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Acute intermittent porphyria in Sweden. Molecular, functional and clinical consequences of some new mutations found in the porphobilinogen deaminase gene.

https://arctichealth.org/en/permalink/ahliterature9889
Source
Clin Genet. 2002 Oct;62(4):288-97
Publication Type
Article
Date
Oct-2002
Author
Y. Floderus
P M Shoolingin-Jordan
P. Harper
Author Affiliation
Porphyria Centre Sweden, Huddinge University Hospital, Stockholm, Sweden.
Source
Clin Genet. 2002 Oct;62(4):288-97
Date
Oct-2002
Language
English
Publication Type
Article
Keywords
Codon, Nonsense
DNA Mutational Analysis
Exons
Female
Genetic Screening
Humans
Hydroxymethylbilane Synthase - blood - chemistry - genetics
Male
Mutation, Missense
Porphyria, Acute Intermittent - genetics - physiopathology
Research Support, Non-U.S. Gov't
Sweden
Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficit of porphobilinogen deaminase (PBGD), the third of eight enzymes in the haem biosynthetic pathway. The overt disease is characterized by neuropsychiatric symptoms that are often triggered by exogenous factors such as certain drugs, stress, and alcohol. The aim of this work has been to identify the underlying genetic defect in each AIP-affected family in order to provide early counselling to assist in the avoidance of precipitating factors. The prevalence of AIP in Sweden is in the order of 1:10 000. The major mutation in Sweden, W198X, is due to a founder effect in the northern part of the country. This mutation, together with a further 11 mutations, have been reported previously. The present communication encompasses the great majority of AIP kindreds in Sweden and includes a further 27 mutations within the PBGD gene. This includes 14 completely new mutations, as well as 11 known mutations detected for the first time in Sweden. The majority of the mutations are located in exons 10 and 12 with fewer in exon 7. The clinical and biochemical outcomes in some patients are described. We also use the three-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the new Swedish missense and nonsense mutations.
PubMed ID
12372055 View in PubMed
Less detail

Acute liver failure meets SOPH syndrome: A case report on an intermediate phenotype.

https://arctichealth.org/en/permalink/ahliterature283558
Source
Pediatrics. 2017 Jan;139(1)
Publication Type
Article
Date
Jan-2017
Author
Fanny Kortüm
Iris Marquardt
Malik Alawi
Georg Christoph Korenke
Stephanie Spranger
Peter Meinecke
Kerstin Kutsche
Source
Pediatrics. 2017 Jan;139(1)
Date
Jan-2017
Language
English
Publication Type
Article
Keywords
Alleles
Child, Preschool
DNA Mutational Analysis
Developmental Disabilities - diagnosis - genetics
Dwarfism - diagnosis - genetics
Exome - genetics
Female
Heterozygote Detection
Humans
Liver Failure, Acute - diagnosis - genetics
Mutation, Missense - genetics
Neoplasm Proteins - deficiency - genetics
Optic Atrophy - diagnosis - genetics
Pelger-Huet Anomaly - diagnosis - genetics
Phenotype
Syndrome
Abstract
Acute liver failure (ALF) is a life-threatening condition in the absence of preexisting liver disease in children. The main clinical presentation comprises hepatic dysfunction, elevated liver biochemical values, and coagulopathy. The etiology of ALF remains unclear in most affected children; however, the recent identification of mutations in the neuroblastoma amplified sequence (NBAS) gene in autosomal recessively inherited ALF has shed light on the cause of a subgroup of fever-triggered pediatric ALF episodes. Previously, biallelic mutations in NBAS have been reported to be associated with a syndrome comprising short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) specifically occurring in the Yakut population. No hepatic phenotype has been observed in individuals with this disorder who all carry the homozygous NBAS founder mutation c.5741G>A [p.(Arg1914His)]. We present the case of a 4-year-old girl with the cardinal features of SOPH syndrome: characteristic facial dysmorphism, postnatal growth retardation, delay of bone age, slender long bones, optic atrophy, and Pelger-Huët anomaly. During the first 2 years of her life, a series of infections with episodes of fever were accompanied by elevated liver enzyme levels, but hyperammonemia, hypoglycemia, coagulopathy, or encephalopathy suggestive of acute and severe liver disease were never observed. Whole exome sequencing in the patient revealed compound heterozygosity of the 2 NBAS variants, p.(Arg1914His) and p.(Glu943*). This case highlights the variability of clinical presentation associated with NBAS deficiency. Absence of severe liver problems in this case and SOPH-affected Yakut subjects suggests that individuals carrying the NBAS missense mutation p.(Arg1914His) are less susceptible to developing ALF.
PubMed ID
28031453 View in PubMed
Less detail

