic mechanisms and phenotypic spectrum of associated disorders. 相似文献
6.
F van Hoorn ME Campian A Spijkerboer MT Blom RN Planken AC van Rossum JM de Bakker AA Wilde M Groenink HL Tan 《PloS one》2012,7(8):e42037
Background
The cardiac sodium channel (Nav1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Nav1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Nav1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Nav1.5 is involved in maintaining cardiac structural integrity.Methods
Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers.Results
SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers.Conclusions
Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis. 相似文献7.
Yasuko Hirata Hilde Brems Mayu Suzuki Mitsuhiro Kanamori Masahiro Okada Rimpei Morita Isabel Llano-Rivas Toyoyuki Ose Ludwine Messiaen Eric Legius Akihiko Yoshimura 《The Journal of biological chemistry》2016,291(7):3124-3134
Constitutional heterozygous loss-of-function mutations in the SPRED1 gene cause a phenotype known as Legius syndrome, which consists of symptoms of multiple café-au-lait macules, axillary freckling, learning disabilities, and macrocephaly. Legius syndrome resembles a mild neurofibromatosis type 1 (NF1) phenotype. It has been demonstrated that SPRED1 functions as a negative regulator of the Ras-ERK pathway and interacts with neurofibromin, the NF1 gene product. However, the molecular details of this interaction and the effects of the mutations identified in Legius syndrome and NF1 on this interaction have not yet been investigated. In this study, using a yeast two-hybrid system and an immunoprecipitation assay in HEK293 cells, we found that the SPRED1 EVH1 domain interacts with the N-terminal 16 amino acids and the C-terminal 20 amino acids of the GTPase-activating protein (GAP)-related domain (GRD) of neurofibromin, which form two crossing α-helix coils outside the GAP domain. These regions have been shown to be dispensable for GAP activity and are not present in p120GAP. Several mutations in these N- and C-terminal regions of the GRD in NF1 patients and pathogenic missense mutations in the EVH1 domain of SPRED1 in Legius syndrome reduced the binding affinity between the EVH1 domain and the GRD. EVH1 domain mutations with reduced binding to the GRD also disrupted the ERK suppression activity of SPRED1. These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome. 相似文献
8.
Johnathan Cooper-Knock Tobias Moll Tennore Ramesh Lydia Castelli Alexander Beer Henry Robins Ian Fox Isabell Niedermoser Philip Van Damme Matthieu Moisse Wim Robberecht Orla Hardiman Monica P. Panades Abdelilah Assialioui Jesus S. Mora A. Nazli Basak Karen E. Morrison Christopher E. Shaw Pamela J. Shaw 《Cell reports》2019,26(9):2298-2306.e5
9.
AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking
Niovi Setta-Kaffetzi Michael?A. Simpson Alexander?A. Navarini Varsha?M. Patel Hui-Chun Lu Michael?H. Allen Michael Duckworth Hervé Bachelez A.?David Burden Siew-Eng Choon Christopher?E.M. Griffiths Brian Kirby Antonios Kolios Marieke?M.B. Seyger Christa Prins Asma Smahi Richard?C. Trembath Franca Fraternali Catherine?H. Smith Jonathan?N. Barker Francesca Capon 《American journal of human genetics》2014,94(5):790-797
Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis. 相似文献
10.
Ugur?M. Ayturk Javier?A. Couto Steven Hann John?B. Mulliken Kaitlin?L. Williams August?Yue Huang Steven?J. Fishman Theonia?K. Boyd Harry?P.W. Kozakewich Joyce Bischoff Arin?K. Greene Matthew?L. Warman 《American journal of human genetics》2016,98(4):789-795
Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors’ different postnatal behaviors. 相似文献
11.
