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We have characterized a mutation in a pro alpha 1(I) procollagen gene (COL1A1) that results in lethal (type II) osteogenesis imperfecta. The mutation is a single base change that results in a cysteine-for-glycine substitution at position... more
We have characterized a mutation in a pro alpha 1(I) procollagen gene (COL1A1) that results in lethal (type II) osteogenesis imperfecta. The mutation is a single base change that results in a cysteine-for-glycine substitution at position 988 of the triple-helical portion of half of the alpha 1(I) chains of type I collagen. The mutation thus disrupts the (Gly-Xaa-Yaa)n pattern necessary for triple-helix formation, where Xaa and Yaa are other amino acids. These experiments establish the minimal mutation in a type I collagen gene capable of producing lethal disease, and the lethality demonstrates a selective mechanism for the stringent maintenance of the collagen gene structure.
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Research Interests: Genetics, Human Genetics, Complementary and Alternative Medicine, Humans, Osteogenesis Imperfecta, and 9 moreMale, Polymerase Chain Reaction, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Newborn Infant, Glycine, Base Sequence, Molecular Sequence Data, DNA mutational analysis, and restriction enzyme
Research Interests: Mental Retardation, Humans, Mutation, Microcephaly, Female, and 17 morePhenylketonuria, Male, Polymerase Chain Reaction, Infant, Mothers, Pedigree, Phenotype, Newborn Infant, Genotype, Adult, Glutamine, Public health systems and services research, Arginine, Base Sequence, Developmental delay, Phenylalanine hydroxylase, and Molecular Sequence Data
In Menkes' disease, a severe disturbance of copper handling appears to render copper unavailable for copper-requiring processes. We have measured the activity of lysyl oxidase, the copper-dependent enzyme that initiates the... more
In Menkes' disease, a severe disturbance of copper handling appears to render copper unavailable for copper-requiring processes. We have measured the activity of lysyl oxidase, the copper-dependent enzyme that initiates the cross-linking of collagen and elastin, in extracts of skin and aorta obtained at autopsy from a patient with unusually marked connective tissue manifestations, and found it to be only 6-12% of normal, thus suggesting a basis for these alterations.
Research Interests: Endocrinology, Genetics, Cardiology, Hematology, Nephrology, and 21 moreNeurology, Oncology, Pulmonology, Rheumatology, Epidemiology, Immunology, Nutrition, Public Health, Allergy, Humans, Collagen, Copper, Male, Connective tissue, Infant, Skin, Pediatric, Fetus, Aorta, lysyl oxidase , and fibroblasts(Neurology, Oncology, Pulmonology, Rheumatology, Epidemiology, Immunology, Nutrition, Public Health, Allergy, Humans, Collagen, Copper, Male, Connective tissue, Infant, Skin, Pediatric, Fetus, Aorta, lysyl oxidase , and fibroblasts)
(Neurology, Oncology, Pulmonology, Rheumatology, Epidemiology, Immunology, Nutrition, Public Health, Allergy, Humans, Collagen, Copper, Male, Connective tissue, Infant, Skin, Pediatric, Fetus, Aorta, lysyl oxidase , and fibroblasts)
Research Interests: Genetics, Human Genetics, Genomics, Complementary and Alternative Medicine, Molecular Genetics, and 18 moreHumans, Genetic Testing, Haplotypes, Connective tissue, Marfan syndrome, Gene, Haploinsufficiency, High Resolution, Gen, Copy Number Variation, Genomic DNA, Single Nucleotide Polymorphism, Genome Rearrangement, Base Sequence, Cohort Studies, Molecular Sequence Data, DNA mutational analysis, and Autosomal Dominant(Humans, Genetic Testing, Haplotypes, Connective tissue, Marfan syndrome, Gene, Haploinsufficiency, High Resolution, Gen, Copy Number Variation, Genomic DNA, Single Nucleotide Polymorphism, Genome Rearrangement, Base Sequence, Cohort Studies, Molecular Sequence Data, DNA mutational analysis, and Autosomal Dominant)
