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S Malcolm

Publications and source records attributed to S Malcolm.

At least 73 records · Page 4Linked to original sources
PubMed1996

Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries.

The nature of the molecular lesions in the alpha-galactosidase A gene causing Fabry disease in 12 unrelated families from the United Kingdom and 4 from other European countries was determined in order to provide precise heterozygote detection and prenatal diagnosis for these families. The entire alpha-galactosidase A coding region and flanking intronic sequences were analyzed by amplification of genomic DNA and solid-phase direct sequencing or by SSCP analysis followed by solid-phase direct sequencing. Fourteen new mutations were identified including 10 missense mutations (M42V, R49S, C56Y, D92H, D93G, P205T, W236C, W287G, N298H, and W340R), 2 nonsense mutations (Q107X and Q119X) and 2 small deletions (257del18 and 1087del1). Together with the previously reported mutations, a total of 33 lesions in the alpha-galactosidase A gene have been identified in unrelated British families, further documenting the molecular genetic heterogeneity of this disease.

Fabry Disease↗
PubMed1996

Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus.

The causative relationship between several of the syndromic forms of craniosynostosis and mutations in the fibroblast growth factor receptor (FGFR) loci is now well established. However, within the group of patients with craniosynostosis, there are several families and sporadic cases whose clinical features differ in variable degrees from the classically described syndromes of craniosynostosis. In this communication we present novel FGFR2 mutations associated with a spectrum of craniosyostosis phenotypes in 4 sporadic cases and in one family in which craniosynostosis segregates. The mutation and phenotype data presented emphasise the clinical variability of mutations at this locus and underline the plasticity of the phenotype-genotype relationship in this important group of congenital malformation syndromes. Mutations found were tyrosine 105 to cysteine, glycine 338 to glutamic acid, serine 351 to cysteine and glycine 384 to arginine. These are the first reported mutations in the first immunoglobulin-like loop (tyrosine 105 to cysteine) and the transmembrane domain (glycine 384 to arginine) of FGFR2, providing further insights into the mechanism of abnormal receptor function in FGFR2 mutations.

Craniosynostoses↗
PubMed1995

Human minisatellite loci composed of interspersed GGA-GGT triplet repeats.

We have isolated two tandemly repeated loci from human DNA which contain long blocks of GGA and GGT trinucleotide repeats. These two repeat unit types, together with other less common variants, are apparently irregularly interspersed along each repeat array. Genotyping methods have been developed for these highly polymorphic loci, including typing by polymerase chain reaction followed by Southern blot hybridization. Linkage analysis in Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees has been used to map the loci to chromosomes 15 and 22. In normal individuals, alleles at these loci can contain thousands of repeats, greatly exceeding repeat copy number at most trinucleotide and other simple repeat loci. No evidence for longer, higher-order repeats was observed among the limited number of repeats sequenced. These loci may represent a transitional state between simple repeat loci and some minisatellites.

Animals↗
PubMed1995

Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4.

Deafness with fixation of the stapes (DFN3) is the most frequent X-linked form of hearing impairment. The underlying gene has been localized to a 500-kilobase segment of the Xq21 band. Here, it is reported that a candidate gene for this disorder, Brain 4 (POU3F4), which encodes a transcription factor with a POU domain, maps to the same interval. In five unrelated patients with DFN3 but not in 50 normal controls, small mutations were found that result in truncation of the predicted protein or in nonconservative amino acid substitutions. These findings indicate that POU3F4 mutations are a molecular cause of DFN3.

Amino Acid Sequence↗
PubMed1995

Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency.

We used specific mutation analysis to estimate the proportions of males and females with ornithine transcarbamylase (OTC) deficiency whose mutations occurred in the germ cells of one of the parents. The mutations were identified in the probands, and subsequently carrier testing was performed on their mothers and some of the grandmothers. Of 28 OTC deficient males, only 2 (7%) had sporadic mutations (95% CI, 0.6-18.5%), whereas of 15 OTC deficient females, 12 (80%) had sporadic mutations (95% CI, 63-99%) (P < 0.001). Based on these results we estimated the male/female mutation rate ratio (nu/mu) in the OTC gene to be approximately 52. Assuming a fitness for males with OTC deficiency of 0 and the proportion of new female mutants at 0.80, the estimated fitness of heterozygous females is 0.4. Because of the difference in mutation rates between male and female germ cells, we suggest that 9/10 or higher, rather than the conventional 2/3 proportion, be applied when estimating prior risk of carrier status in a mother of one affected male. The prior risk of a mother of an affected female is much lower, approximately 2/10.

