Internist, Clinical Geneticist and Molecular biologist with practice, laboratory and consulting experience. Long history of studies of amyloid diseases and proteins.
Glycogen storage diseases (GSDs) comprise a group of rare inherited disorders caused by dysfuncti... more Glycogen storage diseases (GSDs) comprise a group of rare inherited disorders caused by dysfunction of the synthesis or degradation of glycogen. Manifestations of GSDs are largely related to their direct effects on liver and/or muscle metabolism. The medical consequences of GSDs directly relate to glycogen's central role in glucose homeostasis. Analyzing this group of disorders has identified most of the enzymes directly related to glycogen metabolism. Recognizing the presence and consequences of GSD is the basis for rational treatment of affected individuals.
Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated ve... more Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.
... HCSMA in Brittany spaniels provides an excellent example of the details that can be establish... more ... HCSMA in Brittany spaniels provides an excellent example of the details that can be established (Cork et al., 1979) by thorough study. ... Nat. Genet. 7, 246-339. Hedhammer,/~., Olsson, S.-E., Andersson, S.-/~. Persson, L., Pettersson, L., Olausson, A., and Sundgren, P.-E. (1979). ...
In situ hybridization was used to demonstrate serum amyloid A (SAA) gene expression in arthritic ... more In situ hybridization was used to demonstrate serum amyloid A (SAA) gene expression in arthritic joint tissue from lentivirus-infected sheep and goats. SAA gene transcription occurs in isolated individual synovial cells and occasional giant cells but not in uninfected or uninflamed synovial tissue. These findings support the notion (derived from in vitro observations) that at least one member of the SAA gene/protein family may function as an autocrine collagenase inducer in inflammatory arthritis. Since we used heterologous DNA probes derived from human clones, our findings also support the growing evidence for interspecies conservation of SAA genes.
Hyperphosphatasia is a heterogeneous group of disorders characterized by a generalized skeletal d... more Hyperphosphatasia is a heterogeneous group of disorders characterized by a generalized skeletal disease and increased alkaline phosphatase. Increased bone remodeling secondary to increased osteoclastic activity appears to be the underlying feature of these disorders. These disorders include juvenile Paget's disease, expansile skeletal hyperphosphatasia, hyperostosis generalisata with striations, and Camurati-Engelmann's disease, type II. The genetic mutations for a number of these disorders have been identified. We present a patient with congenital hyperphosphatasia whose clinical and radiographic features were somewhat different from these other well-defined syndromes. The patient was followed for 45 years until his death of at age 49. The patient had massive osteoectasia with dense striations involving the entire shaft of his long bones. His spine, pelvis, short tubular bones, and calvarium were also involved. He suffered hearing loss and optic atrophy, but he kept his teeth throughout his life. He was tall with a marfanoid habitus, and he had hypogonadism and hypothyroidism. There was no evidence of mental retardation, and other laboratory studies where within normal limits. This case, as well as other manifestations of hyperphosphatasia, attests to the complexity of the bone remodeling system.
The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated i... more The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated in 27 AMN patients and 31 age-matched controls by using the Farnsworth-Munsell 100 Hue test. Twelve (44%) of 27 patients showed test scores significantly above normal. The axes of bipolarity determined by the testing differed widely between the patients with abnormal scores, compatible with the notion that different alterations in visual pigment genes occur in different AMN kindreds. These observations confirm our earlier impression that the frequency of abnormal color vision is increased in these kindreds, and it supports our contentions that (1) AMN (and its companion, adrenoleukodystrophy) are very closely linked to the visual pigment loci at Xq28 and (2) this proximity might provide the opportunity to observe contiguous gene defects.
