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C Gosden

Publications and source records attributed to C Gosden.

At least 19 recordsLinked to original sources
PubMed1998

Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life.

In adult life, the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11betaHSD2) protects the mineralocorticoid receptor (MR) from glucocorticoid by inactivating cortisol to cortisone. 11betaHSD2 activity has been reported in human fetal tissues, where glucocorticoids may impair fetal growth yet are also required for normal fetal development. Using digoxigenin-labeled complementary ribonucleic acid (RNA) probes and an in-house 11betaHSD2 antiserum, we have analyzed the expression of 11betaHSD2, MR, and glucocorticoid receptor (GR) in human fetal tissues of gestational age 6-17 weeks (n=15). 11BetaHSD2 expression was absent at gestational age 6+ weeks, but was expressed in abundance in many fetal tissues between 8-12 weeks. At this time, 11betaHSD2 colocalized with GR messenger RNA (mRNA) expression in metanephros, gut, muscle, spinal cord and dorsal root ganglia, periderm, sex chords of testis, and adrenal. In particular within fetal kidney, intense expression of 11betaHSD2 and GR mRNA was observed over Bowman's capsule and the vascular tufts of developing glomeruli as they migrated from the surface of the kidney to the inner cortex. Only lung and adrenal medullary rests demonstrated high levels of GR mRNA but low levels of 11betaHSD2. 11BetaHSD2 mRNA and immunoreactivity staining patterns were similar, with the exception of the fetal adrenal, where mRNA was localized to the outer definitive zone but immunoreactivity was localized to the inner fetal zone. Colocalization of 11betaHSD2 (and GR mRNA) with MR mRNA was observed principally within epithelial cells of collecting ducts, particularly after 16 weeks gestation when the pattern of distribution of 11betaHSD2 became more adult in nature. High levels of MR mRNA were observed within developing bone. The data indicate that 11betaHSD2 in fetal life principally modulates ligand access to the GR in most fetal tissues, notably glomeruli and tubules in the developing kidney, testis, and periderm, and this may be have ramifications for fetal sodium homeostasis and differentiation. The development of tissues previously shown to have a critical requirement for glucocorticoids, such as lung and adrenal medulla, is facilitated by the expression of GR mRNA, but not 11betaHSD2. The expression of MR mRNA in high abundance in bone suggests a role for corticosteroids in human bone development, and the low/absent expression of 11betaHSD2 at this site suggests that it is functionally acting as a GR.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Seeding of YACs over regions 1q41-q42.3 and 11q14.3-q23 with microdissection clones.

We describe the use of pooled, region-specific hybridisation probes to screen high-density replica filters of a human genome YAC library. The probes were derived by microdissection of an approximately 30-Mbp region subtending the translocation breakpoint on a der(1)(1;11)(q42.1;q14.3) chromosome. Of 70 microdissection clones used in pools of 4-10, 47 identified a total of 77 YAC recombinants, representing over 50% of the microdissected region. This strategy can easily be adapted to other poorly mapped subchromosomal regions of the human or other mammalian genomes and will provide a solid framework for detailed contig map constructions.

Chromosomes, Artificial, Yeast↗
PubMed1994

Schizophrenia and mental retardation associated in a pedigree with retinitis pigmentosa and sensorineural deafness.

A family is presented with multiple cases of mild mental retardation, schizophrenia and other functional psychoses, progressive hearing loss, and retinitis pigmentosa (RP). It closely resembles a previously reported Finnish family. We suggest that the phenotypes are not associated in this family by chance, but define a novel syndrome which may be caused by a mutant allele at a single genetic locus.

Adolescent↗
PubMed1993

Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.

