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M D Benson

Publications and source records attributed to M D Benson.

At least 19 recordsLinked to original sources
PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗
PubMed1992

Low cerebrospinal-fluid concentrations of soluble amyloid beta-protein precursor in hereditary Alzheimer's disease.

In Alzheimer's disease, deposits of amyloid beta-protein are apparently derived from intracellular processing of a large precursor protein. We have measured concentrations of this precursor in cerebrospinal fluid (CSF) from six members of a family affected by presenile Alzheimer's disease associated with a point mutation of the precursor gene. One gene carrier with clinical signs of the disorder had low CSF concentrations of the precursor, similar to those of three patients with sporadic Alzheimer's disease subsequently confirmed at necropsy. Two symptom-free gene carriers had CSF precursor concentrations similar to those of non-demented controls, though the value was lower in one, who had deficits revealed on neuropsychological testing, than in the other. These findings suggest that low concentrations of soluble amyloid precursor proteins in the CSF reflect the process that results in amyloid plaque formation and vascular deposition in Alzheimer's disease.

Adult↗
PubMed1992

Production and functional analysis of normal and variant recombinant human transthyretin proteins.

The most common form of hereditary systemic amyloidosis is familial amyloidotic polyneuropathy associated with single amino acid changes in the plasma protein, transthyretin. In addition, there are two variants of transthyretin (Ser6 and Thr109) not associated with familial amyloidotic polyneuropathy but with familial euthyroid hyperthyroxinemia, also an autosomal dominant disorder. In these autosomal dominant diseases, most affected individuals are heterozygous and therefore have hybrid forms of the tetrameric plasma transthyretin. In order to study the structure/function relationships of homozygous variant transthyretins, normal human transthyretin and five variant transthyretins (Gly6----Ser, Leu58----His, Thr60----Ala, Ile84----Ser, and Ala109----Thr) were produced in Escherichia coli using the expression vector, pCZ11, and site-directed mutagenesis. These recombinant transthyretin (r-TTR) proteins showed the correct size (14 kilodaltons) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western analysis and self-associated into tetramers as determined by size exclusion chromatography. Recombinant normal, Ser6, and Ala60 r-TTRs had an affinity for thyroxine indistinguishable from normal human TTR purified from plasma, whereas His58 and Ser84 r-TTRs had significantly reduced affinity. On the other hand, Thr109 r-TTR had a much higher affinity, probably due to its position within the thyroxine-binding pocket. Expression of mutant transthyretins in E. coli provides the opportunity to study structure/function relationships and amyloid-forming capabilities induced by single amino acid substitutions in the transthyretin molecule.

Amino Acid Sequence↗
PubMed1992

Alteration in molecular structure which results in disease: the Met-30 variant of human plasma transthyretin.

The structure of a variant transthyretin has been determined by X-ray crystallography at 2.3 A resolution in order to investigate those changes which lead to amyloid formation. This variant transthyretin, in which the internal valyl residue at position 30 is replaced by methionyl, is associated with the most common form of familial amyloidotic polyneuropathy (FAP). Comparison to the known structure of the normal transthyretin tetramer shows that the bulkier methionine residue 30 which lies between the nearly orthogonal beta sheets of the dimer, results in the sheets being displaced an average of 0.4 A. The internal structure of the sheets and of the monomer-monomer interface is maintained. Such global changes may affect the metabolic properties and the tendency towards polymerization of the mutant protein. These findings may form a basis for understanding other amyloid-deposition diseases.

Amino Acid Sequence↗
PubMed1992

Spectrum of amyloid beta-protein immunoreactivity in hereditary Alzheimer disease with a guanine to thymine missense change at position 1924 of the APP gene.

We studied neuropathologically 3 patients of a previously unreported kindred of presenile Alzheimer disease (AD), characterized by a G to T mutation at base pair 1924 (695 transcript) of the amyloid precursor protein gene. Classic features of presenile AD are observed. Neurofibrillary tangles with paired helical filaments as well as neuritic plaques are found in large number in neocortex and hippocampus. beta-Protein deposits in meningeal and parenchymal vessels are present, but not severe. Prominent subpial ribbon-like deposits are detected with antibodies to a 28-residue synthetic peptide; however, only occasionally can they be seen in thioflavin S treated sections. Along with a mild involvement of vessels, as demonstrated by beta-protein immunolabeling, parenchymal involvement is also seen in the cerebellar molecular layer. In the course of the study, we have not detected neuropathologic changes, which are mutation specific. Further investigations of familial Alzheimer disease with known genetic mutations will clarify whether correlations exist between specific mutations and neuropathologic phenotypes.

Adult↗
PubMed1992

A new mutant transthyretin (Arg 10) associated with familial amyloid polyneuropathy.

We report a new kindred with systemic amyloidosis presenting as peripheral neuropathy in the sixth and seventh decades of life. Polymorphism in exon 2 of the transthyretin (TTR) gene was suggested by single strand conformation polymorphism analysis and determined by direct DNA sequencing. We also developed restriction fragment length polymorphism analysis by polymerase chain reaction using a primer with an induced mutation. The point mutation (cytosine for thymine at position 1038 of the TTR gene) is responsible for substitution of arginine for cysteine at position 10 of the TTR molecule. It is hypothesised that the TTR molecules which have no cysteine have a unique structure in heterozygous TTR polymers and are responsible for amyloid fibril formation.

