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Lanping Jiang Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Nephrology & Key Laboratory of Nephrology, National Health Commission and Guangdong Province, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

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Xiaoyan Peng Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Renal Division, Children’s Hospital Affiliated to Capital Institute of Pediatrics, Beijing, China

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Bingbin Zhao Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Lei Zhang Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Lubin Xu Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Xuemei Li Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Min Nie Department of Endocrinology & Key Laboratory of Endocrinology, National Health and Family Planning Commission, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Limeng Chen Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Purposes

This study was conducted to identify the frequent mutations from reported Chinese Gitelman syndrome (GS) patients, to predict the three-dimensional structure change of human Na–Cl co-transporter (hNCC), and to test the activity of these mutations and some novel mutations in vitro and in vivo.

Methods

SLC12A3 gene mutations in Chinese GS patients previously reported in the PubMed, China National Knowledge Infrastructure, and Wanfang database were summarized. Predicted configurations of wild type (WT) and mutant proteins were achieved using the I-TASSER workplace. Six missense mutations (T60M, L215F, D486N, N534K, Q617R, and R928C) were generated by site-directed mutagenesis. 22Na+ uptake experiment was carried out in the Xenopus laevisoocyte expression system. In the study, 35 GS patients and 20 healthy volunteers underwent the thiazide test.

Results

T60M, T163M, D486N, R913Q, R928C, and R959frameshift were frequent SLC12A3 gene mutations (mutated frequency >3%) in 310 Chinese GS families. The protein’s three-dimensional structure was predicted to be altered in all mutations. Compared with WT hNCC, the thiazide-sensitive 22Na+ uptake was significantly diminished for all six mutations: T60M 22 ± 9.2%, R928C 29 ± 12%, L215F 38 ± 14%, N534K 41 ± 15.5%, Q617R 63 ± 22.1%, and D486N 77 ± 20.4%. In thiazide test, the net increase in chloride fractional excretion in 20 healthy controls was significantly higher than GS patients with or without T60M or D486N mutations.

Conclusions

Frequent mutations (T60M, D486N, and R928C) and novel mutations (L215F, N534K, and Q617R) lead to protein structure alternation and protein dysfunction verified by 22Na+ uptake experiment in vitro and thiazide test on the patients.

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Simon Chang Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Biochemistry, Hospital of South West Jutland, Esbjerg, Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Department of Internal Medicine, Lillebaelt Hospital, Kolding, Denmark

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Arkadiusz J Goszczak NanoSYD, The Mads Clausen Institute, University of Southern Denmark, Sønderborg, Denmark

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Anne Skakkebæk Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

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Jens Fedder Centre of Andrology and Fertility Clinic, Odense University Hospital, Odense, Denmark

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Anders Bojesen Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

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M Vakur Bor Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Biochemistry, Hospital of South West Jutland, Esbjerg, Denmark

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Moniek P M de Maat Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Biochemistry, Hospital of South West Jutland, Esbjerg, Denmark
Department of Haematology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands

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Claus H Gravholt Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

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Anna-Marie B Münster Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Biochemistry, Hospital of South West Jutland, Esbjerg, Denmark

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Objective

Klinefelter syndrome (KS) is associated with increased risk of thrombosis. Hypogonadism and accumulating body fat in KS have a potential impact on fibrinolysis. In this study, we assessed the fibrinolytic system and the association with testosterone levels in KS.

Design

This study is a cross-sectional comparison of men with KS and age-matched male controls.

Methods

Fibrin clot lysis was evaluated by turbidity measurements and by measuring levels of individual fibrinolytic proteins in plasma samples. Fibrin clot structure was evaluated by scanning electron microscopy. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Body fat was evaluated by dual-energy X-ray absorptiometry.

Results

In this study, 45 men with KS and 45 age- and education-matched controls were included. Men with KS had a 24% reduction in fibrin clot lysis compared with controls (46.2 ± 17.1 vs 60.6 ± 18.8 %/h, P  = 0.0003) and higher levels of fibrinogen, factor XIII (P ≤ 0.01), and plasminogen activator inhibitor type 1 (P  = 0.04). Men with KS had lower total testosterone (P  = 0.008) and higher body fat (P  = 0.001). In KS, reduced fibrin clot lysability was associated with higher fibrinogen and body fat related to decreasing total testosterone and hypogonadism among men with KS. Fibrin clot structure was not different compared to KS and controls.

Conclusions

Fibrin clot lysis in KS was markedly reduced, potentially contributing to a prothrombotic state and increasing thrombotic risk. Hypogonadism in KS was associated with increased fibrinogen and total body fat, predicting reduced fibrin clot lysis.

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