(Humans, Genetic Testing, Haplotypes, Connective tissue, Marfan syndrome, Gene, Haploinsufficiency, High Resolution, Gen, Copy Number Variation, Genomic DNA, Single Nucleotide Polymorphism, Genome Rearrangement, Base Sequence, Cohort Studies, Molecular Sequence Data, DNA mutational analysis, and Autosomal Dominant)
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In this study, we present a versatile new procedure for the analysis of transferrin and its isoforms isolated from human body fluids such as serum, plasma, and cerebrospinal fluid. This method is based on a three-step procedure: (i)... more
In this study, we present a versatile new procedure for the analysis of transferrin and its isoforms isolated from human body fluids such as serum, plasma, and cerebrospinal fluid. This method is based on a three-step procedure: (i) isolation of transferrins using anion-exchange chromatography with UV detection; (ii) concentration of the transferrin fraction; (iii) detection of the transferrins with liquid chromatography-electrospray mass spectrometry. Pre-analytical sample procedures can be omitted and no immunoaffinity columns or transferrin-specific immunoassays were used. Anticoagulants such as heparin, EDTA, citrate, and oxalate do not interfere with our analysis. According to their respective molecular masses, up to ten different isoforms of transferrin could be identified in a serum sample from a patient with a congenital disorder of glycosylation type Ia (CDG-Ia). The method was successfully applied to different pathological samples from patients with CDG-Ia, CDG-Ib, CDG-Ic, CDG-Ie, CDG-If, and CDG-IIa. Additionally, samples from alcohol consumers that were found with turbidimetric immunoassay to contain increased levels of carbohydrate-deficient transferrin were analyzed.
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BackgroundThe Ehlers-Danlos syndrome type VI (EDSVI) is an autosomal recessive connective tissue disease which is characterized by severe hypotonia at birth, progressive kyphoscoliosis, skin hyperelasticity and fragility, joint... more
BackgroundThe Ehlers-Danlos syndrome type VI (EDSVI) is an autosomal recessive connective tissue disease which is characterized by severe hypotonia at birth, progressive kyphoscoliosis, skin hyperelasticity and fragility, joint hypermobility and (sub-)luxations, microcornea, rupture of arteries and the eye globe, and osteopenia. The enzyme collagen lysyl hydroxylase (LH1) is deficient in these patients due to mutations in the PLOD1 gene.Case PresentationWe report a 17-year-old boy, born to related parents, with severe kyphoscoliosis, scar formation, joint hypermobility and multiple dislocations, muscular weakness, rupture of an ocular globe, and a history of severe infantile hypotonia. EDS VI was suspected clinically and confirmed by an elevated ratio of urinary total lysyl pyridinoline to hydroxylysyl pyridinoline, abnormal electrophoretic mobility of the α-collagen chains, and mutation analysis.ConclusionBecause of the high rate of consanguineous marriages in Iran and, as a consequence thereof, an increased rate of autosomal recessive disorders, we urge physicians to consider EDS VI in the differential diagnosis of severe infantile hypotonia and muscular weakness, a disorder which can easily be confirmed by the analysis of urinary pyridinolines that is highly specific, sensitive, robust, fast, non-invasive, and inexpensive.
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... Xia Cao, Pei Yean Cheah Department of Colorectal Surgery, Singapore General Hospital, Outram Road, Singapore 169608, Singapore, e-mail: gcscao@sgh.com.sg, Tel.: +65-63213636, Fax: +65 ... Eva Brauers, Thomas Eggermann Institute of... more
... Xia Cao, Pei Yean Cheah Department of Colorectal Surgery, Singapore General Hospital, Outram Road, Singapore 169608, Singapore, e-mail: gcscao@sgh.com.sg, Tel.: +65-63213636, Fax: +65 ... Eva Brauers, Thomas Eggermann Institute of Human Genetics, Pauwelsstr. ...
