Search PubMed⌕ Search

Biomedical subjects

S Malcolm

Publications and source records attributed to S Malcolm.

At least 145 records · Page 8Linked to original sources
PubMed1991

Arginine 109 to glutamine mutation in a girl with ornithine carbamoyl transferase deficiency.

We studied DNA from 29 families with at least one member with ornithine carbamoyl transferase (OCT) deficiency and have found a mutation in the TaqI site within exon 5 of the OCT gene in a female presenting at the age of 21 months. Hybridisation with site specific oligonucleotides shows that the mutation is a C to T substitution resulting in a glutamine for arginine substitution at amino acid 109.

Alleles↗
PubMed1991

Chromosome 15 uniparental disomy is not frequent in Angelman syndrome.

Genetic imprinting has been implicated in the etiology of two clinically distinct but cytogenetically indistinguishable disorders--Angelman syndrome (AS) and Prader-Willi syndrome (PWS). This hypothesis is derived from two lines of evidence. First, while the molecular extents of de novo cytogenetic deletions of chromosome 15q11q13 in AS and PWS patients are the same, the deletions originate from different parental chromosomes. In AS, the deletion occurs in the maternally inherited chromosome 15, while in PWS the deletion is found in the paternally inherited chromosome 15. The second line of evidence comes from the deletion of an abnormal parental contribution of 15q11q13 in PWS patients without a cytogenetic and molecular deletion. These patients have two maternal copies and no paternal copy of 15q11q13 (maternal uniparental disomy) instead of one copy from each parent. By qualitative hybridization with chromosome 15q11q13 specific DNA markers, we have now examined DNA samples from 10 AS patients (at least seven of which are familial cases) with no cytogenetic or molecular deletion of chromosome 15q11q13. Inheritance of one maternal copy and one paternal copy of 15q11q13 was observed in each family, suggesting that paternal uniparental disomy of 15q11q13 is not responsible for expression of the AS phenotype in these patients.

Abnormalities, Multiple↗
PubMed1990

Recent advances in the molecular analysis of inherited disease.

Many important human genes have been cloned during the last ten years. In some cases, using reverse genetic techniques [Orkin, S. H. (1986) Cell 47, 845-850], disease-causing genes have been isolated whose product was previously unknown. Important examples include the dystrophin protein which, when mutated, gives rise to either Duchenne or Becker muscular dystrophy [Koenig, M., Hoffman, E. P., Bertelson, C. J., Monaco, A. P., Feener, C. and Kunkel, L. M. (1987) Cell 50, 509-517; Monaco, A. P., Bertelson, C. J., Liechti-Gallati, S. & Kunkel, L. M. (1988) Genomics 2, 90-95; Koenig, M., Monaco, A. P. & Kunkel, L. M. (1988) Cell 53, 219-228] and the cystic fibrosis transmembrane conductance regulator (CFTR) [Riordan, J. R., Rommens, J. M., Kerem, B.-S., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.-L., Drumm, M. L., Ianuzzi, M. C., Collins, F. S. & Tsui, L.-C. (1989) Science 245, 1066-1073]. Recently the technology for systematically detecting single base-pair changes by chemical methods, enzymatic methods or direct DNA sequencing has greatly expanded and simplified. In addition to providing structural information about these clinically important genes and information on disease-causing mutations, these studies have led to an increased understanding of mechanisms of mutation, to the discovery of novel genetic mechanisms and to important clinical applications of carrier detection and pre-natal diagnosis. The recent rapid progress has been made possible by the development of DNA amplification using the polymerase chain reaction (pcr) invented by Saiki and colleagues [Saiki, R. K., Chang, C-A., Levenson, C. H., Warren, T. C., Boehm, C. D., Kazazian, H. H. & Ehrlich, H. A. (1988) N. Engl. J. Med. 319, 537-541].

Chromosome Aberrations↗
PubMed1990

RFLP and deletion analysis for X-linked chronic granulomatous disease using the cDNA probe: potential for improved prenatal diagnosis and carrier determination.

The molecular basis of X-linked chronic granulomatous disease (X-CGD) has recently been elucidated and the defective gene identified and isolated. Two restriction fragment-length polymorphisms have been identified using the X-CGD cDNA probe. We have analyzed eight families with X-CGD and seven normal, unrelated females and have demonstrated that these polymorphisms are not in linkage disequilibrium. This should increase to approximately 50% the proportion of families to whom first-trimester prenatal diagnosis can be offered. Unambiguous determination of carrier status in related females in informative families will also be possible. In addition, we have identified an apparently unique small deletion in the X-CGD gene in a family affected by this disease, members of which are not informative for either polymorphism. This will allow prenatal diagnosis and carrier determination in this family.