Aged↗
PubMed1992

In vivo metabolism of a mutant apolipoprotein, apoA-IIowa, associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis.

Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). A kindred has been identified in which a glycine to arginine mutation at residue 26 in apoA-I is associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis. We isolated the mutant protein, termed apoA-IIowa, from the plasma of an affected subject and studied its in vivo metabolism compared to that of normal apoA-I in two heterozygous apoA-IIowa subjects and two normal controls. Normal and mutant apoA-I were radioiodinated with 131I and 125I, respectively, reassociated with autologous plasma lipoproteins, and simultaneously injected into all subjects. Kinetic analysis of the plasma radioactivity curves demonstrated that the mutant apoA-IIowa was rapidly cleared from plasma (mean fractional catabolic rate [FCR] 0.559 day-1) compared with normal apoA-I (mean FCR 0.244 day-1) in all four subjects. The FCR of normal apoA-I was also substantially faster in the heterozygous apoA-IIowa subjects (mean FCR 0.281 days-1) than in the normal controls (mean FCR 0.203 days-1). Despite the rapid removal from plasma of apoA-IIowa, the cumulative urinary excretion of its associated radioactivity after 2 weeks (44%) of the injected dose) was substantially less than that associated with normal apoA-I (78% of injected dose), indicating extravascular sequestration of radiolabeled apoA-IIowa.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.

Alzheimer's disease is a form of localized amyloidosis characterized by cerebral cortical amyloid plaques, neurofibrillary tangles, and amyloid deposits within the walls of leptomeningeal vessels. Although most cases of Alzheimer's disease are sporadic, kindreds with autosomal-dominant inheritance of the syndrome suggest that a single mutation may be important in pathogenesis. Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein. This mutation correlates with the presence of Alzheimer's disease in all patients in this study, and may be the inherited factor causing both amyloid fibril formation and dementia.

Alzheimer Disease↗
PubMed1991

Preparation and crystallization of human transthyretin (prealbumin) variants.

Naturally occurring variants of human serum transthyretin (prealbumin) have been prepared by recombinant DNA methods and crystallized from ammonium sulfate solutions to give crystals suitable for x-ray crystallographic analysis. Included are variants which are known to be associated with familial amyloidotic polyneuropathy. Dyes which have been used as histochemical stains to identify amyloid tissue deposits: Congo Red, Methylene Blue and Bromophenol Blue, have been co-crystallized with the transthyretin variants. Congo Red was found to be very selective while Methylene Blue actually assisted in the formation of crystals. All crystal forms which were examined were isomorphous to the structure of normal transthyretin.

Base Sequence↗
PubMed1991

Biochemical and clinical characterization of prealbuminCHICAGO: an apparently benign variant of serum prealbumin (transthyretin) discovered with high-resolution two-dimensional electrophoresis.

We report identification, biochemical, clinical, and genetic studies of an apparently benign, electrophoretic variant of serum prealbumin (PALB, transthyretin, TTR) in a North American kindred of Swedish ancestry. The variant polypeptide stems from a C to T point mutation in exon 4 which results in methionine instead of threonine at position 119 of the mature molecule. It was discovered incidentally in a girl with classic alpha-1-anti-trypsin (A1AT) deficiency and her father during diagnostic A1AT phenotyping by ISO-DALT high-resolution two-dimensional electrophoresis (2DE). Twelve relatives in the four-generation paternal kindred, including five individuals who were heterozygous for the variant prealbumin, were studied. In each of these five heterozygotes, the variant allele product was equimolar and isoelectric with the normal protein, yet migrated with an apparently lower mass in the SDS-PAGE dimension. The inheritance pattern was consistent with autosomal dominant transmission. Histories and physical examinations showed no evidence of amyloidosis, as has been observed with other variants of prealbumin. Mean values of serum prealbumin and retinol binding protein levels were higher in the carriers as compared to the normal relatives in the family, but the difference was not statistically significant. Thyroid hormone levels and distribution of thyroxine and triiodothyronine among binding proteins in serum were within reference limits. Four members of the lineage had dominant, scalp-restricted keratinaceous cysts, yet only three of these four individuals had the variant. We counseled the family that this is likely a benign variant with regard to amyloidosis-related morbidity or shortened life span, although senile effects cannot be entirely ruled out. The provisional designation assigned to this allele is PALBCHICAGO. The substitution of methionine at position 119, as predicted by the DNA sequence, was confirmed by amino acid sequencing of CNBr and tryptic peptides. This substitution occurs at a CpG dinucleotide that may be a point mutational "hot spot," as has been postulated for the methionine-30 and isoleucine-122 PALB variants. The apparently lower mass of the variant probably results from a more compact conformation in SDS. With the exception of histidine-58, a charge substitution, all other amyloidosis-related prealbumin variant polypeptides had normal mobility in the ISO-DALT 2DE system.