Research Interests: Genetics, Human Genetics, Complementary and Alternative Medicine, Blindness, Pakistan, and 40 moreElectroencephalography, Membrane Proteins, Clinical and Molecular Human Genetics, Macular Degeneration, Humans, Child, Pyruvate Kinase, Mutation, Microcephaly, Female, Male, Young Adult, Netherlands, Proteins, Gene, Gene Duplication, Glycoproteins, Duchenne Muscular Dystrophy, Introns, Angelman Syndrome, CADASIL, Hemophilia A, Adenomatous Polyposis-coli, Codon, factor VIII, Base Sequence, Amino Acid Substitution Rates, Dystrophin, Erythrocytes, Charcot Marie Tooth Disease, Protein Tyrosine Phosphatases, Syndrome, Parkinson Disease, Blood Proteins, Nucleotides, Guanylate Cyclase, Molecular Sequence Data, DNA mutational analysis, Child preschool, and Atlantic Islands(Electroencephalography, Membrane Proteins, Clinical and Molecular Human Genetics, Macular Degeneration, Humans, Child, Pyruvate Kinase, Mutation, Microcephaly, Female, Male, Young Adult, Netherlands, Proteins, Gene, Gene Duplication, Glycoproteins, Duchenne Muscular Dystrophy, Introns, Angelman Syndrome, CADASIL, Hemophilia A, Adenomatous Polyposis-coli, Codon, factor VIII, Base Sequence, Amino Acid Substitution Rates, Dystrophin, Erythrocytes, Charcot Marie Tooth Disease, Protein Tyrosine Phosphatases, Syndrome, Parkinson Disease, Blood Proteins, Nucleotides, Guanylate Cyclase, Molecular Sequence Data, DNA mutational analysis, Child preschool, and Atlantic Islands)
(Electroencephalography, Membrane Proteins, Clinical and Molecular Human Genetics, Macular Degeneration, Humans, Child, Pyruvate Kinase, Mutation, Microcephaly, Female, Male, Young Adult, Netherlands, Proteins, Gene, Gene Duplication, Glycoproteins, Duchenne Muscular Dystrophy, Introns, Angelman Syndrome, CADASIL, Hemophilia A, Adenomatous Polyposis-coli, Codon, factor VIII, Base Sequence, Amino Acid Substitution Rates, Dystrophin, Erythrocytes, Charcot Marie Tooth Disease, Protein Tyrosine Phosphatases, Syndrome, Parkinson Disease, Blood Proteins, Nucleotides, Guanylate Cyclase, Molecular Sequence Data, DNA mutational analysis, Child preschool, and Atlantic Islands)
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Research Interests: Humans, Epinephrine, Copper, Female, Male, and 6 moreNorepinephrine, Lancet, Aged, Middle Aged, Adult, and Syndrome
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Research Interests: Biological Chemistry, Biological Sciences, Humans, Mutation, Osteogenesis Imperfecta, and 12 moreFemale, Male, Polymerase Chain Reaction, Skin, Newborn Infant, CHEMICAL SCIENCES, Genetic variation, Amino Acid Sequence, Base Sequence, Molecular Sequence Data, fibroblasts, and Chromosome 22q11 deletion
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Research Interests: Genetics()
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Research Interests: Genetics, Human Genetics, International organizations, Complementary and Alternative Medicine, DNA, and 10 moreHumans, Mutation, Triple Helix, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, Ehlers-Danlos Syndrome, International Organizations, Amino Acid Substitution Rates, Blood Vessel, Molecular Structure, and fibroblasts
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Research Interests: Adolescent, Humans, Collagen, Female, Male, and 6 moreSkin, Pedigree, Lysine, Adult, Ehlers-Danlos Syndrome, and fibroblasts
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Research Interests: Dentistry, Adolescent, Humans, Collagen, Osteogenesis Imperfecta, and 5 moreFemale, Genes, Dentin, Tooth, and Bone and Bones
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The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum.... more
The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died...
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Ein Handbuch für Betroffene seltener Krankheiten und ihr Umfeld. Das Bewältigen einer chronischen Krankheit stellt an die betroffenen Menschen hohe Anforderungen. Erst recht, wenn die Krankheit selten ist. Wie gehen sie damit um? Welche... more
Ein Handbuch für Betroffene seltener Krankheiten und ihr Umfeld. Das Bewältigen einer chronischen Krankheit stellt an die betroffenen Menschen hohe Anforderungen. Erst recht, wenn die Krankheit selten ist. Wie gehen sie damit um? Welche Unterstützung erhalten sie von ihrem sozialen und vom professionellen Umfeld? Was bedeuten «Gesundheits- kompetenz» und «Empowerment» für sie – in der Gesundheitsversorgung und im Alltag? Am Beispiel des Marfan-Syndroms sind Betroffene und Fachleute diesen Fragen aus verschiedenen Blickwinkeln nachgegangen.