Chromosome Deletion↗
PubMed1990

Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse.

Two experiments have been conducted to determine the effects of calorie restriction on cellular proliferation in female mouse tissues. In the first experiment, 25% calorie restriction led to a decrease in cellular proliferation, measured by the [3H]thymidine labeling index, in each of the 7 tissues examined. The duct lining cells of the mammary gland were the most affected. This conclusion was confirmed in the second experiment in which levels of 0, 10, 20, 30 and 40% calorie restriction were employed. The difference in response of the duct cells of the mammary gland and the crypt cells of the colo-rectum is discussed in light of the opinion that the formation of cancer of these tissues in humans may be markedly affected by diet.

Analysis of Variance↗
PubMed1990

The major cystic fibrosis mutation in a British population.

We have studied 72 families with at least one child with cystic fibrosis (CF); they were referred because they had requested prenatal diagnosis in a future pregnancy. The delta F508 mutation was found in 108/140 CF chromosomes (77%). In 41/72 families (57%), both parents carried a deleted chromosome and the child was doubly deleted. In only 4 families, 2 of them being consanguineous, did neither parent carry a deleted chromosome. Meconium ileus was associated with children who were delta F508/delta F508, delta F508/non-deleted and non-deleted/non-deleted.

Cystic Fibrosis↗
PubMed1990

Possible genetic heterogeneity in X linked hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia has been mapped to Xq11-q13 by linkage studies and by a translocation in a manifesting female. We report a family with hypohidrotic ectodermal dysplasia in which the disease did not segregate with this region of the X chromosome as expected. Ten DNA probes which are localised between Xp11 and Xq22 were used in the investigation. The difficulties in diagnosing the carrier state in this condition and the possibility of non-allelic heterogeneity are discussed.

Chromosome Mapping↗
PubMed1990

Linkage of hereditary motor and sensory neuropathy type I to the pericentromeric region of chromosome 17.

Vance et al. have reported linkage of hereditary motor and sensory neuropathy type I (HMSN I) to the pericentromeric region of chromosome 17. We have studied eight families with HMSN I (also called the hypertrophic form of Charcot-Marie-Tooth disease) for linkage of the disease locus to polymorphic loci in the centromeric region of chromosome 17. Linkage has been confirmed for D17S58 (EW301) with a maximum lod score of 5.89 at theta = 0.08 and for D17S71 (pA10-41) with a maximum lod score of 3.22 at theta = 0.08. EW301 is on 17p, 5.5 centimorgans from the centromere. Two families, previously reported as being linked to the Duffy blood group locus on chromosome 1, were included in this study, and one now provides positive lod scores for chromosome 17 markers. There was no evidence of heterogeneity.

Charcot-Marie-Tooth Disease↗
PubMed1990

The use of locus-specific minisatellite probes to check engraftment following allogeneic bone marrow transplantation for severe combined immunodeficiency disease.

The graft status of 14 patients, 13 of whom had received an allogeneic bone marrow transplant (BMT) for severe combined immunodeficiency disease (SCID) and one patient with SCID in whom intrauterine maternal engraftment was suspected, was examined using bone marrow or peripheral blood DNA and a combination of locus-specific minisatellite probes for the sex-matched and locus-specific and a Y specific probe for the sex-mismatched patients. The sensitivity of the assay systems was such that less than 0.1% recipient DNA was detectable in a background of donor DNA. Graft status could be satisfactorily documented by 2.5 weeks post-transplant and in one case was of particular value as immunological parameters were misleading. In the six long-term survivors of allogeneic BMT for SCID, the use of the locus-specific probes showed total donor lymphoid and myeloid haemopoietic engraftment in five cases and mixed host/donor populations in one case. The diagnosis in approximately 10% of cases of SCID may prove difficult due to engraftment of the fetus by maternal cells. Diagnosis may be facilitated by the use of the locus specific minisatellite probes and indeed we found specific evidence for such maternal engraftment in one patient at presentation. The combination of these probes together with a Y specific probe thus provides a rapid and accurate method of assessing graft take following allogeneic BMT for SCID. The simple pattern of inheritance obtained and the high level of sensitivity of detection of low numbers of allogeneic cells make the techniques amenable for use in any routine DNA diagnostic laboratory.