Adult↗
PubMed1991

Nonexpression of the human serum amyloid A three (SAA3) gene.

Serum amyloid A (SAA) is a major acute-phase plasma protein synthesized by the liver. In addition to the two major plasma isoforms described in humans (SAA1 and SAA2), a third form (SAA3) has been demonstrated in several other species and is distinguished by predominant extrahepatic expression. Two clones, Ch11g5-1-1 and HDg1-1, containing the human SAA3 gene are described in this report. The human SAA3 gene is comparable in organization to the SAA1 and SAA2 genes and shares with them 87% nucleotide identity in the region spanning exon 3 through exon 4. Sequences 5' to exon 3, however, are strikingly different from those in the SAA1 and SAA2 genes. For instance, the sequence deduced for amino acids 1-12 (exon 2) has only 25% identity with human SAA1 and SAA2; it most closely resembles that of rabbit SAA3 isolated from synovial fibroblast cultures (75% identity). Although rabbit SAA3 induces collagenase production in an autocrine fashion the human SAA3 gene is not expressed. This is shown by: (i) a single base insertion in the sequence corresponding to codon 31, (ii) the inability of a 918-bp fragment immediately upstream from SAA3 exon sequences to direct transcription of a chloramphenicol acetyltransferase reporter gene, and (iii) the absence of detectable human SAA3 in mRNA.

Amino Acid Sequence↗
PubMed1991

The primary structure of serum amyloid A protein in the rabbit: comparison with serum amyloid A proteins in other species.

Rabbit serum amyloid A (SAA) protein was isolated from acute-phase serum by ultracentrifugation, molecular seive chromatography, and ion-exchange chromatography. The complete amino acid sequence of the protein was established by sequence analysis of peptides derived from trypsin and Staphylococcus proteinase digestion of the protein. The molecule consisted of 104 amino acids and had an amino terminus that was blocked by pyrrolidonecarboxylic acid. Heterogeneity was not observed at any residue, which suggests that the material sequenced consisted of a single serum amyloid A species. The protein is highly homologous to serum amyloid A from humans and other animals, particularly in the middle portion of the molecule (positions 33 to 63), which suggests that this region may be important in its function. This highly conserved region may also contain the determinants for amyloid formation.

Amino Acid Sequence↗
PubMed1991

Senile cardiac amyloidosis associated with homozygosity for a transthyretin variant (ILE-122).

Senile cardiac amyloidosis, also known as senile systemic amyloidosis, is a sporadic disease of late onset but with increasing incidence with age. Recently it has been shown in one case that amyloid deposits contained a transthyretin variant with an isoleucine for valine substitution at position 122. A second case with the transthyretin isoleucine 122 variant is reported here. This individual, who died with restrictive cardiomyopathy, was found to be homozygous for this transthyretin variant and his son heterozygous for the variant. A brother of the propositus was also homozygous for the variant but died of a cerebral vascular accident without being evaluated for amyloidosis. These studies show genetic transmission of the isoleucine-122 transthyretin variant associated with this form of cardiac amyloidosis.

Aged↗
PubMed1990

Diagnosis of Maryland/German familial amyloidotic polyneuropathy using allele-specific, enzymatically amplified, genomic DNA.

Diagnoses of familial amyloidotic polyneuropathies have been traditionally based on attempts to distinguish clinical features and ancestry or geographic origin of cases. Most are associated with extracellular deposition of a variant prealbumin (also known as transthyretin). Recent molecular studies demonstrated eight distinct amyloid-associated point mutations in the prealbumin gene on the long arm of chromosome 18 that are associated with hereditary amyloidosis. These findings provide for means of diagnosis using recombinant DNA methods. In a family with the Maryland/German type of familial amyloidotic polyneuropathy, the proband and 2 of 5 at-risk offspring were diagnosed using the polymerase chain reaction. Allele-specific enzymatic amplification of genomic DNA demonstrated the histidine-58 variant prealbumin gene. This study confirms the point mutation of the prealbumin gene as a cause for this type of familial amyloidotic polyneuropathy. Preclinical diagnosis illustrates the potential for development of treatment strategies prior to disease onset.

Adult↗
PubMed1990

Familial amyloid polyneuropathy: alanine-for-threonine substitution in the transthyretin (prealbumin) molecule.

A previously reported family with amyloid polyneuropathy (FAP) was reinvestigated to determine the type of mutation in the transthyretin (prealbumin) molecule. Transthyretin was isolated from amyloid-laden myocardium and serum, and tryptic peptides were resolved by high-performance liquid chromatography. Amino acid sequencing of an anomalous peptide revealed an alanine-for-threonine substitution corresponding to position No. 60 of the transthyretin monomer. Detection of the FAP gene in asymptomatic carriers was accomplished by hybrid isoelectric focusing of transthyretin in the presence of dithiothreitol and high concentrations of urea, and by Southern blotting of Pvull-digested leukocyte deoxyribonucleic acid. This type of FAP was found to be identical to the previously described Appalachian amyloid. Patients with FAP and their asymptomatic gene-carrying offspring had significantly reduced levels of serum transthyretin and retinol-binding protein.

Adult↗