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J R Yates

Publications and source records attributed to J R Yates.

At least 127 records · Page 7Linked to original sources
PubMed1996

Improved genetic mapping of X linked retinoschisis.

X linked retinoschisis (RS) causes poor vision in affected males owing to radial cystic changes at the macula. Genetic linkage analysis was carried out in 16 British families with X linked retinoschisis using markers from the Xp22 region. Linkage was confirmed between the RS locus and the markers DXS207 (lod score, Zmax = 17.9 at recombination fraction theta = 0.03; confidence interval for theta = 0.007-0.09), DXS1053 (Zmax = 18.0 at theta = 0.01, CI = 0.001-0.06), DXS43 (Zmax = 12.9 at theta = 0.03, CI = 0.004-0.09), DXS1195 (Zmax = 6.4 at theta = 0.00), DXS418 (Zmax = 8.2 at theta = 0.00), DXS999 (Zmax = 21.2 at theta = 0.01, CI = 0.001-0.05), DXS443 (Zmax = 14.2 at theta = 0.03, CI = 0.004-0.09), DXS365 (Zmax = 24.5 at theta = 0.008, CI = 0.001-0.04). Key recombinants placed RS between DXS43 distally and DXS999 proximally. Multipoint linkage analysis gave odds of 344:1 in favour of this location for RS and supported the map Xpter-(DXS207, DXS1053)-DXS43-1 cM-RS-1 cM-DXS999-DXS443-DXS365-DXS1052-Xcen.

Chromosome Mapping↗
PubMed1996

Loss of heterozygosity in tuberous sclerosis hamartomas.

We have previously described in tuberous sclerosis (TSC) hamartomas the phenomenon of loss of heterozygosity (LOH) for DNA markers in the region of both the TSC2 gene on chromosome 16p13.3 and the TSC1 gene on 9q34. We now describe the spectrum of LOH in 51 TSC hamartomas from 34 cases of TSC. DNA was extracted from leucocytes or normal paraffin embedded tissue, and from frozen paraffin embedded hamartoma tissue from the same patient. The samples were analysed for 11 markers spanning the TSC1 locus and nine markers spanning the TSC2 locus. Twenty-one of 51 hamartomas showed LOH (41%). There was significantly more LOH on 16p13.3, with 16 hamartomas showing LOH around TSC2, and five in the vicinity of TSC1. No hamartoma showed LOH for markers around both loci. All the areas of LOH on chromosome 9 were large, but the smallest region of overlap lay between the markers D9S149 and D9S114, providing independent evidence for the localisation of the TSC1 gene. These data show that LOH is a common finding in a wide range of hamartomas, affecting the same TSC locus in different lesions from the same patient but not affecting both loci. These data support the hypothesis that both the TSC genes act as tumour suppressors and that the manifestations of TSC in patients with germline TSC mutations rise from "second hit" somatic mutations inactivating the remaining normal copy of the TSC gene.

Angiomyolipoma↗
PubMed1996

A study of FRAXE in mentally retarded individuals referred for fragile X syndrome (FRAXA) testing in the United Kingdom.

The folate-sensitive fragile site FRAXE is located in proximal Xq28 of the human X chromosome and lies approximately 600 kb distal to the fragile X syndrome (FRAXA) fragile site at Xq27.3. The cytogenetic expression of FRAXE is thought to be associated with mental handicap, but this is usually mild compared to that of the more common fragile X syndrome that is associated with the expression of the FRAXA fragile site. The exact incidence of FRAXE mental retardation is uncertain. We describe here the results of a U.K. survey designed to assess the frequency of FRAXE in a population of individuals referred for fragile X syndrome testing and found to be negative for expansion events at the FRAXA locus. No FRAXE expansion events were found in 362 cytogenetically negative males studied, and one expansion event was identified in a sample of 534 males for whom cytogenetic analyses were either unrecorded or not performed. Further FRAXE expansion events were detected in two related females known to be cytogenetically positive for a fragile site in Xq27.3-28. To gain insight into the FRAXE phenotype, the clinical details of the identified FRAXE male plus three other FRAXE individuals identified through previous referrals for fragile X syndrome testing are presented. For the population studied, we conclude that FRAXE mental retardation is a relatively rare but significant form of mental retardation for which genetic diagnosis would be appropriate.

Base Sequence↗
PubMed1995

Mining genomes: correlating tandem mass spectra of modified and unmodified peptides to sequences in nucleotide databases.

