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Biomedical subjects

M Hultén

Publications and source records attributed to M Hultén.

At least 19 recordsLinked to original sources
PubMed2001

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.

Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. We review the literature on MECP2 mutations in Rett syndrome. This analysis has permitted us to produce a map of the recurrent mutations identified in this and previous studies. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, which is conserved among brain-specific regulatory factors.

Adolescent↗
PubMed2000

Mammalian meiotic telomeres: protein composition and redistribution in relation to nuclear pores.

Mammalian telomeres consist of TTAGGG repeats, telomeric repeat binding factor (TRF), and other proteins, resulting in a protective structure at chromosome ends. Although structure and function of the somatic telomeric complex has been elucidated in some detail, the protein composition of mammalian meiotic telomeres is undetermined. Here we show, by indirect immunofluorescence (IF), that the meiotic telomere complex is similar to its somatic counterpart and contains significant amounts of TRF1, TRF2, and hRap1, while tankyrase, a poly-(ADP-ribose)polymerase at somatic telomeres and nuclear pores, forms small signals at ends of human meiotic chromosome cores. Analysis of rodent spermatocytes reveals Trf1 at mouse, TRF2 at rat, and mammalian Rap1 at meiotic telomeres of both rodents. Moreover, we demonstrate that telomere repositioning during meiotic prophase occurs in sectors of the nuclear envelope that are distinct from nuclear pore-dense areas. The latter form during preleptotene/leptotene and are present during entire prophase I.

Animals↗
PubMed1998

Rapid and simple prenatal DNA diagnosis of Down's syndrome.

BACKGROUND: Prenatal diagnosis of chromosomal abnormality requires cytogenetic analysis of amniotic fetal cells. The necessary culture time delays diagnosis, is expensive, and requires substantial scientific expertise. In a masked prospective study, we investigated the feasibility of PCR amplification of chromosome 21 markers for the prenatal diagnosis of Down's syndrome. METHODS: The study population consisted of 2167 pregnant women, undergoing amniocentesis for prenatal diagnosis. In this cohort at least 1.5 mL amniotic fluid was available surplus to the requirements for traditional diagnostic methods. DNA was extracted from the surplus amniotic fluid and amplified in fluorescence-based PCR reactions, with three small-tandem-repeat markers located on chromosome 21. The products of the reactions were analysed on a DNA sequencer to identify the presence of two or three copies of chromosome 21. FINDINGS: In 2083 (97.4%) of 2139 samples of amniotic fluid that were not macroscopically blood-stained, two DNA markers gave an informative and correct result, identifying 2053 fetuses as normal and 30 as having trisomy 21 Down's syndrome (as confirmed by cytogenetic analysis). An extra marker was informative in 32 of 41 other clear samples. Thus a total of 99.6% informative results was achieved with these three markers. Macroscopically blood-stained samples (28 [1.3%]) were unsuitable for DNA testing. They gave a typical but non-informative result. There were no false-positive or false-negative results. INTERPRETATION: The PCR-based DNA diagnostic test has great potential for improved prenatal diagnosis of Down's syndrome, with the advantage that results may be available within a day.

Amniocentesis↗
PubMed1995

Southern analysis reveals a large deletion at the hypoxanthine phosphoribosyltransferase locus in a patient with Lesch-Nyhan syndrome.

Whole genomic hprt clones were used in Southern analysis to screen the integrity of the hprt gene in a family that includes a patient with HPRT enzyme deficiency causal to Lesch-Nyhan syndrome. A 5 kb DNA sequence deletion was found to have its endpoints in the first and third introns. The probes identified the carrier status of female family members, aided by an RFLP carried by the mother's normal X-chromosome.

Adult↗
PubMed1995

Molecular variation of the human elastin (ELN) gene in a normal human population.