Adrenomyeloneuropathy: report of a new mutation in a French Canadian female.

https://arctichealth.org/en/permalink/ahliterature173849
Source
Can J Neurol Sci. 2005 May;32(2):261-3
Publication Type
Article
Date
May-2005
Author
Annie Dionne
Denis Brunet
Alexander McCampbell
Nicolas Dupré
Author Affiliation
Départment des Sciences Neurologiques, CHAUQ-Hôpital Enfant-Jésus, McGill University, QC, Canada.
Source
Can J Neurol Sci. 2005 May;32(2):261-3
Date
May-2005
Language
English
Publication Type
Article
Keywords
ATP-Binding Cassette Transporters - genetics
Adrenoleukodystrophy - genetics - metabolism - physiopathology
Amino Acid Sequence - genetics
Amino Acid Substitution - genetics
Chromosomes, Human, X - genetics
DNA Mutational Analysis
Diagnosis, Differential
Exons - genetics
Family Health
Female
Genetic Testing
Humans
Middle Aged
Mutation, Missense - genetics
Pedigree
Phenotype
Quebec - ethnology
Sex Factors
Abstract
X-linked adrenoleukodystrophy is a peroxisomial disorder caused by mutations in the ABCD1 gene. Adrenomyeloneuropathy is the second most frequent phenotype (25-46%) of this disease and classically presents in adulthood with spastic paraparesis. Female heterozygotes can be symptomatic, but they are frequently misdiagnosed as having multiple sclerosis.
We report a novel missense mutation in the ABCD1 gene in a 47-year-old French-Canadian female with spastic paraparesis and no confirmed family history of X-linked adrenoleukodystrophy. The mutation is located on exon 1 and causes the amino acid substitution of a valine for an alanine in a region of the protein highly conserved between mouse and man.
Adrenomyeloneuropathy must be considered in the differential diagnosis of spastic paraparesis in men or women. This is an initial report of an ABCD1 gene mutation in the French-Canadian population, which should lead to the recognition of other cases in the future.
PubMed ID
16018167 View in PubMed
Less detail

Adult-onset autosomal dominant spastic paraplegia linked to a GTPase-effector domain mutation of dynamin 2.

https://arctichealth.org/en/permalink/ahliterature272909
Source
BMC Neurol. 2015;15:223
Publication Type
Article
Date
2015
Author
Nyamkhishig Sambuughin
Lev G Goldfarb
Tatiana M Sivtseva
Tatiana K Davydova
Vsevolod A Vladimirtsev
Vladimir L Osakovskiy
Al'bina P Danilova
Raisa S Nikitina
Anastasia N Ylakhova
Margarita P Diachkovskaya
Anna C Sundborger
Neil M Renwick
Fyodor A Platonov
Jenny E Hinshaw
Camilo Toro
Source
BMC Neurol. 2015;15:223
Date
2015
Language
English
Publication Type
Article
Keywords
Adult
DNA Mutational Analysis
Dynamins - genetics
Exome
Family Health
Female
GTP Phosphohydrolases - chemistry - genetics
Genetic Variation
Hela Cells
Humans
Male
Middle Aged
Mutation
Mutation, Missense
Phenotype
Siberia
Spastic Paraplegia, Hereditary - genetics
Abstract
Hereditary Spastic Paraplegia (HSP) represents a large group of clinically and genetically heterogeneous disorders linked to over 70 different loci and more than 60 recognized disease-causing genes. A heightened vulnerability to disruption of various cellular processes inherent to the unique function and morphology of corticospinal neurons may account, at least in part, for the genetic heterogeneity.
Whole exome sequencing was utilized to identify candidate genetic variants in a four-generation Siberian kindred that includes nine individuals showing clinical features of HSP. Segregation of candidate variants within the family yielded a disease-associated mutation. Functional as well as in-silico structural analyses confirmed the selected candidate variant to be causative.
Nine known patients had young-adult onset of bilateral slowly progressive lower-limb spasticity, weakness and hyperreflexia progressing over two-to-three decades to wheel-chair dependency. In the advanced stage of the disease, some patients also had distal wasting of lower leg muscles, pes cavus, mildly decreased vibratory sense in the ankles, and urinary urgency along with electrophysiological evidence of a mild distal motor/sensory axonopathy. Molecular analyses uncovered a missense c.2155C > T, p.R719W mutation in the highly conserved GTP-effector domain of dynamin 2. The mutant DNM2 co-segregated with HSP and affected endocytosis when expressed in HeLa cells. In-silico modeling indicated that this HSP-associated dynamin 2 mutation is located in a highly conserved bundle-signaling element of the protein while dynamin 2 mutations associated with other disorders are located in the stalk and PH domains; p.R719W potentially disrupts dynamin 2 assembly.
This is the first report linking a mutation in dynamin 2 to a HSP phenotype. Dynamin 2 mutations have previously been associated with other phenotypes including two forms of Charcot-Marie-Tooth neuropathy and centronuclear myopathy. These strikingly different pathogenic effects may depend on structural relationships the mutations disrupt. Awareness of this distinct association between HSP and c.2155C > T, p.R719W mutation will facilitate ascertainment of additional DNM2 HSP families and will direct future research toward better understanding of cell biological processes involved in these partly overlapping clinical syndromes.
Notes
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PubMed ID
26517984 View in PubMed
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Alterations of E-cadherin and beta-catenin in gastric cancer.