The correlation of uninterpreted tandem mass spectra of modified and unmodified peptides, produced under low-energy (10-50 eV) collision conditions, with nucleotide sequences is demonstrated. In this method nucleotide databases are translated in six reading frames, and the resulting amino acid sequences are searched "on the fly" to identify and fit linear sequences to the fragmentation patterns observed in the tandem mass spectra of peptides. A cross-correlation function is then used to provide a measurement of similarity between the mass-to-charge ratios for the fragment ions predicted by amino acid sequences translated from the nucleotide database and the fragment ions observed in the tandem mass spectrum. In general, a difference greater than 0.1 between the normalized cross-correlation functions for the first- and second-ranked search results indicates a successful match between sequence and spectrum. Measurements of the deviation from maximum similarity employing the spectral reconstruction method are made. The search method employing nucleotide databases is also demonstrated on the spectra of phosphorylated peptides. Specific sites of modification are identified even though no specific information relevant to sites of modification is contained in the character-based sequence information of nucleotide databases.

Amino Acid Sequence↗
PubMed1995

Method to correlate tandem mass spectra of modified peptides to amino acid sequences in the protein database.

A method to correlate uninterpreted tandem mass spectra of modified peptides, produced under low-energy (10-50 eV) collision conditions, with amino acid sequences in a protein database has been developed. The fragmentation patterns observed in the tandem mass spectra of peptides containing covalent modifications is used to directly search and fit linear amino acid sequences in the database. Specific information relevant to sites of modification is not contained in the character-based sequence information of the databases. The search method considers each putative modification site as both modified and unmodified in one pass through the database and simultaneously considers up to three different sites of modification. The search method will identify the correct sequence if the tandem mass spectrum did not represent a modified peptide. This approach is demonstrated with peptides containing modifications such as S-carboxymethylated cysteine, oxidized methionine, phosphoserine, phosphothreonine, or phosphotyrosine. In addition, a scanning approach is used in which neutral loss scans are used to initiate the acquisition of product ion MS/MS spectra of doubly charged phosphorylated peptides during a single chromatographic run for data analysis with the database-searching algorithm. The approach described in this paper provides a convenient method to match the nascent tandem mass spectra of modified peptides to sequences in a protein database and thereby identify previously unknown sites of modification.

Algorithms↗
PubMed1995

Localization of the disulfide bond involved in post-translational processing of glycosylasparaginase and disrupted by a mutation in the Finnish-type aspartylglycosaminuria.

The heavy chain of human glycosylasparaginase (N4-(beta-N-acetylglucosaminyl)-L-asparaginase (EC 3.5.1.26)) has five cysteinyl residues (Cys-61, Cys-64, Cys-69, Cys-163, and Cys-179). A Cys-163 to serine substitution due to a point mutation in the glycosylasparaginase gene causes the most common disorder of glycoprotein degradation, the Finnish-type aspartylglycosaminuria. To localize the potential disulfide bonds, the isolated heavy chain of human leukocyte glycosylasparaginase was treated with the enzyme alpha-chymotrypsin, and the resulting peptides were separated by high performance liquid chromatography prior to and after reduction and S-carboxymethylation. The peptide containing the Cys-163 residue and the peptide to which it is connected with a disulfide were structurally characterized by mass spectrometry. The disulfide bond crucial for catalytic activity, subunit processing, and biological transport of glycosylasparaginase was located close to the carboxyl terminus of the heavy chain at positions 163 and 179.

Amino Acid Sequence↗
PubMed1995

Direct database searching with MALDI-PSD spectra of peptides.

The analysis of matrix-assisted laser desorption ionization post-source decay (MALDI-PSD) mass spectra of peptides by using the cross-correlation method for database searching is illustrated. MALDI-PSD mass spectra are shown to contain sufficient fragmentation information to uniquely identify the correct amino acid sequence from large protein databases (approximately 160,000 entries). A search employing the MALDI-PSD mass spectrum of a phosphorylated peptide that correctly identifies the amino acid sequence and the site of phosphorylation is also illustrated.

Amino Acid Sequence↗
PubMed1995

Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease.

The Emery-Dreifuss Muscular Dystrophy (EDMD) is an X-linked recessive muscular disorder characterized by early contractures of the elbows, Achilles tendons and postcervical muscles, slowly progressing muscle wasting and weakness and a cardiomyopathy characterized by conduction defects. Heart block is a frequent cause of death. Finding of mutations in one of the transcripts in the critical region in distal Xq28 led to the identification of the gene responsible for the disease. We now report the sequence of the gene which is 2100 bp long and the development of a set of primers to amplify and sequence the gene from patients' DNA. Eight unrelated X-linked familial cases were studied and they all carried different mutations, showing that lack of emerin in cardiac and skeletal muscle is the cause of the X-linked disease. No mutations were found in a family where the female carrier was affected nor in a sporadic case with a well established diagnosis of EDMD. Our findings suggest genetic heterogeneity of EDMD, and that at least two genes, the X-linked STA gene and one unidentified autosomal gene, are responsible for the disease.