《Cell cycle (Georgetown, Tex.)》2013,12(15):1607-1611
Ras proteins control a variety of critical cellular processes, and somatic mutations in RAS genes (and other members of signaling networks regulated by Ras) are common in human malignancies. Ras proteins are guanosine triphosphate (GTP)-binding proteins that cycle between active GTP-bound and inactive guanosine diphosphate (GDP) bound conformations. Cancer-associated Ras mutations typically alter amino acids G12, G13 or Q61. These mutant Ras proteins display impaired GTPase activity and are resistant to GTPase activating proteins (GAPs). We and others recently discovered novel germline KRAS mutations in individuals diagnosed with Noonan or cardio-facio-cutanous (CFC) syndrome, two clinically overlapping disorders characterized by short stature, distinct facial anomalies, heart defects, and other developmental abnormalities. We found that the mutant K-Ras proteins encoded by NS-associated alleles have less pronounced biochemical defects than known Ras oncoproteins, which likely explains why these mutations are tolerated in the germline. Together with the recent findings of mutations in other members of the Ras signaling cascade in CFC syndrome and in Costello syndrome, another clinically related disorder, it is now clear that Noonan-like features are common phenotypic consequences of systemic deregulation of the Ras pathway. The discovery of germline mutations in this group of related genetic disorders underscores the pivotal role of the degree and duration of Ras activation in cell fate decisions during embryonic development and morphogenesis. 相似文献
12.
Gina M. DeStefano Mazen Kurban Kwame Anyane-Yeboa Claudia Dall'Armi Gilbert Di Paolo Heather Feenstra Nanette Silverberg Luis Rohena Larissa D. López-Cepeda Vaidehi Jobanputra Katherine A. Fantauzzo Maija Kiuru Marija Tadin-Strapps Antonio Sobrino Anna Vitebsky Dorothy Warburton Brynn Levy Julio C. Salas-Alanis Angela M. Christiano 《PLoS genetics》2014,10(5)
13.
Yung‐Hsuan Shen Wei‐Shiung Yang Tzong‐Hsi Lee Long‐Teng Lee Ching‐Yu Chen Kuo‐Chin Huang 《Obesity (Silver Spring, Md.)》2005,13(7):1238-1245
Objectives: The metabolic syndrome has become a significant health problem worldwide. In this study, we investigated the relationship between the metabolic syndrome, bright liver (BL) by ultrasonography (US), and plasma alanine aminotransferase (ALT) levels among apparently healthy adults. Research Methods and Procedures: A total of 15, 430 nonalcoholic healthy adults without hepatitis B or C were recruited from four nationwide MJ Health Screening Centers in Taiwan in 2000. Metabolic syndrome was defined using the National Cholesterol Education Panel (NCEP) metabolic syndrome criteria or modified NCEP criteria. Based on liver US, subjects were classified into either having BL or not. The relationship between the metabolic syndrome, BL, and ALT levels was examined using multivariate logistic regression analysis. Results: The crude OR of the metabolic syndrome was 13.92 (12.19 using modified NCEP criteria), and the age‐BMI‐sex—adjusted OR was 3.77 (3.71 using modified NCEP criteria) in subjects with BL vs. subjects without BL, respectively. The ORs of the metabolic syndrome were significantly higher in subjects with elevated ALT levels than in those with normal ALT levels. After adjustment for age, sex, and BMI, BL and elevated ALT level were independently associated with increased risk of the metabolic syndrome. Discussion: Presence of BL and elevated plasma ALT level was independently associated with increased risk of the metabolic syndrome in adults. These factors contribute to a list of well‐known risk factors, including obesity, aging, and male sex, and thus can be applied as an additional evaluation for the metabolic syndrome in a clinical setting. 相似文献
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15.
Xue Gao Guo-Jian Wang Yong-Yi Yuan Feng Xin Ming-Yu Han Jing-Qiao Lu Hui Zhao Fei Yu Jin-Cao Xu Mei-Guang Zhang Jiang Dong Xi Lin Pu Dai 《PloS one》2014,9(7)
Usher syndrome is an autosomal recessive disease characterized by sensorineural hearing loss, age-dependent retinitis pigmentosa (RP), and occasionally vestibular dysfunction. The most severe form is Usher syndrome type 1 (USH1). Mutations in the MYO7A gene are responsible for USH1 and account for 29–55% of USH1 cases. Here, we characterized a Chinese family (no. 7162) with USH1. Combining the targeted capture of 131 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified two deleterious compound heterozygous mutations in the MYO7A gene: a reported missense mutation c.73G>A (p.G25R) and a novel nonsense mutation c.462C>A (p.C154X). The two compound variants are absent in 219 ethnicity-matched controls, co-segregates with the USH clinical phenotypes, including hearing loss, vestibular dysfunction, and age-dependent penetrance of progressive RP, in family 7162. Therefore, we concluded that the USH1 in this family was caused by compound heterozygous mutations in MYO7A. 相似文献
16.