Bone Marrow Transplantation↗
PubMed1989

Rapid sexing of human embryos by non-radioactive in situ hybridization: potential for preimplantation diagnosis of X-linked disorders.

Sixty spare human embryos at various stages of preimplantation development were prepared for cytogenetic analysis. Fluorescent staining of those with metaphases allowed scoring for the presence of a Y chromosome. In situ hybridization was then performed using a biotinylated Y-specific sequence, and the probe was detected by a standard streptavidin-linked alkaline phosphatase system. This enabled comparison of the chromosomal sex with that obtained after in situ hybridization in 28 embryos, and the sexing result obtained by the two methods was concordant in all cases. A further 21 embryos in which no metaphase chromosomes were obtained were sexed by biotinylated in situ hybridization only. Overall, 66 per cent of male interphase nuclei demonstrated a Y-specific hybridization signal. Results were obtained in under 24 h, which may permit the sexing of an embryo biopsied during cleavage and the transfer of sexed embryos at the blastocyst stage to the mother's uterus in the same cycle as oocytes are collected for in vitro fertilization.

Blastocyst↗
PubMed1989

Linkage of PGK1 to X-linked severe combined immunodeficiency (IMD4) allows predictive testing in families with no surviving male.

We present a linkage map of DNA probes around the X-linked severe combined immunodeficiency (IMD4) locus at Xq11-13. DXS159 and PGK1 show no cross-overs with the disease locus (Lod 3.01 at theta = 0.00). The order of loci is DXS1-DXS106-(DXS159-PGK1-IMD4)-DXS72 -DXYS1. Members of families whose carrier status has been established by X-inactivation patterns were included in the analysis. As the probe (pSPT/PGK), which is used for investigation of X-inactivation patterns, has been shown to be linked to the disease itself, it is possible to assign phase in mothers of sporadic cases who have been shown to be carriers, even when they have no surviving male offspring.

Blotting, Southern↗
PubMed1989

Absence of linkage of hereditary motor and sensory neuropathy type I to chromosome 1 markers.

Although one large family with hereditary motor and sensory neuropathy (HMSN) type I that showed linkage to the Duffy blood group (FY) on chromosome 1 has previously been reported, we have failed to find evidence for such linkage after examining 14 markers from chromosome 1 in 12 pedigrees. We have excluded linkage between HMSN I and FY up to theta = 0.15 (lod = -3.01) and also between HMSN I and markers flanking FY; amylase (AMY), polymorphic urinary mucin (PUM), serum amyloid protein (APCS), and alpha-spectrin (SPTA). We have excluded HMSN I from 70 cM around this linkage group. Other markers examined were MS1, oncogene L-myc (MYCL), beta-subunit of nerve growth factor (NGFB), oncogene N-ras (NRAS), glucocerebrosidase (GBA), apolipoprotein AII (APOA2), antithrombin III (AT3), renin (REN), and MS32. These cover both the long and the short arms of chromosome 1 in addition to the centromeric region and yielded no evidence of linkage to HMSN I. Two-point lod scores between these markers are also presented. It is possible that there are two or more loci for HMSN I and it will be necessary to obtain significant lod scores from individual families to resolve this issue. This is increasingly possible now that hypervariable genetic markers such as PUM are available.

Chromosome Mapping↗
PubMed1989

Absence of Y specific DNA sequences in two siblings with 46XX hermaphroditism.

We report two siblings with 46XX hermaphroditism in whom we were unable to show the presence of Y specific DNA sequences using the DNA probes Y-190, GMGY-7, pHY2.1, pDP34, and 27a. We conclude that an autosomal or X chromosome gene mutation is the most likely mechanism of inheritance in this family with 46XX hermaphroditism.

DNA↗
PubMed1989

Three infants having null acute lymphoblastic leukemia with chromosome rearrangements at 11q23: no involvement of a heritable fragile site in this band.

Three families are presented in which an infant with null acute lymphoblastic leukemia had a karyotype rearrangement involving a break at 11q23. Peripheral blood was obtained, where possible, from both parents and from the child during periods of remission. The blood was stimulated with phytohemagglutinin and cultured under conditions that enhance expression of heritable folate-sensitive fragile sites. In all individuals studied very low levels of fra(11)(q23.3) were observed. These levels were far below those recorded for expression of the heritable folate-sensitive site fra(11)(q23.3) but are comparable with expression of the common fragile site fra(11)(q23.3) under these conditions.

Chromosome Banding↗