Base Sequence↗
PubMed1995

Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism.

The locus for ocular albinism type 1 (OA1) has been assigned to the Xp22.3 region through both linkage and deletion mapping. The disorder was found to be genetically homogeneous, as all informative families showed convincing linkage data with markers on Xp22.3 and all identified deletions involved in the same region. The OA1 gene recently was cloned and several intragenic deletions were identified in affected individuals. We have characterized the genomic structure of the OA1 gene, which spans approximately 40 kb of genomic DNA and contains nine exons. A highly polymorphic dinucleotide repeat was identified in intron 1, that provides a useful tool for molecular diagnosis. Knowledge of the intron/exon boundaries allowed us to search for point mutations in patients' genomic DNA. All nine exons of the OA1 gene, as well as the 5' and 3' untranslated regions, were scanned for point mutations in PCR-amplified DNA from 60 OA1 patients. The mutations identified include: two frameshifts and a splice site mutation leading to truncated OA1 proteins; a deletion of a threonine codon at position 290; and four missense mutations,two of which involve amino acids located within putative transmembrane domains. Two of the mutations each occur in three apparently unrelated families, consistent with previous observations of a founder effect in OA1. Surprisingly, mutations were detected in only one-third of the patients (21 of 60) ascertained. We postulate that mutations not yet identified in either regulatory elements of the OA1 gene, or in other gene(s) located within the same chromosomal region, may be common cause of X-linked ocular albinism.

Albinism, Ocular↗
PubMed1995

Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1).

A young adult female with multiple exostoses, short stature, autism, mental retardation and 46,X,t(X;8)(p22.13;q22.1) is described. Although the clinical features and translocation breakpoints raise the possibility of a number of specific conditions, the constellation of problems is not consistent with any previously reported genetic syndrome. It is argued that her clinical disorder is likely due to the chromosomal abnormality and that further detailed molecular genetic investigation may shed light on the genetic basis to various components of her phenotype including the autism.

Abnormalities, Multiple↗
PubMed1995

Linkage detection under heterogeneity and the mixture problem.

Linkage analysis has contributed to the localization of many human disease genes. The presence of locus heterogeneity reduces statistical power and can prejudice the detection of linkage if the analysis assumes homogeneity. Nevertheless, mixed genetic models are not routinely used in gene searches. The null distribution of the test statistic is not uniquely defined. In this paper, a transformation is used to determine an approximate asymptotic distribution of the test statistic under a mixture model. The equivalent critical values of the test are computed and the performance of the test under various levels of heterogeneity and family size is investigated. For gene searches, we recommend the routine use of an admixture model with a critical lod score of 3.44.

Algorithms↗
PubMed1995

Severe microcephaly with normal intellectual development: the Nijmegen breakage syndrome.

A brother and sister are described with severe microcephaly of prenatal onset, normal intellectual and motor development, chromosomal breakage and cellular immunodeficiency, which is characteristic of the autosomal recessive condition, Nijmegen breakage syndrome. The proband was a girl who presented at 15 months, with normal developmental milestones and an extremely small head circumference of 36 cm. Twenty per cent of her lymphocytes showed spontaneous translocations involving chromosome 7p13, 7q35, 14q11, and 14q32. The lymphocytes also showed excessive x ray induced chromosome damage. She had T cell lymphopenia, but normal immunoglobulins, and a normal alpha fetoprotein. A brother was born shortly after her diagnosis was made. He also had extreme microcephaly of 28 cm, with similar spontaneous and x ray induced chromosomal breakage, and T cell lymphopenia. Neither child has clinical evidence of immunodeficiency. To test the hypothesis that Nijmegen breakage syndrome and ataxia telangiectasia are allelic disorders, haplotype analysis was carried out in the family using DNA markers spanning the AT locus on chromosome 11q22. The affected boy had a different haplotype from his affected sister. Thus in this family, the Nijmegen breakage syndrome is not allelic to the ataxia telangiectasia locus on chromosome 11q, and the two conditions are genetically distinct. The normal intellect in these children raises questions about normal brain development in the presence of severe microcephaly.

Ataxia Telangiectasia↗
PubMed1995

Infantile presentation of X linked retinoschisis.

