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J A Trofatter

Publications and source records attributed to J A Trofatter.

At least 19 recordsLinked to original sources
PubMed1992

New variant in exon 3 of the proteolipid protein (PLP) gene in a family with Pelizaeus-Merzbacher disease.

A C--greater than G transversion has been found in exon 3 of the PLP gene of affected males and their mother in a single sibship with Pelizaeus-merzbacher disease (PMD). The transversion should not result in an amino acid change in the protein but it does result in the loss of a HaeIII restriction endonuclease cleavage site. It is concordant with the disease in this family. One-hundred-ten unrelated X chromosomes are negative for this mutation. No other sequence defect was found in the PLP exons of the affected males. The cause of disease in this family remains unknown, but the association between this rare mutation and PMD is intriguing. The mutation can serve as a marker for following segregation of the PLP gene.

Base Sequence↗
PubMed1991

A new mutation in the proteolipid protein (PLP) gene in a German family with Pelizaeus-Merzbacher disease.

A C-to-T transition in exon 4 of the PLP gene was found in 2 affected males and two obligate carriers in a German family with Pelizaeus-Merzbacher disease. The mutation, which causes loss of an HphI site and changes amino acid 155 from threonine to isoleucine, was absent from 108 normal chromosomes. There are 5 concordances and 1 discrepancy between these results and those obtained by magnetic resonance imaging in this family.

Diffuse Cerebral Sclerosis of Schilder↗
PubMed1991

A highly polymorphic dinucleotide repeat on the proximal short arm of the human X chromosome: linkage mapping of the synapsin I/A-raf-1 genes.

A compound (AC)n repeat located 1,000 bp downstream from the human synapsin I gene and within the last intron of the A-raf-1 gene has been identified. DNA data-base comparisons of the sequences surrounding the repeat indicate that the synapsin I gene and the A-raf-1 gene lie immediately adjacent to each other, in opposite orientation. PCR amplification of this synapsin I/A-raf-1 associated repeat by using total genomic DNA from members of the 40 reference pedigree families of the Centre d'Etude du Polymorphisme Humaine showed it to be highly polymorphic, with a PIC value of .84 and a minimum of eight alleles. Because the synapsin I gene has been mapped previously to the short arm of the human X chromosome at Xp11.2, linkage analysis was performed with markers on the proximal short arm of the X chromosome. The most likely gene order is DXS7SYN/ARAF1TIMPDXS255DXS146, with a relative probability of 5 x 10(8) as compared with the next most likely order. This highly informative repeat should serve as a valuable marker for disease loci mapped to the Xp11 region.

Amino Acid Sequence↗
PubMed1990

Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene.

Hyperkalemic periodic paralysis (HYPP) is an autosomal dominant disorder characterized by episodes of muscle weakness due to depolarization of the muscle cell membrane associated with elevated serum potassium. Electrophysiological studies have implicated the adult muscle sodium channel. Here, portions of the adult muscle sodium channel alpha-subunit gene were cloned and mapped near the human growth hormone locus (GH1) on chromosome 17. In a large pedigree displaying HYPP with myotonia, these two loci showed tight linkage to the genetic defect with no recombinants detected. Thus, it is likely that the sodium channel alpha-subunit gene contains the HYPP mutation.

Adult↗
PubMed1990

Autosomal dominant retinitis pigmentosa: linkage to rhodopsin and evidence for genetic heterogeneity.

Retinitis pigmentosa (RP) is the most prevalent human retinopathy of genetic origin. Chromosomal locations for X-linked RP and autosomal dominant RP genes have recently been established. Multipoint analyses with ADRP and seven markers on the long arm of chromosome 3 demonstrate that the gene for rhodopsin, the pigment of the rod photoreceptors, cosegregates with the disease locus with a maximum lod score of approximately 19, implicating rhodopsin as a causative gene. Recent studies have indicated the presence of a point mutation at codon 23 in exon 1 of rhodopsin which results in the substitution of histidine for the highly conserved amino acid proline, suggesting that this mutation is a cause of rhodopsin-linked ADRP. This mutation is not present in the Irish pedigree in which ADRP has been mapped close to rhodopsin. Another mutation in the rhodopsin gene or in a gene closely linked to rhodopsin may be involved. Moreover, the gene in a second ADRP pedigree, with Type II late onset ADRP, does not segregate with chromosome 3q markers, indicating that nonallelic as well as perhaps allelic genetic heterogeneity exists in the autosomal dominant form of this disease.

Amino Acid Sequence↗
PubMed1989

Denaturing gradient gel analysis of single-base substitutions at a mouse adenine phosphoribosyltransferase splice acceptor site.