The triad of nephropathy, partial gonadal dysgenesis and Wilms' tumour (WT) is known as Denys-Drash syndrome (DDS). The WT predisposition gene WT1, which plays a vital role in both genital and renal development, is known to be mutated in DDS patients. The WT1 mutations in these patients are constitutional point mutations clustered in the zinc finger (ZF) encoding exons, particularly the exons encoding ZF2 and ZF3. The predicted functional alteration in WT1 is thought to underlie DDS aetiology either by abolishing binding of the WT1 ZF domain to its normal target DNA binding site(s), perhaps blocking the binding of the wild type WT1 present (dominant negative mutation), and/or by conferring the ability to recognise novel but inappropriate DNA binding sites (dominant mutation). We report here on the analysis of WT1 in a further five cases of DDS. In each case a constitutional point mutation was detected in either ZF2 or ZF3. Three of these mutations are novel, with two affecting the conserved histidine and cysteine residues crucial for ZF tertiary structure. The protein product of the third is predicted to lack ZF2, 3 and 4 as a result of a chain termination mutation, and is presumably incapable of binding DNA. However since the DDS phenotype is only elicited by mutations which lead to loss or alteration of ZF function (presumably DNA binding) while the N-terminal upstream portion of the gene remains intact, we suggest that a dominant negative mechanism is at work here.

Amino Acid Sequence↗
PubMed1993

New syndrome with features overlapping the Baller-Gerold and Roberts syndromes.

A male fetus is described with multiple congenital abnormalities including craniosynostosis and bilateral radial aplasia. There are many similarities to the case recently reported by Imaizumi and Kuroki (Am J Med Genet 41: 162-163). These cases may represent a new syndrome with overlapping features of the Baller-Gerold and Roberts syndromes.

Abnormalities, Multiple↗
PubMed1993

Craniofrontonasal dysplasia in two male sibs.

Craniofrontonasal dysplasia (CFND) was diagnosed in a male child who had bilateral coronal craniosynostosis, midline facial clefting with cleft lip and palate, a broad and high forehead, and hypertelorism. The parents were normal and there was no family history suggestive of CFND. A small recurrence risk was counselled and prenatal ultrasound was recommended in the next pregnancy. At 23 weeks, the ultrasound scan detected a number of dysmorphic features and the pregnancy was terminated. Autopsy of the aborted male foetus showed the following features: High arched palate, a sloping forehead, flattened nose and receding chin, multiple joint contractures, particularly of the mid phalangeal joints, elbows and ankles. This report highlights the occurrence of CFND in two male siblings born to normal parents, and therefore the need to perform prenatal ultrasound in a subsequent pregnancy, even if CFND is diagnosed in an isolated case.

Abnormalities, Multiple↗
PubMed1992

Fetal renal defects: associated malformations and chromosomal defects.

During a 6-year period (1985-1990) blood karyotyping was performed in 682 fetuses with renal defects. There were: 276 fetuses with mild hydronephrosis; 206 with moderate/severe hydronephrosis; 173 with multicystic dysplasia, and 27 with renal agenesis. The overall incidence of chromosomal abnormalities was 12% (trisomies, n = 63; deletions, n = 9; triploidies, n = 5, and sex chromosome aneuploidies, n = 8). There were more than twice as many males than females, but the incidence of chromosomal defects in females was almost double (18%) than in males (10%). Furthermore, compared to the overall maternal age-related risk, the risk for fetal chromosomal abnormalities was three times higher when there was an isolated renal defect and thirty times higher when there were additional malformations. The risk of chromosomal abnormalities was similar for fetuses with unilateral or bilateral involvement, different types of renal defects, urethral or ureteric obstruction, and oligohydramnios or normal/reduced amniotic fluid volume. Nevertheless, the patterns of chromosomal abnormalities, and consequently that of associated malformations, were related to the different types of renal defects.

Abnormalities, Multiple↗
PubMed1992

Fetal gastro-intestinal and abdominal wall defects: associated malformations and chromosomal abnormalities.

During an 8-year period (1983-1991), blood karyotyping was performed in 235 fetuses with abdominal wall or gastro-intestinal tract defects. The overall incidence of chromosomal abnormalities was 29% (trisomy 21, n = 12; trisomy 18, n = 44; trisomy 13, n = 7; deletion of the short arm of chromosome 5, n = 1; unbalanced translocation involving chromosomes 4 and 15, n = 1; triploidy, n = 1; Klinefelter's syndrome, n = 1; and Beckwith-Wiedemann syndrome with mosaic duplication 11p15, n = 1). The karyotype was abnormal in 42 (36%) of the 116 fetuses with exomphalos, in none of the 26 with gastroschisis, in 10 (43%) of the 23 with duodenal atresia, in 18 (75%) of the 24 with lack of visible stomach, in 1 (4%) of the 24 with dilated bowel and in 2 (7%) of the 27 with echogenic hepatic nodules or abdominal cysts. Abnormal karyotypes were more commonly encountered when there was ultrasonographic evidence of multiple malformations (43%) compared to isolated defects (2%). Survival in fetuses with exomphalos (33%), absent stomach (4%), and large bowel obstruction (13%) was poor, whereas in those with gastroschisis (73%) or abdominal cysts (88%) survival was high; in small bowel obstruction and in duodenal atresia, survival was 65 and 57%, respectively.