https://arctichealth.org/en/permalink/ahliterature19398
Source
BMC Cancer. 2001;1:16
Publication Type
Article
Date
2001
Author
C. Huiping
S. Kristjansdottir
J G Jonasson
J. Magnusson
V. Egilsson
S. Ingvarsson
Author Affiliation
Department of Pathology, National University Hospital, 101 Reykjavík, Iceland. chen@rsp.is
Source
BMC Cancer. 2001;1:16
Date
2001
Language
English
Publication Type
Article
Keywords
Age of Onset
Aged
Breast Neoplasms - genetics - pathology
Cadherins - genetics - physiology
Cell Adhesion - genetics - physiology
Chromosomes, Human, Pair 16 - genetics
Cytoskeletal Proteins - genetics - physiology
DNA Mutational Analysis - methods
DNA, Neoplasm - genetics
Female
Gene Expression Regulation, Neoplastic - genetics - physiology
Germ-Line Mutation - genetics - physiology
Humans
Loss of Heterozygosity - genetics
Male
Mutation, Missense - genetics - physiology
Prostatic Neoplasms - genetics - pathology
Research Support, Non-U.S. Gov't
Skin Neoplasms - genetics - pathology
Stomach Neoplasms - genetics - pathology
Trans-Activators - genetics - physiology
beta Catenin
Abstract
BACKGROUND: The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. METHODS: We studied the alterations of E-cadherin and beta-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC). RESULTS: A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and beta-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for beta-catenin IHC. An association was found between reduced expression of E-cadherin and beta-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype. CONCLUSION: Our results support the hypothesis that alterations of E-cadherin and beta-catenin play a role in the initiation and progression of gastric cancer.
PubMed ID
11747475 View in PubMed
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Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer.

https://arctichealth.org/en/permalink/ahliterature124013
Source
Fam Cancer. 2012 Sep;11(3):525-8
Publication Type
Article
Date
Sep-2012
Author
Silva Saarinen
Pia Vahteristo
Rainer Lehtonen
Kristiina Aittomäki
Virpi Launonen
Tuula Kiviluoto
Lauri A Aaltonen
Author Affiliation
Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland. silva.saarinen@helsinki.fi
Source
Fam Cancer. 2012 Sep;11(3):525-8
Date
Sep-2012
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
Carrier Proteins - genetics
Esophageal Neoplasms - genetics
Female
Finland
Humans
Keratoderma, Palmoplantar, Diffuse - genetics
Male
Middle Aged
Mutation, Missense
Pedigree
Abstract
Tylosis with esophageal cancer (TOC) is a rare familial cancer syndrome inherited in an autosomal-dominant manner and characterized by esophageal cancer susceptibility and hyperkeratotic skin lesions. Two heterozygous missense mutations in the RHBDF2 gene were recently reported to be associated with TOC in three families: a p.Ile186Thr mutation was found in families from the UK and the US and a p.Pro189Leu mutation was detected in a German TOC family. We aimed to validate these novel results in an independent material by screening RHBDF2 in a previously unreported Finnish TOC family. We identified a new missense mutation, p.Asp188Asn, segregating with TOC in the Finnish family, and interestingly the detected mutation alters a codon located between the two previously reported mutation sites. Thus, we confirmed RHBDF2 mutations as the underlying cause of the TOC syndrome and our results suggest that the TOC associated mutations might be specific for this particular site in the RHBDF2 gene. These results enable the genetic counseling and diagnostic mutation screening of the members of TOC families.
PubMed ID
22638770 View in PubMed
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Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961-2009.