Five infants who presented with nystagmus and/or strabismus were found to have bilateral highly elevated bullous retinoschisis involving the macula. Haemorrhage was present within the schisis cavity or the vitreous in four patients. The bullous retinoschisis eventually reattached spontaneously leaving pigment demarcation lines. A family history of X linked retinoschisis (XLRS) was known in two of the patients but in the other three subsequent investigation showed other male family members to be affected. It is important to recognise this uncommon presentation of XLRS so that the correct diagnosis is made and appropriate genetic counselling is given. Surgical treatment is not usually indicated and the visual prognosis is better than the initial appearance may suggest.

Electroretinography↗
PubMed1994

Invariant-cognate peptide exchange restores class II dimer stability in HLA-DM mutants.

Class II presentation mutants have mutations in the HLA-DMA or B genes and are defective in the presentation of whole exogenous Ags restricted by HLA-DR, -DQ, and -DP. The functional defect in Ag presentation is accompanied by an altered conformation of cell surface class II molecules and instability of extracted class II dimers in SDS-PAGE; the latter can be corrected by incubation of mutant cells in an acidic pH in the presence of cognate peptide. Here we investigated the basis for correction of class II dimer instability by acid/cognate peptide treatment and the extent to which this treatment corrects the class II conformational defect in DMB mutants. We found that an acidic pH generates peptide binding sites in class II molecules of DMB mutants by eluting invariant chain (li)-derived peptides from them. Cognate peptides can then bind to the empty binding sites of class II molecules in a pH-independent manner, which results in stabilization of class II dimers. Acid/peptide treatment also restores the DR polymorphic epitope recognized by mAb 7.3.19.1 but not the DR polymorphic epitope recognized by mAb 16.23; low pH gradually destroys the 16.23 epitope in nonmutant cells. Mutant 10.24.6, which has a mutation in the DRA coding region creating an extra glycosylation site, also has unstable DR dimers whose stability is restored by acid/peptide treatment. These results suggest that the primary phenotypic defect in both the DMB and 10.24.6 mutants is the abundance of li peptides and lack of cognate peptides bound to class II molecules.

Amino Acid Sequence↗
PubMed1994

A new human gene (DXS1357E) with ubiquitous expression, located in Xq28 adjacent to the adrenoleukodystrophy gene.

We have isolated a new human gene (DXS1357E; laboratory name: CDM) localized in Xq28. This gene is transcribed from the same CpG island as the adrenoleukodystrophy gene (ALD) and oriented in the opposite direction. It encodes a 1.5-kb transcript that exhibits ubiquitous expression and contains a single open reading frame. The 246 deduced amino acid sequence suggests the presence of membrane-associated segments and a weak similarity with the rod-like tail portion of heavy chain myosins from different species. The DXS1357E gene may be a candidate for one of the many diseases mapping to this region. A preliminary analysis did not show rearrangements of the gene in 19 independent patients with Emery-Dreifuss muscular dystrophy.

Adrenoleukodystrophy↗
PubMed1994

Second-trimester maternal serum screening using alpha-fetoprotein, human chorionic gonadotrophin, and unconjugated oestriol: experience of a regional programme.

Over a 2-year period from January 1991 to December 1992, second-trimester maternal serum screening for Down's syndrome using alpha-fetoprotein (alpha FP), human chorionic gonadotrophin (hCG), and unconjugated oestriol (uE3) was made available to five health districts in East Anglia, with a total population of 1.2 million. Amniocentesis was offered when the risk of Down's syndrome at term was 1:200 or greater. 25,359 singleton pregnancies were screened, representing an uptake of 77 per cent. The recall rate for the 24 per cent of women who had not had a dating scan prior to the test was 9.4 per cent compared with 3.9 per cent for those who had been scanned (P < 0.0005). Seventy-five per cent (36/48) of Down's syndrome pregnancies were detected for a false-positive rate of 4.0 per cent. Twenty-five out of 36 of detected Down's syndrome pregnancies were dated by scan prior to sampling, and in the 11 remaining cases, the dates were confirmed by scan after a high-risk result was obtained. The exclusion of uE3 from the screening protocol would have reduced the detection rate to 52 per cent (25/48) for the same false-positive rate. Eighty-five per cent of women identified at high risk accepted the offer of an amniocentesis. Other fetal abnormalities detected were trisomy 18 (3), trisomy 13 (2), 45,X (6), 69,XXX (5), other chromosome abnormalities (9), open neural tube defects (26), hydrocephalus (7), abdominal wall defects (4), and steroid sulphatase deficiency (6).

Adult↗