DNA sequence diversity in the human elastin genomic region has been estimated by RFLP analysis in a normal human population. The proportion of polymorphic nucleotides and the degree of nucleotide diversity were 0.0034 and 0.0018 respectively. It is argued that the estimate of nucleotide diversity does not indicate strong purifying selection in the region. A total of 144 restriction sites were sampled in each of 80 independent chromosomes representing the screening of 58080 bp overall. Six main haplotypes were constructed; they represent at least 84% of the 80 chromosomes sampled. Analysis for linkage disequilibrium revealed two statistically significant comparisons out of 54 tests, approximately the proportion that would be statistically significant at the 5% level by chance. A higher order quadrigenic disequilibrium was detected. The relationship between the physical distance separating polymorphic restriction sites and linkage disequilibrium is discussed. The development of elastin haplotypes and knowledge of the pattern of linkage disequilibrium should aid the study of elastin related disease and human evolution.

Blotting, Southern↗
PubMed1995

ATP-dependent reorganization of human sperm nuclear chromatin.

Chromosomes in terminally differentiated mammalian spermatozoa are extensively condensed by protamines but a small proportion of histones remain. We examined the primary organization of somatic-type chromatin in lysolecithin-permeabilized human sperm nuclei and report that nucleosomes are closely packed with a periodicity of approximately 150 bp. Incubation of nuclei in the presence of exogenous Mg2+ and ATP induced chromatin reorganization leading to an increase in spacing of the nucleosomes to approximately 190 bp. This ATP-dependent chromatin rearrangement involved phosphorylation of both protamine and histone H2a. Increase in linker length between nucleosomes correlated with the phosphorylation of H2aX, the major H2a variant in human spermatozoa, predominantly at the C-terminal end. Chromatin reorganization was independent of detectable nuclear dispersion, which is an early chromosomal event in male pronuclear formation during fertilization.

Adenosine Triphosphate↗
PubMed1994

Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization.

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe developmental disorder observed in XX individuals with distal Xp segmental monosomy. The phenotype of this syndrome overlaps with that of both Aicardi (MIM 304050) and Goltz (MIM 305600) syndromes, two X-linked dominant, male-lethal disorders. Here we report the clinical, cytogenetic, and molecular characterization of 3 patients with this syndrome. Two of these patients are females with a terminal Xpter-p22.2 deletion. One of these 2 patients had an aborted fetus with anencephaly and the same chromosome abnormality. The third patient is an XX male with Xp/Yp exchange spanning the SRY gene which results in distal Xp monosomy. The extensive clinical variability observed in these patients and the results of the molecular analysis suggest that X-inactivation plays an important role in determining the phenotype of the MLS syndrome. We propose that the MLS, Aicardi, and Goltz syndromes are due to the involvement of the same gene(s), and that different patterns of X-inactivation are responsible for the phenotypic differences observed in these 3 disorders. However, we cannot rule out that each component of the MLS phenotype is caused by deletion of a different gene (a contiguous gene syndrome).

Abnormalities, Multiple↗
PubMed1994

Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis.

Mutations in the adenomatous polyposis coli (APC) gene are responsible for the disease familial adenomatous polyposis (FAP), a dominantly inherited predisposition to colorectal cancer. The most common extra-colonic manifestation is congenital hypertrophy of the retinal pigment epithelium (CHRPE), expressed in up to 90% of FAP kindreds. Chain-terminating APC mutations were characterised in 26 unrelated FAP patients. Results show that CHRPE expression is determined by the length of truncated protein product. CHRPE is therefore the first extracolonic manifestation of FAP to be shown to be under the control of the APC mutation site and should facilitate the detection of constitutional APC mutations in FAP kindreds.

Adenomatous Polyposis Coli↗
PubMed1994

Exclusion of an elastin gene (ELN) mutation as the cause of pseudoxanthoma elasticum (PXE) in one family.

An intragenic elastin Hinf I polymorphism has been used to study the inheritance of elastin alleles in a family considered to show recessive inheritance of pseudoxanthoma elasticum (PXE). The marker has proved informative, excluding the elastin gene as a cause of PXE in this family. In addition, whole genomic human elastin clones were used in Southern analysis to screen the family for gross elastin gene rearrangements, but none were detected.

Adolescent↗
PubMed1993

Screening practice for familial adenomatous polyposis: the potential for regional registers.