https://arctichealth.org/en/permalink/ahliterature116865
Source
Virol J. 2013;10:32
Publication Type
Article
Date
2013
Author
Emily Abernathy
Min-hsin Chen
Jayati Bera
Susmita Shrivastava
Ewen Kirkness
Qi Zheng
William Bellini
Joseph Icenogle
Author Affiliation
National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Source
Virol J. 2013;10:32
Date
2013
Language
English
Publication Type
Article
Keywords
Cluster analysis
Conserved Sequence
Female
Genetic Variation
Genome, Viral
Genotype
Humans
Molecular Sequence Data
Mutation, Missense
Phylogeny
Pregnancy
RNA, Viral - genetics
Rubella virus - classification - genetics - isolation & purification
Sequence Analysis, DNA
Sequence Deletion
United States
Abstract
Rubella virus is the causative agent of rubella, a mild rash illness, and a potent teratogenic agent when contracted by a pregnant woman. Global rubella control programs target the reduction and elimination of congenital rubella syndrome. Phylogenetic analysis of partial sequences of rubella viruses has contributed to virus surveillance efforts and played an important role in demonstrating that indigenous rubella viruses have been eliminated in the United States. Sixteen wild-type rubella viruses were chosen for whole genome sequencing. All 16 viruses were collected in the United States from 1961 to 2009 and are from 8 of the 13 known rubella genotypes. Phylogenetic analysis of 30 whole genome sequences produced a maximum likelihood tree giving high bootstrap values for all genotypes except provisional genotype 1a. Comparison of the 16 new complete sequences and 14 previously sequenced wild-type viruses found regions with clusters of variable amino acids. The 5' 250 nucleotides of the genome are more conserved than any other part of the genome. Genotype specific deletions in the untranslated region between the non-structural and structural open reading frames were observed for genotypes 2B and genotype 1G. No evidence was seen for recombination events among the 30 viruses. The analysis presented here is consistent with previous reports on the genetic characterization of rubella virus genomes. Conserved and variable regions were identified and additional evidence for genotype specific nucleotide deletions in the intergenic region was found. Phylogenetic analysis confirmed genotype groupings originally based on structural protein coding region sequences, which provides support for the WHO nomenclature for genetic characterization of wild-type rubella viruses.
Notes
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PubMed ID
23351667 View in PubMed
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APC I1307K and E1317Q variants are rare or do not occur in Swedish colorectal cancer patients.

https://arctichealth.org/en/permalink/ahliterature19920
Source
Eur J Cancer. 2001 Mar;37(4):499-502
Publication Type
Article
Date
Mar-2001
Author
S. Evertsson
A. Lindblom
X F Sun
Author Affiliation
Department of Oncology, Institute of Biomedicine and Surgery, Linköping University, S-581 85, Linköping, Sweden.
Source
Eur J Cancer. 2001 Mar;37(4):499-502
Date
Mar-2001
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Arabidopsis Proteins
Calcium-Binding Proteins - genetics
Colorectal Neoplasms - epidemiology - genetics
Female
Humans
Male
Middle Aged
Mutation, Missense - genetics
Pedigree
Polymerase Chain Reaction - methods
Research Support, Non-U.S. Gov't
Sweden - epidemiology - ethnology
Abstract
Recently, a germ line mutation of the APC gene, I1307K, was discovered in a subset of Ashkenazi jews. The mutation involves an amino acid exchange and creates a tract consisting of eight contiguous adenosine residues believed to cause hypermutability in this region. Another germ line missense variant, E1317Q, not restricted to a certain ethnic population, could functionally alter the protein. These APC variants have been linked with increased colorectal cancer risk in several studies. However, they have not yet been investigated in Swedish colorectal cancer patients. Thus, our aim was to investigate the prevalence of I1307K and E1317Q in Swedish colorectal cancer patients in order to determine if these genetic variants are important predisposing factors to colorectal cancer in this population. To this end, sequence analysis was carried out of the APC gene in order to identify any I1307K and E1317Q variants in 106 unselected cases and 88 hereditary/familial colorectal cancer cases including 22 cases of hereditary non-polyposis colorectal cancer (HNPCC) fulfilling the Amsterdam criteria. Out of a total of 194 cases examined, we did not find any variants. It seems that these alterations are rare or absent in the Swedish population.
PubMed ID
11267860 View in PubMed
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The Arctic mutation alters helix length and type in the 11-28 beta-amyloid peptide monomer-CD, NMR and MD studies in an SDS micelle.