DNA Mutational Analysis↗
PubMed1995

Investigation of the effect of coffee lipids on serum cholesterol in hamsters.

The effect of coffee total lipids (CTL), coffee non-saponifiable matter (NSM) and coffee diterpene alcohols (DTA) extracted from Coffea arabica beans on serum cholesterol in adult male Syrian hamsters was examined. The animals were fed either a commercial laboratory chow diet (study 1), containing 5% fat and low in saturated fat (1.46 g/100 g diet) and cholesterol (0.03 g/100 g diet) or a semi-synthetic diet (study 2) set in gelatine, containing 10% fat and high in saturated fat (4 g/100 g diet) and cholesterol (0.5 g/100 g diet). The coffee lipid extracts were dissolved in olive oil (concentration either 5 mg CTL, 0.5 mg NSM or 0.5 mg DTA per 250 microliters olive oil) in study 1 and in coconut oil (concentration either 20 mg CTL, 2 mg NSM or 2 mg DTA per 250 microliters) in study 2. A dose of 250 microliters of these solutions was administered daily to hamsters by gavage. Control animals received 250 microliters vehicle only. For serum lipid analysis, blood samples were obtained on days 0, 7 and 14 in study 1 and on days 0, 7, 14 and 21 in study 2. Statistical analyses of the data in Study 1 indicated a tendency for serum total cholesterol and high density lipoprotein-cholesterol to increase with administration of CTL, NSM and DTA. In contrast, in study 2 there were no significant differences in serum lipid levels between control and coffee lipid-treated groups across time. In either study, total serum cholesterol levels of the three coffee lipid groups were not significantly different from each other. These results support the concept that coffee lipids may be hypercholesterolaemic and indicate that diterpenes could be the lipid component responsible for such an effect. However, it appears that this hypercholesterolaemic effect is apparent only when the background diet is low in saturated fat and cholesterol. A high saturated fat/high cholesterol diet may mask the hypercholesterolaemic effect of coffee lipids.

Animals↗
PubMed1995

Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been identified in Crouzon syndrome, an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis). A mutation in FGFR1 has been established in several families with Pfeiffer syndrome, where craniosynostosis is associated with specific digital abnormalities. We now report point mutations in FGFR2 in seven sporadic Pfeiffer syndrome patients. Six of the seven Pfeiffer syndrome patients share two missense mutations, which have also been reported in Crouzon syndrome. The Crouzon and Pfeiffer phenotypes usually breed true within families and the finding of identical mutations in unrelated individuals giving different phenotypes is a highly unexpected observation.

Acrocephalosyndactylia↗
PubMed1995

A duplication/paracentric inversion associated with familial X-linked deafness (DFN3) suggests the presence of a regulatory element more than 400 kb upstream of the POU3F4 gene.

X-linked deafness with stapes fixation (DFN3) is caused by mutations in the POU3F4 gene at Xq21.1. By employing pulsed field gel electrophoresis (PFGE) we identified a chromosomal aberration in the DNA of a DFN3 patient who did not show alterations in the open reading frame (ORF) of POU3F4. Southern blot analysis indicated that a DNA segment of 150 kb, located 170 kb proximal to the POU3F4 gene, was duplicated. Fluorescence in situ hybridization (FISH) analysis, PFGE, and detailed Southern analysis revealed that this duplication is part of a more complex rearrangement including a paracentric inversion involving the Xq21.1 region, and presumably the Xq21.3 region. Since at least two DFN3-associated minideletions are situated proximal to the duplicated segment, the inversion most likely disconnects the POU3F4 gene from a regulatory element which is located at a distance of at least 400 kb upstream of the POU3F4 gene.

Blotting, Southern↗
PubMed1995

A case of Pelizaeus-Merzbacher disease showing increased dosage of the proteolipid protein gene.