Pricilla E. Day Georgia Ntani Sarah R. Crozier Pam A. Mahon Hazel M. Inskip Cyrus Cooper Nicholas C. Harvey Keith M. Godfrey Mark A. Hanson Rohan M. Lewis Jane K. Cleal 《PloS one》2015,10(12)
Introduction
Maternal environment and lifestyle factors may modify placental function to match the mother’s capacity to support the demands of fetal growth. Much remains to be understood about maternal influences on placental metabolic and amino acid transporter gene expression. We investigated the influences of maternal lifestyle and body composition (e.g. fat and muscle content) on a selection of metabolic and amino acid transporter genes and their associations with fetal growth.Methods
RNA was extracted from 102 term Southampton Women’s Survey placental samples. Expression of nine metabolic, seven exchange, eight accumulative and three facilitated transporter genes was analyzed using quantitative real-time PCR.Results
Increased placental LAT2 (p = 0.01), y + LAT2 (p = 0.03), aspartate aminotransferase 2 (p = 0.02) and decreased aspartate aminotransferase 1 (p = 0.04) mRNA expression associated with pre-pregnancy maternal smoking. Placental mRNA expression of TAT1 (p = 0.01), ASCT1 (p = 0.03), mitochondrial branched chain aminotransferase (p = 0.02) and glutamine synthetase (p = 0.05) was positively associated with maternal strenuous exercise. Increased glutamine synthetase mRNA expression (r = 0.20, p = 0.05) associated with higher maternal diet quality (prudent dietary pattern) pre-pregnancy. Lower LAT4 (r = -0.25, p = 0.05) and aspartate aminotransferase 2 mRNA expression (r = -0.28, p = 0.01) associated with higher early pregnancy diet quality. Lower placental ASCT1 mRNA expression associated with measures of increased maternal fat mass, including pre-pregnancy BMI (r = -0.26, p = 0.01). Lower placental mRNA expression of alanine aminotransferase 2 associated with greater neonatal adiposity, for example neonatal subscapular skinfold thickness (r = -0.33, p = 0.001).Conclusion
A number of maternal influences have been linked with outcomes in childhood, independently of neonatal size; our finding of associations between placental expression of transporter and metabolic genes and maternal smoking, physical activity and diet raises the possibility that their effects are mediated in part through alterations in placental function. The observed changes in placental gene expression in relation to modifiable maternal factors are important as they could form part of interventions aimed at maintaining a healthy lifestyle for the mother and for optimal fetal development. 相似文献17.
Ellen Knierim Hiromi Hirata Nicole?I. Wolf Susanne Morales-Gonzalez Gudrun Schottmann Yu Tanaka Sabine Rudnik-Sch?neborn Mickael Orgeur Klaus Zerres Stefanie Vogt Anne van?Riesen Esther Gill Franziska Seifert Angelika Zwirner Janbernd Kirschner Hans?Hilmar Goebel Christoph Hübner Sigmar Stricker David Meierhofer Werner Stenzel Markus Schuelke 《American journal of human genetics》2016,98(3):473-489
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AP1S3 Mutations Are Associated with Pustular Psoriasis and Impaired Toll-like Receptor 3 Trafficking
Niovi Setta-Kaffetzi Michael A. Simpson Alexander A. Navarini Varsha M. Patel Hui-Chun Lu Michael H. Allen Michael Duckworth Hervé Bachelez A. David Burden Siew-Eng Choon Christopher E.M. Griffiths Brian Kirby Antonios Kolios Marieke M.B. Seyger Christa Prins Asma Smahi Richard C. Trembath Franca Fraternali Catherine H. Smith Jonathan N. Barker Francesca Capon 《American journal of human genetics》2014
20.
Xianglong Yi Liping Du Shengping Hou Fuzhen Li Yuanyuan Chen Aize Kijlstra Peizeng Yang 《PloS one》2013,8(7)