https://arctichealth.org/en/permalink/ahliterature100702
Source
J Struct Biol. 2008 Nov;164(2):199-209
Publication Type
Article
Date
Nov-2008
Author
Sylwia Rodziewicz-Motowidlo
Paulina Czaplewska
Emilia Sikorska
Marta Spodzieja
Aleksandra S Kolodziejczyk
Author Affiliation
Faculty of Chemistry, University of Gdansk, Sobieskiego 18, 80-952 Gdansk, Pomorskie, Poland. sylwia@chem.univ.gda.pl
Source
J Struct Biol. 2008 Nov;164(2):199-209
Date
Nov-2008
Language
English
Publication Type
Article
Keywords
Amyloid beta-Peptides - chemistry - genetics
Circular Dichroism
Humans
Magnetic Resonance Spectroscopy
Micelles
Molecular Dynamics Simulation
Mutation, Missense
Peptide Fragments - chemistry - genetics
Protein Structure, Secondary - genetics
Sodium Dodecyl Sulfate
Abstract
The beta-amyloid (Abeta) is the major peptide constituent of neuritic plaques in Alzheimer's disease, and its aggregation is believed to play a central role in the pathogenesis of the disease. Naturally occurring mutations resulting in changes in the Abeta sequence (pos. 21-23) are associated with familial Alzheimer's-like diseases with extensive cerebrovascular pathology. It has been demonstrated that such mutations alter the aggregation ability of Abeta and its neurotoxicity. Among the five mutations at positions 21-23 there is one with distinct clinical characteristics and a potentially distinct pathogenic mechanism-the Arctic (E22G) mutation. We have examined the structures of fragment 11-28 of the native peptide and its E22G variant. This fragment was chosen because it has been shown to be a good model for conformational and aggregation studies as it contains the hydrophobic core responsible for aggregation and the residues critical to alpha-secretase cleavage of APP. The detailed structure of the two peptides was determined using CD, 2D NMR and molecular dynamics techniques under water-SDS micelle conditions. Our studies indicated the existence of partially alpha- and 3(10)-helical conformations in the native and mutated peptide, respectively.
PubMed ID
18765285 View in PubMed
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Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family.

https://arctichealth.org/en/permalink/ahliterature197962
Source
Br J Haematol. 2000 Jun;109(3):523-8
Publication Type
Article
Date
Jun-2000
Author
R. Schwaab
J. Oldenburg
G. Kemball-Cook
T. Albert
C. Juhler
P. Hanfland
J. Ingerslev
Author Affiliation
Institute for Experimental Haematology and Transfusion Medicine, Bonn, Germany. schwra@mailer.meb.uni-bonn.de
Source
Br J Haematol. 2000 Jun;109(3):523-8
Date
Jun-2000
Language
English
Publication Type
Article
Keywords
Blood Coagulation
Blood Coagulation Tests
Denmark
Factor VIII - genetics
Female
Hemophilia A - blood - genetics
Homozygote
Humans
Male
Models, Molecular
Mutation, Missense
Pedigree
Predictive value of tests
Abstract
Factor VIII gene analysis in a large consanguinous Danish family comprising 24 affected males and four homozygously affected females revealed an Asn694Ile mutation within the A2 domain. The factor VIII gene mutation led to a mild haemophilia A phenotype with factor VIII function displaying discordance between one-stage clotting and chromogenic two-stage assays. In one-stage assays, values ranged from 0.05 to 0.30 IU/ml (males) and from 0.19 to 0.29 IU/ml (homozygous affected females), whereas the chromogenic two-stage assay produced values of around only 50% of the one-stage result [0. 02-0.12 IU/ml (males); 0.06-0.10 IU/ml (females)]. The differences are suggested to be caused by the effect of the mutation on the active cleaved form of the factor (F)VIII protein. As the original amino acid (Asn) is conserved in all known FVIII A2 sequences, but not in ceruloplasmin, we suggest that Asn694 is involved in an A2-specific functional role. Examination of a homology model of the A domains predicts that the Asn694Ile mutation (i) results in the loss of two potential hydrogen-bonding interactions and (ii) hampers the integration of the bulky side-chain of Ile into the A2 domain core, probably causing an altered stability and/or folding of the protein. Interestingly, the disease in this Danish family was originally proposed to be von Willebrand-Jürgens disease. However, the current study rules out the co-existence of either von Willebrand's disease or the presence of the Normandy variant of von Willebrand factor (type 2N).
PubMed ID
10886198 View in PubMed
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299 records – page 1 of 30.