Existing screening practice for familial adenomatous polyposis (FAP) was evaluated in 47 families with FAP notified to the West Midlands Polyposis Register between February 1988 and July 1990. Of these 269 individuals, 107 were known to be affected and 162 were at 50 per cent prior risk of developing FAP; 35 decreased affected individuals from living generations were included in the analysis. Of 105 individuals in the at-risk group aged between 12 and 40 years, only 55 (52 per cent) were under follow-up by bowel examination. Thirty-seven affected individuals had developed colorectal carcinoma before diagnosis; the incidence was three of 51 (6 per cent) in those diagnosed through screening compared with 34 of 53 (64 per cent) in the unscreened group (P < 0.001). A total of 28 individuals (26 per cent of the FAP population) died from advanced colorectal carcinoma; all were from the unscreened population. In 22 (59 per cent) of the cases of colorectal carcinoma and 17 (61 per cent) of the deaths from advanced colorectal cancer there was a positive family history of FAP; these tumours were therefore potentially preventable through screening and prophylactic surgery. Since establishing the register the median age at diagnosis of the affected patients has been reduced from 32 to 23 years (P = 0.0004) and the incidence of colorectal cancer has fallen from 35 to 14 per cent (P < 0.05). It is concluded that by providing more comprehensive case ascertainment a regional register can have a dramatic effect on this largely preventable form of colorectal cancer. Regional registers are recommended as an essential component of screening for this disease.

Adenomatous Polyposis Coli↗
PubMed1993

Chromosome complements in 695 sperm from three men heterozygous for reciprocal translocations, and a review of the literature.

Sperm chromosome complements were analysed in three men heterozygous for reciprocal translocations. A total of 695 sperm were karyotyped after in vitro penetration of hamster oocytes: 275 sperm from t(7;20)(q33.2;p13), 268 from t(3;11)(q25.3;q25) and 152 from t(15;22)(q26.1;q11.2). All possible 2:2 and 3:1 meiotic segregations were observed for all three translocations. The frequencies of alternate, adjacent 1, adjacent 2, and 3:1 segregations were 38%, 40%, 16%, and 5% for t(7;20); 48%, 46%, 6%, and 1% for t(3;11); and 34%, 40%, 22%, and 4% for t(15;22), respectively. Within the alternate segregation, the number of normal sperm was not significantly different from the number of sperm carrying a balanced form of the translocation for any of the translocations, as theoretically expected. The percentage of sperm with an unbalanced form of the translocation was 62% for t(7;20), 52% for t(3;11) and 66% for t(15;22). Sperm chromosome complements were observed in all three translocations that could be attributed to crossing-over in the interstitial segment, although nondisjunction at anaphase II could also account for the complements. There was no evidence for an interchromosomal effect in any of the translocations since the frequencies of numerical abnormalities unrelated to the translocation were within the normal range of control donors. Data from a total of 27 reciprocal translocations studied by sperm chromosomal analysis were reviewed.

Adult↗
PubMed1992

Predictive diagnosis of familial adenomatous polyposis with linked DNA markers: population based study.

OBJECTIVES: To evaluate the use of polymorphic DNA probes linked to the APC gene in the presymptomatic diagnosis of familial adenomatous polyposis. DESIGN: Four DNA probes were tested on an unselected population of patients at risk of familial adenomatous polyposis. SUBJECTS: The first 47 families notified to the West Midlands familial adenomatous polyposis register. Plus five families sent to our hospital as part of the West of Britain DNA consortium. MAIN OUTCOME MEASURES: The proportion of families and family members in whom DNA testing could be used to adjust the estimate of risk. RESULTS: Only 17 families on the register (containing 46% (74/162) of the population at risk) had a suitable pedigree structure for DNA analysis. DNA was analysed in 12 of these families plus the five families from the West of Britain consortium. At least one probe was informative in 27 of the 33 subjects born with 50% risk, but the most informative probe (pi 227) was the one with the highest recombination rate (10%). Flanking markers were informative in only four of the 33 subjects. CONCLUSIONS: These findings confirm the potential for accurate predictive diagnosis of familial adenomatous polyposis with polymorphic DNA probes, but such an approach is currently limited to about one third of affected families. A combined approach to presymptomatic diagnosis, which includes DNA testing and indirect ophthalmoscopy, is advocated.

Adenomatous Polyposis Coli↗