Denaturing gradient gel electrophoresis (DGGE) can detect single-base changes in DNA. We used site-directed mutagenesis to produce all six possible single-base substitutions at a splice acceptor consensus AG dinucleotide within the mouse adenine phosphoribosyltransferase (aprt) gene. Studies of mouse and Chinese hamster cell aprt indicate a high level of both spontaneous and induced mutations in this region. We systematically evaluated each of the six mutations by DGGE. Five of the six mutant sequences could be distinguished from wildtype by DGGE analysis of a 560-bp fragment containing the mutation. However, one mutant could not be distinguished from wild-type, and some of the mutant constructs could not be distinguished from each other. Analysis of DNA heteroduplexes consisting of wild-type and mutant strands or two different mutant strands enabled all mutant constructs to be distinguished from wild-type and from each other. The pairwise mixtures resulted in 24 different heteroduplexes, all of which were less stable than the parental homoduplexes. End labeling of DNA prior to heteroduplex formation and subsequent DGGE analysis enabled us to determine the relative destabilization caused by different types of single-base mismatches.

Adenine Phosphoribosyltransferase↗
PubMed1989

A genetic linkage map of the long arm of human chromosome 22.

We have used a recombinant phage library enriched for chromosome 22 sequences to isolate and characterize eight anonymous DNA probes detecting restriction fragment length polymorphisms on this autosome. These were used in conjunction with eight previously reported loci, including the genes BCR, IGLV, and PDGFB, four anonymous DNA markers, and the P1 blood group antigen, to construct a linkage map for chromosome 22. The linkage group is surprisingly large, spanning 97 cM on the long arm of the chromosome. There are no large gaps in the map; the largest intermarker interval is 14 cM. Unlike several other chromosomes, little overall difference was observed for sex-specific recombination rates on chromosome 22. The availability of a genetic map will facilitate investigation of chromosome 22 rearrangements in such disorders as cat eye syndrome and DiGeorge syndrome, deletions in acoustic neuroma and meningioma, and translocations in Ewing sarcoma. This defined set of linked markers will also permit testing chromosome 22 for the presence of particular disease genes by family studies and should immediately support more precise mapping and identification of flanking markers for NF2, the defective gene causing bilateral acoustic neurofibromatosis.

Chromosomes, Human, Pair 22↗
PubMed1989

Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant.

Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred.

Base Sequence↗
PubMed1988

Localization of the gene for X-linked nephrogenic diabetes insipidus to Xq28.

X-linked nephrogenic diabetes insipidus (NDI) was segregating in a large Indiana family. It was tested for linkage of the NDI gene to X-chromosome molecular markers. Maximum lod scores of 3.15 and 3.01 (theta = 0) obtained for the molecular markers F8A (F8C) and DXS15 (DX13) respectively, indicate that the NDI gene is located in Xq28. A lod score of 3.61 (theta = 0) was obtained with multipoint linkage analysis of F8A and DXS15.

Chromosome Mapping↗
PubMed1988

Genetic linkage studies in Alzheimer's disease families.

Alzheimer's disease is a devastating neurological disorder and the leading cause of dementia among the elderly. Recent studies have localized the gene for familial Alzheimer's disease to chromosome 21 in a series of early onset AD families (mean age of onset less than 60). Familial late onset AD (mean age of onset greater than 60) is a more common clinical form of the disorder. Thirteen families with multiply affected Alzheimer's disease family members were identified and sampled. Ten of these families were of the late onset Alzheimer's disease type. Simulation studies were used to evaluate the usefulness of these pedigrees in linkage studies in familial Alzheimer's disease. Linkage studies undertaken to test the localization of both early onset and late onset Alzheimer's disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimer's disease gene was localized. These findings suggest that more than one etiology may exist for familial Alzheimer's disease and indicate the need for continued screening of the genome in familial Alzheimer's disease families.

Alzheimer Disease↗
PubMed1988

Human monoamine oxidase gene (MAOA): chromosome position (Xp21-p11) and DNA polymorphism.

An essentially full-length cDNA clone for the human enzyme monoamine oxidase type A (MAO-A) has been used to determine the chromosomal location of a gene encoding it. This enzyme is important in the degradative metabolism of biogenic amines throughout the body and is located in the outer mitochondrial membrane of many cell types. Southern blot analysis of PstI-digested human DNA revealed multiple fragments that hybridized to this probe. Using rodent-human somatic cell hybrids containing all or part of the human X chromosome, we have mapped these fragments to the region Xp21-p11. A restriction fragment length polymorphism (RFLP) for this MAOA gene was identified and used to evaluate linkage distances between this locus and several other loci on Xp. The MAOA locus lies between DXS14 and OTC, about 29 cM from the former.

Alleles↗