Abdominal Muscles↗
PubMed1991

Fetal nuchal cystic hygromata: associated malformations and chromosomal defects.

During a 6-year period (1985-1990), blood karyotyping was performed in 44 fetuses with septated, bilateral, dorsal, cervical cystic hygromata. This condition constitutes a different entity from nuchal oedema. There were 33 (75%) chromosomal abnormalities, including Turner's syndrome (n = 31), trisomy 18 (n = 1) and trisomy 21 (n = 1). Congenital heart defects (CHD), mainly coarctation of the aorta, were present in 15 of the fetuses with Turner's and in 1 of the chromosomally normal fetuses. The incidence of CHD was higher in the fetuses with ultrasonographic evidence of moderate/severe hydrops (41%; 13 of 32 cases) than in those with mild or no hydrops (25%; 3 of 12 cases). Although both the biparietal diameter (BPD) and femur length (FL) were reduced in all fetuses, the FL to BPD ratio was below the 5th percentile in 29 of the 33 (88%) chromosomally abnormal fetuses, but in only 4 of the 11 (36%) chromosomally normal ones. In the chromosomally normal group, 3 of the fetuses had multiple pterygium syndromes, and in such cases the risk of recurrence may be high. In contrast, in the group of mutant chromosomal disorders with monosomy or trisomy, the risk of recurrence is in the order of 1%.

Chromosome Aberrations↗
PubMed1990

The candidate Wilms' tumour gene is involved in genitourinary development.

Wilms' tumour is an embryonic kidney tumour thought to arise through aberrant mesenchymal stem cell differentiation and to result from loss of function of a 'tumour suppressor' gene(s). Both sporadic and syndrome-associated Wilms' tumours are accompanied by an increased frequency of abnormalities of the urinary tract and genitalia. Deletional analysis of individuals with the WAGR syndrome (for, Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) showed that a Wilms' tumour gene lies at chromosomal position 11p13. This led to the isolation of a candidate Wilms' tumour gene, encoding a zinc-finger protein which is likely to be a transcription factor. To gain insight into the role of this candidate gene in normal development and tumorigenesis, we have now performed in situ messenger RNA hybridization on sections of human embryos and Wilms' tumours. The candidate Wilms' tumour gene is expressed specifically in the condensed mesenchyme, renal vesicle and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli and in cells approximating these structures in tumours. The other main sites of expression are the genital ridge, fetal gonad and mesothelium. These data suggest that (1) this candidate is indeed a Wilms' tumour gene, (2) the associated genital abnormalities are pleiotropic effects of mutation in the Wilms' tumour gene itself, in support of recent genetic analysis, and (3) this gene has a specific role in kidney development and a wider role in mesenchymal-epithelial transitions.

Blotting, Northern↗
PubMed1990

Association within a family of a balanced autosomal translocation with major mental illness.

282 pedigrees in the MRC Cytogenetics Registry, Edinburgh, with familial autosomal anomalies were examined for the presence of associated mental illness. In one large pedigree there were 23 cases of mental and/or behavioural disorders meeting Research Diagnostic Criteria. 34 of the 77 family members available for cytogenetic analysis carried a balanced translocation t(1:11) (q43,q21). Psychiatric diagnoses had been recorded for 16 of the 34 members with the translocation compared with only 5 of the 43 without it. The lod scores (against chance linkage of the translocation with mental illness) were greatest when the mental disorders in the phenotype were restricted to schizophrenia, schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. Although the mental illness in this family may not be typical of that in the general population, the findings suggest that the q21-22 region of chromosome 11 may be a promising area to examine for genes predisposing to major mental illness.

