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Biomedical subjects

J Goodship

Publications and source records attributed to J Goodship.

At least 19 recordsLinked to original sources
PubMed2006

A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus.

The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.

Birth Weight↗
PubMed2006

Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation.

We describe three families with X-linked mental retardation, two with a deletion of a single amino acid and one with a missense mutation in the proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90 kDa, polypeptide 3) protein similar to mutations found in Coffin-Lowry syndrome (CLS). In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation. In the third family, although CLS had been suspected, the clinical features were atypical and the degree of intellectual disability much less than expected. These families show that strict reliance on classical clinical criteria for mutation testing may result in a missed diagnosis. A less targeted screening approach to mutation testing is advocated.

Amino Acid Sequence↗
PubMed2001

Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism.

AIMS: To describe the phenotype in three family members affected by a novel mutation in the gene coding for the enzyme tissue inhibitor of metalloproteinase-3 (TIMP-3). METHODS: Three members of the same family were seen with a history of nyctalopia and visual loss due to maculopathy. Clinical features were consistent with Sorsby's fundus dystrophy. Exon 5 of the gene coding for TIMP-3 was amplified by the polymerase chain reaction, single strand conformation polymorphism analysis undertaken and exon 5 amplicons were directly sequenced. RESULTS: Onset of symptoms was in the third to fourth decade. Five of six eyes had geographic macular atrophy rather than neovascularisation as a cause for central visual loss. Peripheral retinal pigmentary disturbances were present. Scotopic ERGs were abnormal in all three. Mutation analysis showed a G-->T transversion in all three resulting in a premature termination codon, E139X, deleting most of the carboxy terminal domain of TIMP-3. CONCLUSIONS: The patients described had a form of Sorsby's fundus dystrophy which fell at the severe end of the spectrum of this disease. Postulated disease mechanisms include deposition of dimerised TIMP-3 protein.

Adult↗
PubMed2000

Autozygosity mapping of a seckel syndrome locus to chromosome 3q22. 1-q24.

Seckel syndrome (MIM 210600) is an autosomal recessive disorder of low birth weight, severe microcephaly, and dysmorphic facial appearance with receding forehead, prominent nose, and micrognathia. We have performed a genomic screen in two consanguineous families of Pakistani origin and found that the disorder segregates with markers between loci D3S1316 and D3S3710, which map to chromosome 3q22.1-q24. Analysis using HOMOZ/MAPMAKER gave a maximum LOD score of 8.72. All five affected individuals were homozygous for the same allele, for two adjacent polymorphic markers within the region segregating with the disease, narrowing the region to 12 cM.

Abnormalities, Multiple↗
PubMed2000

Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.

Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions.

Alternative Splicing↗
PubMed2000

Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus.

Char syndrome is an autosomal dominant trait characterized by patent ductus arteriosus, facial dysmorphism and hand anomalies. Using a positional candidacy strategy, we mapped TFAP2B, encoding a transcription factor expressed in neural crest cells, to the Char syndrome critical region and identified missense mutations altering conserved residues in two affected families. Mutant TFAP2B proteins dimerized properly in vitro, but showed abnormal binding to TFAP2 target sequence. Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism. Our work shows that TFAP2B has a role in ductal, facial and limb development and suggests that Char syndrome results from derangement of neural-crest-cell derivatives.

3T3 Cells↗
PubMed1999

Left-isomerism sequence and maternal type-1 diabetes.

Defects of lateralisation have previously been recognised in the offspring of women with type-1 diabetes. In a 3-year period, three of the six cases of left isomerism sequence notified to the Northern Region Congenital Abnormality Survey were the infants of diabetic mothers. This finding suggests a specific association between bilateral left-sidedness and maternal type-1 diabetes.

Abnormalities, Multiple↗
PubMed1998

Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse.