Abstract Nine lines of doubly cloned Simian Virus 40 transformed human fibroblasts have been isol... more Abstract Nine lines of doubly cloned Simian Virus 40 transformed human fibroblasts have been isolated. Precrisis in vitro characteristics of growth rate, saturation density, T antigen expression, growth in methylcellulose suspension, protease production and infectious center formation were widely divergent, although distinct for individual lines. Lines with higher T antigen expression had higher growth rates and saturation densities but grew less well in methylcellulose. Chromosome counts in most proliferating lines were in the 38–48 range; one line had 67, whereas another, poorly growing line showed 22. No distinguishing chromosomal abnormalities were present. This biologic heterogeneity suggests distinct molecular differences underlying transformation in the lines and emphasizes the importance of considering various factors as indicative of the transformed state.
The nucleic acid of an SV-lO-like virus isolated from a patient with progressive multifocal leuko... more The nucleic acid of an SV-lO-like virus isolated from a patient with progressive multifocal leukoencephalopathy has been compared with t.he DNA of a laboratory strain of SV40. DNA of this isolate (designated PML-2) is a covalently closed circular duplex with the same sedimentation rate as SV40 DNA. Denatured PML-2 DNA hybridizes with denatured SV40 DNA at about the same rate as homologous DNA. When digested with Hemophilus i?r,flue?zzae restriction endonuclease, PML-2 DNA yielded 11 fragments separable by electrophoresis, nine of which co-migrated with fragments of SV40 DNA, and two of which did not. We conclude that the PML-2 virus is avariant of SV40.
Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy show... more Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy shows common features. Migratory thrombophlebitis occurred in 96 patients while at least a single episode of thrombophlebitis was noted in 113. Seventy-five of the patients bled and 45 had arterial emboli in various organs. Twelve patients had the triad of thrombophlebitis, hemorrhage, and arterial emboli, often sequentially. Hematologic data showed derangements associated with intravascular coagulation, the most prominent of which were hypofibrinogenemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen-fibrin degradation products, decreased levels of factors V and VIII, cryofibrinogenemia, and microangiopathic hemolytic anemia. Forty-one patients had lesions of non-bacterial thrombotic endocarditis at autopsy; 31 of these had arterial emboli during life. None of the lesions were infected. Mitral and aortic valves were most frequently involved. No single mechanism that causes the disseminated intravascular coagulopathy has been identified. However, cell products--secretions and enzymes--and the cells themselves have been proposed as the procoagulant(s) responsible for the syndrome. In addition to treatment of the underlying neoplasm, symptomatic disseminated intravascular coagulopathy should be controlled. Heparin is the drug of choice for treatment of this problem, very little benefit having been observed with warfarin therapy. Long-term use of anticoagulants is potentially feasible for control of chronic disseminated intravascular coagulopathy, but without effective control of the underlying tumor ultimately will be unsuccessful.
A physical map of the Simian virus 40 genome has been constructed on the basis of specific cleava... more A physical map of the Simian virus 40 genome has been constructed on the basis of specific cleavage of Simian virus 40 DNA by bacterial restriction endonucleases. The 11 fragments produced by enzyme from Hemophilus influenzae have been ordered by analysis of partial digest products and by analysis of an overlapping set of fragments produced by enzyme from Hemophilus parainfluenzae. In addition, the single site in SV40 DNA cleaved by the Escherichia coli RI restriction endonuclease has been located. With this site as a reference point, the H. influenzae cleavage sites and the H. parainfluenzae cleavage sites have been localized on the map.
All amyloid comprises fibrillar polymers of tightly associated protein monomers. Central to the f... more All amyloid comprises fibrillar polymers of tightly associated protein monomers. Central to the fibril structure is a highly ordered β-pleated sheet domain although this interacting region may only be a relatively short stretch of each constituent polypeptide chain. Fibril formation begins as a nucleation event based either on the constituent monomer protein or its proteolytic fragment(s). The resulting fibrils are generally chemically inert and very stable.
A father and daughter with arthrogryposis multiplex congenita and similar dermatoglyphic patterns... more A father and daughter with arthrogryposis multiplex congenita and similar dermatoglyphic patterns are described. No evidence was found of chromosomal abnormality, neuropathy or myopathy, and there were no other affected family members. The findings are compatible with autosomal dominant inheritance.