Adolescent↗
PubMed1990

A balanced chromosomal translocation partially co-segregating with psychotic illness in a family.

Psychotic illness was associated with an apparently balanced 6;11 chromosomal translocation in a three-generation family. The mother and son carrying the translocation suffer from a chronic psychotic illness, a daughter who was a translocation carrier committed suicide, and her twin daughters who both carry the translocation have not yet reached the age of risk for developing this psychiatric illness, although one has attempted suicide. Two older members of the family have the translocation and have never suffered from a psychiatric disorder. The pattern of dominant inheritance of the psychotic illness only occurring in individuals carrying the translocation suggests that there may be a major genetic component in the etiology of the psychosis in this family. Genes at the chromosomal break points may be candidate genes implicated in this particular form of psychotic illness.

Adult↗
PubMed1990

Fetal lateral cerebral ventriculomegaly: associated malformations and chromosomal defects.

In 267 consecutive cases of fetal lateral cerebral ventriculomegaly, additional fetal malformations were detected by ultrasonography in 209 (78%) of the cases. On the basis of the ultrasound findings, the patients were subdivided into three groups: (i) isolated ventriculomegaly (n = 58), (ii) ventriculomegaly and open spina bifida only (n = 172), and (iii) ventriculomegaly and other malformations (n = 37) with or without spina bifida. Antenatal karyotyping was performed in 64 cases from groups (i) and (iii), and 11 (18%) of the fetuses had chromosomal abnormalities. The incidence of chromosomal abnormalities was strongly related to the presence of multisystem malformations. Thus, only 3% of fetuses with isolated ventriculomegaly as opposed to 36% of those with additional malformations had chromosomal defects. Furthermore, the degree of ventriculomegaly in the chromosomally abnormal fetuses was relatively mild. In the chromosomally normal fetuses, mild, static ventriculomegaly was associated with apparently normal subsequent mental development.

Abnormalities, Multiple↗
PubMed1990

Fetal holoprosencephaly: associated malformations and chromosomal defects.

In 38 fetuses with holoprosencephaly, cordocentesis and blood karyotyping was performed. The karyotype was normal in all 12 cases with isolated holoprosencephaly, and in all 5 with holoprosencephaly and facial defects only. In contrast, 11 of the 21 (52%) fetuses with extrafacial malformations were chromosomally abnormal [47xx+13, n = 6; 47xy+13, n = 2; 47xx+18, n = 1; 46xx-18+i(18q), n = 1; 46xy 21q-, n = 1]. In the chromosomally normal group, there was parental consanguinity in 2 cases and recurrence of holoprosencephaly in 3.

Adult↗
PubMed1988

Fetal blood sampling in investigation of chromosome mosaicism in amniotic fluid cell culture.

41 pregnancies in which mosaicism had been found on amniotic fluid culture (AFC) were investigated by fetal blood and repeat AFC karyotyping. Results of both investigations, and the infants, were normal in 15 of 16 cases of autosomal trisomy (including trisomies 8, 9, 13, 18, and 21) and in the 8 cases of sex chromosome mosaicism. In 1 case of trisomy 20 mosaicism the fetal blood karyotype and the infant were normal but the repeat AFC showed mosaicism. Abnormality was confirmed in 5 of 11 cases of mosaicism for structural chromosomal rearrangements and in 4 of 6 cases with de-novo supernumerary marker mosaicism. These findings indicate the potential danger of terminating pregnancies because of trisomic mosaicism in AFC, and the importance of identifying the clinical significance of certain chromosome rearrangements which, even in mosaic form, might lead to severe mental and developmental handicap.

Adult↗
PubMed1988

Pleistocene dates for the human occupation of New Ireland, northern Melanesia.

Pleistocene dates from three cave sites indicate the human capacity to colonise across two oceanic straits to the east of a former Tasmania-Australia-New Guinea continent by 33 kyr BP. The sites demonstrate exploitation of costal marine and lowland tropical forest resources. They extend Pleistocene occupation into island Melanesia and demonstrate that the large islands of northern Melanesia have an antiquity of human occupation of the same order as the adjacent Greater Australian continent.

Animals↗