We identified a splicing mutation in a patient with Ehlers-Danlos syndrome type IV, a heritable connective tissue disorder associated with dysfunctions of type III collagen. The mutation was first localized in the patient's type III... more
We identified a splicing mutation in a patient with Ehlers-Danlos syndrome type IV, a heritable connective tissue disorder associated with dysfunctions of type III collagen. The mutation was first localized in the patient's type III procollagen mRNA by amplifying the reverse transcribed product in several overlapping fragments using the polymerase chain reaction. Amplified products spanning exon 24-26 sequences displayed two distinct fragments, one of normal size and the other lacking the 99 base pairs of exon 25. Sequencing of amplified genomic products identified a G to T transversion at position +5 of the splice donor site of intron 25 in one of the patient's procollagen III genes. Expression of allelic minigene constructs correlated the T for G substitution with skipping of exon 25 sequences. Like previously characterized splicing mutations in other collagen genes, lowering the temperature at which the patient's fibroblasts were incubated nearly abolished exon skippi...
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A case of congenital familial ptosis with simultaneous Ehlers-Danlos syndrome type II is presented. Since coincidence of these two rare hereditary diseases would be unlikely, the ptosis in this case may be a so far undocumented... more
A case of congenital familial ptosis with simultaneous Ehlers-Danlos syndrome type II is presented. Since coincidence of these two rare hereditary diseases would be unlikely, the ptosis in this case may be a so far undocumented manifestation of EDS.
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A patient with Ehlers-Danlos syndrome Type VIIB was found to have an interstitial deletion of 18 amino acids in approximately half of the pro-alpha 2(I) chains of Type I procollagen. Analysis of pepsin-solubilized tissue and fibroblast... more
A patient with Ehlers-Danlos syndrome Type VIIB was found to have an interstitial deletion of 18 amino acids in approximately half of the pro-alpha 2(I) chains of Type I procollagen. Analysis of pepsin-solubilized tissue and fibroblast collagen revealed an abnormal additional chain, alpha 2(I)', which migrated in sodium dodecyl sulfate-5% polyacrylamide gel electrophoresis between the normal alpha 1(I) and alpha 2(I) chains. The apparent ratio of normal alpha 1(I):mutant alpha 2(I)':normal alpha 2(I) was 4:1:1. Procollagen studies and enzyme digestion studies of native mutant collagen suggested defective removal of the amino propeptide. Sieve chromatography of CNBr peptides from purified alpha 2(I)' chains revealed the absence of the normal amino telopeptide fragment CB 1 and the appearance of a larger new peptide of approximately 60 residues (CB X). Compositional and sequencing studies of this peptide identified normal amino propeptide sequences. However, the most carbo...
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The cause of the Ehlers-Danlos syndrome Type VII (EDS VII) is considered to be defective removal of the amino-terminal propeptide (N-propeptide) of Type I procollagen due to deficiency of procollagen N-proteinase, the enzyme responsible... more
The cause of the Ehlers-Danlos syndrome Type VII (EDS VII) is considered to be defective removal of the amino-terminal propeptide (N-propeptide) of Type I procollagen due to deficiency of procollagen N-proteinase, the enzyme responsible for the normal proteolytic excision of this precursor-specific domain. Molecules retaining the N-propeptide (pN-collagen molecules) are thought to cause defective fibrillogenesis and cross-linking which eventuate in dramatic joint laxity and joint dislocations, the clinical hallmark of this variety of EDS. Recent studies demonstrate that some EDS VII patients harbor small deletions of either the pro-alpha 1(I) or pro-alpha 2(I) chain of Type I procollagen. We have found an 18-amino acid deletion (due to exon outsplicing) in a mutant pro-alpha 2(I) chain from such a patient. The deleted peptide is the junctional segment (N-telopeptide) linking the alpha 2(I) N-propeptide and major triple helical domains; loss of this short segment results in union of ...