... 71) were the first to show dependence of the frequency of virus-induced events on the ... Dif... more ... 71) were the first to show dependence of the frequency of virus-induced events on the ... Differences in DNA restriction endonuclease cleavage patterns have been de-scribed for these ... Morphologic Changes Changes in cell morphology after viral infection are first observed in the ...
... 1 15 Page 14. Chun ef nl. mucopolysaccharidoses (Ken yon ef d., 1972; Franqois, 1974; Kenyon,... more ... 1 15 Page 14. Chun ef nl. mucopolysaccharidoses (Ken yon ef d., 1972; Franqois, 1974; Kenyon, 1976). ... Descemet's membrane has been reported as 'always normal' in any type of systemic mucopolysaccharidosis, including Hurler syndrome (Franqois, 1974; Klintworth, 1982). ...
As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino ac... more As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino acids in humans) and remarkably well-conserved in mammalian evolution. They are synthesized prominently, but not exclusively, in the liver. Fragments of SAA can associate into insoluble fibrils (called "amyloid") characteristic of "secondary" amyloid disease in which they can interrupt normal physiology and lead to organ failure. SAA proteins comprise a family of molecules, two members of which (SAA1 and SAA2) are (along with C-reactive protein, CRP) the most prominent members of the acute phase response (APR) during which their serum levels rise dramatically after trauma, infection and other stimuli. Biologic function (s) of SAA are unresolved but features are consistent with a prominent role in primordial host defense (including the APR ). SAA proteins are lipophilic and contribute to high density lipoproteins (HDL) and cholesterol transport. SAA proteins interact with specific receptors and have been implicated in tissue remodeling through metalloproteinases, local tissue changes in atherosclerosis, cancer metastasis, lung inflammation, maternal-fetal health and intestinal physiology. Molecular details of some of these are emerging.
Glycogen storage diseases (GSDs) comprise a group of rare inherited disorders caused by dysfuncti... more Glycogen storage diseases (GSDs) comprise a group of rare inherited disorders caused by dysfunction of the synthesis or degradation of glycogen. Manifestations of GSDs are largely related to their direct effects on liver and/or muscle metabolism. The medical consequences of GSDs directly relate to glycogen's central role in glucose homeostasis. Analyzing this group of disorders has identified most of the enzymes directly related to glycogen metabolism. Recognizing the presence and consequences of GSD is the basis for rational treatment of affected individuals.
Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated ve... more Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.
... HCSMA in Brittany spaniels provides an excellent example of the details that can be establish... more ... HCSMA in Brittany spaniels provides an excellent example of the details that can be established (Cork et al., 1979) by thorough study. ... Nat. Genet. 7, 246-339. Hedhammer,/~., Olsson, S.-E., Andersson, S.-/~. Persson, L., Pettersson, L., Olausson, A., and Sundgren, P.-E. (1979). ...
In situ hybridization was used to demonstrate serum amyloid A (SAA) gene expression in arthritic ... more In situ hybridization was used to demonstrate serum amyloid A (SAA) gene expression in arthritic joint tissue from lentivirus-infected sheep and goats. SAA gene transcription occurs in isolated individual synovial cells and occasional giant cells but not in uninfected or uninflamed synovial tissue. These findings support the notion (derived from in vitro observations) that at least one member of the SAA gene/protein family may function as an autocrine collagenase inducer in inflammatory arthritis. Since we used heterologous DNA probes derived from human clones, our findings also support the growing evidence for interspecies conservation of SAA genes.