Clinical, neuropathological and molecular genetic studies in a 9 month old boy with Pelizaeus-Merzbacher disease are described. The principal clinical features were developmental delay, nystagmus, stridor and seizures. Both brain and spinal cord showed almost complete absence of stainable central myelin, while cranial and spinal root myelin was preserved. Probes for cDNA in the boy and his asymptomatic mother indicated an increase in the dosage of proteolipid protein gene (of at least twofold) compared with controls.

DNA Probes↗
PubMed1995

Nonsyndromic cleft lip with or without cleft palate: evidence of linkage to BCL3 in 17 multigenerational families.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common craniofacial developmental defect. Recent segregation analyses have suggested that major genes play a role in the etiology of CL/P. Linkage to 22 candidate genes was tested in 11 multigenerational families with CL/P, and 21 of these candidates were excluded. APOC2, 19q13.1, which is linked to the proto-oncogene BCL3, gave suggestive evidence for linkage to CL/P. The study was expanded to include a total of 39 multigenerational CL/P families. Linkage was tested in all families, using an anonymous marker, D19S178, and intragenic markers in BCL3 and APOC2. Linkage was tested under two models, autosomal dominant with reduced penetrance and affecteds only. Homogeneity testing on the two-point data gave evidence of heterogeneity at APOC2 under the affecteds-only model. Both models showed evidence of heterogeneity, with 43% of families linked at zero recombination to BCL3 when marker data from BCL3 and APOC2 were included. A maximum multipoint LOD score of 7.00 at BCL3 was found among the 17 families that had posterior probabilities > = 50% in favor of linkage. The transmission disequilibrium test provided additional evidence for linkage with the 3 allele of BCL3 more often transmitted to affected children. These results suggest that BCL3, or a nearby gene, plays a role in the etiology of CL/P in some families.

B-Cell Lymphoma 3 Protein↗
PubMed1994

Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.

Crouzon syndrome is an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis) and maps to chromosome 10q25-q26. We now present evidence that mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome. We found SSCP variations in the B exon of FGFR2 in nine unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in three unrelated multigenerational families. In four sporadic cases, the normal parents did not have SSCP variation. Finally, direct sequencing has revealed specific mutations in the B exon in all nine sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in five patients.

Base Sequence↗
PubMed1994

A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome.

Pfeiffer syndrome (PS) is one of the classic autosomal dominant craniosynostosis syndromes with craniofacial anomalies and characteristic broad thumbs and big toes. We have previously mapped one of the genes for PS to the centromeric region of chromosome 8 by linkage analysis. Here we present evidence that mutations in the fibroblast growth factor receptor-1 (FGFR1) gene, which maps to 8p, cause one form of familial Pfeiffer syndrome. A C to G transversion in exon 5, predicting a proline to arginine substitution in the putative extracellular domain, was identified in all affected members of five unrelated PS families but not in any unaffected individuals. FGFR1 therefore becomes the third fibroblast growth factor receptor to be associated with an autosomal dominant skeletal disorder.

Abnormalities, Multiple↗
PubMed1994

Normative hematologic and serum biochemical values for adult and infant rhesus monkeys (Macaca mulatta) in a controlled laboratory environment.

During the conduct of a long-term toxicity/reproduction study using rhesus monkeys (Macaca mulatta), periodic hematologic and serum biochemical analyses were undertaken on blood obtained from 15 untreated (vehicle control) adult female monkeys over a period of 3 yr, 20 untreated adult males over a period of 6 yr, and 9 infants (5 male, 4 female, whose dams were the vehicle control females) from 12 wk through 2 yr of age. All samples were obtained by femoral puncture. To facilitate handling, ketamine hydrochloride (Ket.HCl) was administered to the males, and for some of the later infant samplings. Complete blood cell counts were performed using electronic cell counters, while reticulocyte counts and leukocyte differentials were assessed manually. The serum biochemistry analyses were performed with automated analyzers. These data were obtained as part of a health monitoring program, with medians and 2.5 to 97.5 percentiles for each parameter indicated. Some monitored parameters were found to be affected by the type of equipment used and by the use of Ket.HCl.

Aging↗