von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
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ADAM Proteins↗
Biomedical subjects
J A Goodship
Publications and source records attributed to J A Goodship.
Genetic studies into inherited and sporadic hemolytic uremic syndrome.
Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for factor H lies within the region. Subsequent mutation analysis of the factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of serum factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with factor H deficiency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.
Adult↗
Another case of maternal uniparental disomy chromosome 14 syndrome.
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Adult↗
Three new polymorphisms in the human complement factor H gene and promoter region.
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Complement Factor H↗
Absence of mutations in the regulatory domain of the gap junction protein connexin 43 in patients with visceroatrial heterotaxy.
OBJECTIVE: To determine the frequency of mutations in the regulatory domain of the gap junction protein connexin 43 in patients with visceroatrial heterotaxy. DESIGN: Mutation screening of the terminal 200 base pairs of connexin43 gene coding sequence in a series of patients from tertiary care centres. PATIENTS: 48 patients with visceroatrial heterotaxy attending UK Regional Paediatric Cardiology Centres. RESULTS: No changes from the published connexin43 consensus sequence were found in any of the 48 patients studied. CONCLUSIONS: Germline mutations of the phosphorylation sites in teh regulatory domain of the connexin43 gene are rare in patients with visceroatrial heterotaxy.
Base Sequence↗
Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study.
We present clinical data on 558 patients with deletions within the DiGeorge syndrome critical region of chromosome 22q11. Twenty-eight percent of the cases where parents had been tested had inherited deletions, with a marked excess of maternally inherited deletions (maternal 61, paternal 18). Eight percent of the patients had died, over half of these within a month of birth and the majority within 6 months. All but one of the deaths were the result of congenital heart disease. Clinically significant immunological problems were very uncommon. Nine percent of patients had cleft palate and 32% had velopharyngeal insufficiency, 60% of patients were hypocalcaemic, 75% of patients had cardiac problems, and 36% of patients who had abdominal ultrasound had a renal abnormality. Sixty-two percent of surviving patients were developmentally normal or had only mild learning problems. The majority of patients were constitutionally small, with 36% of patients below the 3rd centile for either height or weight parameters.
Adolescent↗
Maternal uniparental disomy for chromosome 2 in association with confined placental mosaicism for trisomy 2 and severe intrauterine growth retardation.
We report a liveborn infant with severe intrauterine growth retardation and renal failure, delivered following detection of non-mosaic trisomy 2 by chorionic villus biopsy in the first trimester. Detailed analysis post-delivery indicated apparent complete trisomy 2 of the chorionic tissues, with a chromosomally normal infant demonstrating maternal uniparental disomy for chromosome 2.
Adult↗
Trisomy 12 mosaicism in a 7 year old girl with dysmorphic features and normal mental development.
We present the case of a mentally normal 7 year old girl with short stature, scoliosis, atrial septal defect, and dysmorphic features including linear pigmented streaks on the forearms and lower legs. Chromosome analysis of cultured fibroblasts showed trisomy 12 in 9% and 13% of cells from two skin biopsies. Two trisomy 12 cells were found in lymphocytes after analysis of 500 metaphases. Her clinical features are compared with those of other liveborn cases of trisomy 12 mosaicism and the problems of prenatal diagnosis of such an abnormality are discussed.
Abnormalities, Multiple↗
Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy.
We have analysed the results of clinical assessment, X-inactivation status, deletion screening and dystrophin analysis in eight manifesting carriers of Duchenne and Becker muscular dystrophy (DMD and BMD). Only two had a prior family history of X-linked muscle disease, all had normal karyotypes and none were twins. Presentation varied from 2 to 25 yr and progression varied from a DMD-like severity to a very mild BMD-like course. In one girl the initial symptoms were restricted to learning difficulties. Where methods for assessing X-inactivation were informative, three patients showed an abnormal pattern. However, in one patient, the obligate carrier daughter of a BMD patient who had presented at the age of 2 yr, X-inactivation appeared normal in lymphocytes and muscle. While dystrophin analysis seems to be reliable in identifying manifesting carriers of DMD and BMD, the relationship between X-inactivation status, dystrophin analysis and phenotype is not simple.
Adolescent↗
Deletions within chromosome 22q11 in familial congenital heart disease.
Because a locus on chromosome 22q11 is deleted in most individuals with DiGeorge and Shprintzen syndromes--conditions in which heart abnormalities are an important feature--we have looked for deletions in nine families with recurrent outflow-tract heart defects. In five families, chromosome 22 deletions were detected in all the living affected individuals studied and also in the clinically normal father of three affected children. The deletion was transmitted from parents to offspring and was associated with an increase in the severity of cardiac defects. No deletions were found in four families in which the parents were normal and affected siblings had anatomically identical defects. We propose that deletions within band q11 of chromosome 22 are an important cause of familial heart defects.
Autoradiography↗
Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus.
The large clinical overlap between DiGeorge syndrome and velo-cardio-facial syndrome suggests an aetiological connection. DiGeorge syndrome is associated with microdeletions of chromosome 22q11 and is therefore likely to be caused by reduced dosage of genes within this region. We present preliminary data that velocardiofacial syndrome patients have similar chromosome deletions, a finding consistent with the hypothesis that these disorders represent part of a spectrum of abnormalities seen with monosomy for 22q11.
Abnormalities, Multiple↗
Prenatal detection of multiple copies of a familial supernumerary marker chromosome.
Direct preparations and long-term cultures from a chorion villus biopsy, taken because of a known maternal additional marker chromosome, showed a 48,XX,+mar,+mar karyotype in all cells examined. The same karyotype was revealed in a subsequent amniotic fluid sample and in cord blood at delivery. Detailed examination of the child at delivery and at 1 year of age showed no evidence of phenotypic abnormality or developmental problems.
Adult↗
Centiles for adult head circumference.
Reference range for head circumference on the Tanner charts do not go beyond age 16. In this study the head circumference and heights of 354 adults in two British centres were measured. The centile charts constructed from these measurements show that adult head circumference is related to height. The mean head circumference of a male of average height is above the 97th centile for a 16 year old on the Tanner charts. The paediatric charts are therefore inappropriate for use in adult males.
Adolescent↗
A prospective cytogenetic study of 36 cases of DiGeorge syndrome.
Cytogenetic analysis was carried out in a prospective series of 36 children with DiGeorge syndrome. High-resolution banding (> 850 bands/haploid set) was achieved in 30 cases. Monosomy 22q11.21-->q11.23 was found in 9 of these 30 cases. In each of these cases monosomy 22q11.21-->q11.23 resulted from an interstitial deletion and not from a translocation. No other chromosome abnormalities were seen.
Child↗
DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin.
DiGeorge syndrome was diagnosed in an infant who had an interrupted aortic arch, hypoparathyroidism, and low T lymphocyte numbers. Two siblings had heart defects that are not commonly described in DiGeorge syndrome (a membranous ventricular septal defect and coarctation of the aorta respectively). These siblings did not have evidence of thymic dysfunction or hypoparathyroidism. Chromosome analysis showed that the mother, whose cardiovascular examination was normal, and her three offspring with heart defects had a 22q11 interstitial deletion, which was confirmed by molecular analysis. This family suggests that 22q11 deletions can cause apparently isolated heart defects and that the range of these defects may be wider than previously recognised. Once the genes that are deleted in this family are characterised they will be useful candidate genes in the investigation of isolated cardiac malformations.
Aortic Coarctation↗