Hyperphosphatasia is a heterogeneous group of disorders characterized by a generalized skeletal d... more Hyperphosphatasia is a heterogeneous group of disorders characterized by a generalized skeletal disease and increased alkaline phosphatase. Increased bone remodeling secondary to increased osteoclastic activity appears to be the underlying feature of these disorders. These disorders include juvenile Paget's disease, expansile skeletal hyperphosphatasia, hyperostosis generalisata with striations, and Camurati-Engelmann's disease, type II. The genetic mutations for a number of these disorders have been identified. We present a patient with congenital hyperphosphatasia whose clinical and radiographic features were somewhat different from these other well-defined syndromes. The patient was followed for 45 years until his death of at age 49. The patient had massive osteoectasia with dense striations involving the entire shaft of his long bones. His spine, pelvis, short tubular bones, and calvarium were also involved. He suffered hearing loss and optic atrophy, but he kept his teeth throughout his life. He was tall with a marfanoid habitus, and he had hypogonadism and hypothyroidism. There was no evidence of mental retardation, and other laboratory studies where within normal limits. This case, as well as other manifestations of hyperphosphatasia, attests to the complexity of the bone remodeling system.
The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated i... more The relationship between abnormal color vision and adrenomyeloneuropathy (AMN) was investigated in 27 AMN patients and 31 age-matched controls by using the Farnsworth-Munsell 100 Hue test. Twelve (44%) of 27 patients showed test scores significantly above normal. The axes of bipolarity determined by the testing differed widely between the patients with abnormal scores, compatible with the notion that different alterations in visual pigment genes occur in different AMN kindreds. These observations confirm our earlier impression that the frequency of abnormal color vision is increased in these kindreds, and it supports our contentions that (1) AMN (and its companion, adrenoleukodystrophy) are very closely linked to the visual pigment loci at Xq28 and (2) this proximity might provide the opportunity to observe contiguous gene defects.
Abstract Nine lines of doubly cloned Simian Virus 40 transformed human fibroblasts have been isol... more Abstract Nine lines of doubly cloned Simian Virus 40 transformed human fibroblasts have been isolated. Precrisis in vitro characteristics of growth rate, saturation density, T antigen expression, growth in methylcellulose suspension, protease production and infectious center formation were widely divergent, although distinct for individual lines. Lines with higher T antigen expression had higher growth rates and saturation densities but grew less well in methylcellulose. Chromosome counts in most proliferating lines were in the 38–48 range; one line had 67, whereas another, poorly growing line showed 22. No distinguishing chromosomal abnormalities were present. This biologic heterogeneity suggests distinct molecular differences underlying transformation in the lines and emphasizes the importance of considering various factors as indicative of the transformed state.
The nucleic acid of an SV-lO-like virus isolated from a patient with progressive multifocal leuko... more The nucleic acid of an SV-lO-like virus isolated from a patient with progressive multifocal leukoencephalopathy has been compared with t.he DNA of a laboratory strain of SV40. DNA of this isolate (designated PML-2) is a covalently closed circular duplex with the same sedimentation rate as SV40 DNA. Denatured PML-2 DNA hybridizes with denatured SV40 DNA at about the same rate as homologous DNA. When digested with Hemophilus i?r,flue?zzae restriction endonuclease, PML-2 DNA yielded 11 fragments separable by electrophoresis, nine of which co-migrated with fragments of SV40 DNA, and two of which did not. We conclude that the PML-2 virus is avariant of SV40.
Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy show... more Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy shows common features. Migratory thrombophlebitis occurred in 96 patients while at least a single episode of thrombophlebitis was noted in 113. Seventy-five of the patients bled and 45 had arterial emboli in various organs. Twelve patients had the triad of thrombophlebitis, hemorrhage, and arterial emboli, often sequentially. Hematologic data showed derangements associated with intravascular coagulation, the most prominent of which were hypofibrinogenemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen-fibrin degradation products, decreased levels of factors V and VIII, cryofibrinogenemia, and microangiopathic hemolytic anemia. Forty-one patients had lesions of non-bacterial thrombotic endocarditis at autopsy; 31 of these had arterial emboli during life. None of the lesions were infected. Mitral and aortic valves were most frequently involved. No single mechanism that causes the disseminated intravascular coagulopathy has been identified. However, cell products--secretions and enzymes--and the cells themselves have been proposed as the procoagulant(s) responsible for the syndrome. In addition to treatment of the underlying neoplasm, symptomatic disseminated intravascular coagulopathy should be controlled. Heparin is the drug of choice for treatment of this problem, very little benefit having been observed with warfarin therapy. Long-term use of anticoagulants is potentially feasible for control of chronic disseminated intravascular coagulopathy, but without effective control of the underlying tumor ultimately will be unsuccessful.