Visceral left-right asymmetry occurs in all vertebrates, but the inversion of embryo turning (inv) mouse, which resulted following a random transgene insertion, is the only model in which these asymmetries are consistently reversed. We report positional cloning of the gene underlying this recessive phenotype. Although transgene insertion was accompanied by neighbouring deletion and duplication events, our YAC phenotype rescue studies indicate that the mutant phenotype results from the deletion. After extensively characterizing the 47-kb deleted region and flanking sequences from the wild-type mouse genome, we found evidence for only one gene sequence in the deleted region. We determined the full-length 5.5-kb cDNA sequence and identified 16 exons, of which exons 3-11 were eliminated by the deletion, causing a frameshift. The novel gene specifies a 1062-aa product with tandem ankyrin-like repeat sequences. Characterization of complementing and non-complementing YAC transgenic families revealed that correction of the inv mutant phenotype was concordant with integration and intact expression of this novel gene, which we have named inversin (Invs).

Amino Acid Sequence↗
PubMed1998

A population study of chromosome 22q11 deletions in infancy.

AIMS: To determine the prevalence of submicroscopic deletions within chromosome band 22q11 in infants with significant heart disease and compare this with the prevalence of other chromosomal abnormalities causing significant heart disease. To determine a minimum prevalence of deletions within chromosome band 22q11 in infants in the general population. METHODS: Chromosome analysis was performed on samples from infants born in the former UK Northern Health Region in 1994 and 1995 who either had significant heart disease or who were suspected to have a chromosome band 22q11 deletion following referral to the Northern Genetics Service. Significant heart disease was defined as major structural malformation or cases where invasive investigation or intervention was required in infancy. RESULTS: Chromosome band 22q11 deletions were identified in nine infants in a population of 69,129 livebirths, giving a minimum prevalence of 13 per 100,000 (95% confidence interval 4.5 to 21.5). Six cases had significant heart disease, one of whom died before diagnosis. In the same population there were 53 cases of trisomy 21, 15 of whom had significant heart disease. CONCLUSION: The most common chromosomal cause of significant congenital heart disease remains trisomy 21, while the second most common chromosomal cause is deletion in chromosome band 22q11.

Abortion, Therapeutic↗
PubMed1998

Prenatal diagnosis of mosaic trisomy 8 with investigations of the extent and origin of trisomic cells.

A case of trisomy 8 mosaicism, which presented at obstetric ultrasound at 18 weeks' gestation with a distended bladder and absence of amniotic fluid, is described. Analysis of DNA microsatellite polymorphisms indicates that the trisomic cell line most likely arose as the result of a post-fertilization non-dysjunction event in early development of a chromosomally normal pre-implantation embryo. The distribution of normal and trisomy 8 cells suggests that in this pregnancy there has been either uneven allocation of abnormal cells to the extra-embryonic mesoderm, or selection against the proliferation of trisomic cells in trophoblast derived cell lineages. This prenatal detection of trisomy would not have been possible if only analysis of direct preparations had been undertaken.

Adult↗
PubMed1997

Renal abnormalities on obstetric ultrasound as a presentation of DiGeorge syndrome.

We describe three pregnancies that presented with renal anomalies on obstetric ultrasound as the main abnormality and were subsequently found to have interstitial deletions within chromosome 22q11. A cardiac defect, double-outlet right ventricle, was also seen in the first case. Amnio infusion was refused in the second pregnancy and the perimembranous ventricular septal defect was not identified prior to termination. In the third case, there was no cardiac defect. The genitourinary abnormalities were a right hydroureter and hydronephrosis with a ureterocele bulging into the bladder lumen, bilateral multicystic kidneys with associated oligohydramnios, and a left multicystic kidney with right renal agenesis and associated oligohydramnios. Absence of thymus at autopsy in all three cases led to fluorescent in situ hybridization studies looking for the submicroscopic deletion of chromosome 22q11 associated with DiGeorge syndrome.

Adolescent↗
PubMed1996

The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.

Brazil↗
PubMed1996

X-inactivation patterns in monozygotic and dizygotic female twins.

We have tested the hypothesis that contrasting X-inactivation patterns could be a trigger for monozygotic twinning in females. X-inactivation patterns were studied in umbilical cord tissue in 43 monozygotic twin pairs and 24 dizygotic twin pairs. Very skewed or non-random X-inactivation patterns were observed in both twins in six of the monozygotic twin pairs and in one of the dizygotic twin pairs. Contrasting X-inactivation patterns occurred in only one of the six monozygotic twin pairs. This does not support the original hypothesis. There is a trend to extreme skewing of X-inactivation pattern occurring more frequently in monozygotic twins.

Base Sequence↗