A physical map of the Simian virus 40 genome has been constructed on the basis of specific cleava... more A physical map of the Simian virus 40 genome has been constructed on the basis of specific cleavage of Simian virus 40 DNA by bacterial restriction endonucleases. The 11 fragments produced by enzyme from Hemophilus influenzae have been ordered by analysis of partial digest products and by analysis of an overlapping set of fragments produced by enzyme from Hemophilus parainfluenzae. In addition, the single site in SV40 DNA cleaved by the Escherichia coli RI restriction endonuclease has been located. With this site as a reference point, the H. influenzae cleavage sites and the H. parainfluenzae cleavage sites have been localized on the map.
All amyloid comprises fibrillar polymers of tightly associated protein monomers. Central to the f... more All amyloid comprises fibrillar polymers of tightly associated protein monomers. Central to the fibril structure is a highly ordered β-pleated sheet domain although this interacting region may only be a relatively short stretch of each constituent polypeptide chain. Fibril formation begins as a nucleation event based either on the constituent monomer protein or its proteolytic fragment(s). The resulting fibrils are generally chemically inert and very stable.
A father and daughter with arthrogryposis multiplex congenita and similar dermatoglyphic patterns... more A father and daughter with arthrogryposis multiplex congenita and similar dermatoglyphic patterns are described. No evidence was found of chromosomal abnormality, neuropathy or myopathy, and there were no other affected family members. The findings are compatible with autosomal dominant inheritance.
... 71) were the first to show dependence of the frequency of virus-induced events on the ... Dif... more ... 71) were the first to show dependence of the frequency of virus-induced events on the ... Differences in DNA restriction endonuclease cleavage patterns have been de-scribed for these ... Morphologic Changes Changes in cell morphology after viral infection are first observed in the ...
... 1 15 Page 14. Chun ef nl. mucopolysaccharidoses (Ken yon ef d., 1972; Franqois, 1974; Kenyon,... more ... 1 15 Page 14. Chun ef nl. mucopolysaccharidoses (Ken yon ef d., 1972; Franqois, 1974; Kenyon, 1976). ... Descemet's membrane has been reported as 'always normal' in any type of systemic mucopolysaccharidosis, including Hurler syndrome (Franqois, 1974; Klintworth, 1982). ...
As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino ac... more As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino acids in humans) and remarkably well-conserved in mammalian evolution. They are synthesized prominently, but not exclusively, in the liver. Fragments of SAA can associate into insoluble fibrils (called "amyloid") characteristic of "secondary" amyloid disease in which they can interrupt normal physiology and lead to organ failure. SAA proteins comprise a family of molecules, two members of which (SAA1 and SAA2) are (along with C-reactive protein, CRP) the most prominent members of the acute phase response (APR) during which their serum levels rise dramatically after trauma, infection and other stimuli. Biologic function (s) of SAA are unresolved but features are consistent with a prominent role in primordial host defense (including the APR ). SAA proteins are lipophilic and contribute to high density lipoproteins (HDL) and cholesterol transport. SAA proteins interact with specific receptors and have been implicated in tissue remodeling through metalloproteinases, local tissue changes in atherosclerosis, cancer metastasis, lung inflammation, maternal-fetal health and intestinal physiology. Molecular details of some of these are emerging.
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Papers by George Sack