Search PubMed⌕ Search

Biomedical subjects

I K Temple

Publications and source records attributed to I K Temple.

At least 37 records · Page 2Linked to original sources
PubMed2000

An imprinted locus associated with transient neonatal diabetes mellitus.

Recently, we reported the localization of a gene for transient neonatal diabetes mellitus (TNDM), a rare form of childhood diabetes, to an approximately 5.4 Mb region of chromosome 6q24. We have also shown that TNDM is associated with both paternal uniparental disomy (UPD) of chromosome 6 and paternal duplications of the critical region. The sequencing of P1-derived artificial chromosome clones from within the region of interest has allowed us to further localize the gene and to investigate the methylation status of the region. The gene is now known to reside in a 300-400 kb region of 6q24 which contains several CpG islands. At one island we have demonstrated differential DNA methylation between patients with paternal UPD of chromosome 6 and normal controls. In addition, two patients with TNDM, in whom neither paternal UPD of chromosome 6 nor duplication of 6q24 have been found, show a DNA methylation pattern identical to that of patients with paternal UPD of chromosome 6. Control individuals show a hemizygous methylation pattern. These results show that TNDM can be associated with a methylation change and identify a novel methylation imprint on chromosome 6 associated with TNDM.

Blotting, Southern↗
PubMed2000

Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes.

Transient neonatal diabetes (TND) is a rare type of diabetes that presents soon after birth, resolves by 18 months, and predisposes to diabetes later in life. A total of 30 patients were ascertained and investigated for aberrations of chromosome 6. A genotype/phenotype study was also performed. Genotypically, these patients can be classified into 4 etiologic groups. Group 1 had paternal uniparental isodisomy of chromosome 6 (11 cases, including 1 set of identical twins). Group 2 had a duplication involving chromosome band 6q24, which was paternal in origin where tested (4 sporadic cases and 7 familial cases from 2 families). Group 3 consisted of 1 patient with a loss of methylation at a CpG island within the TND critical region (1 sporadic case). Group 4 had no identifiable rearrangement of chromosome 6 (7 sporadic cases). Most patients were growth retarded at birth, presented at a median age of 3 days, and recovered at a median age of 12 weeks. In group 2, 2 relatives of the TND patients who presented with type 2 diabetes and no early history of TND had inherited an identical duplication. An abnormality of chromosome 6 was identified in approximately 70% of sporadic TND cases and in all familial cases. No significant clinical differences were found between the 4 etiological groups. The study has broadened the clinical spectrum of TND to include type 2 diabetes presenting in later life with no neonatal presentation. The findings are consistent with an imprinted gene for diabetes mapping to 6q24, which we predict will have an important function in normal pancreatic development.

Aneuploidy↗
PubMed1999

Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome.

Silver-Russell syndrome (SRS) has been associated with maternal uniparental disomy (UPD) of chromosome 7 in approximately 10% of cases, suggesting that at least one imprinted gene on chromosome 7 is involved in the pathogenesis of the disease. We report a proximal 7p interstitial inverted duplication in a mother and daughter both of whom have features of SRS, including marked short stature, low birth weight, facial asymmetry and 5th finger clinodactyly. Fluorescence in situ hybridisation (FISH) with YAC probes enabled delineation of the duplicated region to 7p12.1-p13. This region of proximal chromosome 7 is known to be homologous to an imprinted region in the mouse chromosome 11 and contains the growth-related genes GRB10 (growth factor receptor-bound protein 10), EGFR (epidermal growth factor receptor) and IGFBP1 (insulin-like growth factor binding protein 1), all of which have been suggested as candidate genes for SRS. Molecular analysis showed that the duplication in both mother and daughter spanned a distance of approximately 10 cM and included GRB10 and IGFBP1 but not EGFR. The de novo duplication in the proband's mother was shown to be of paternal origin. In order to test the hypothesis that sub-microscopic duplications of 7p, whether maternal or paternal in origin, are responsible for at least some cases of SRS, we screened a further eight patients referred to our laboratory for SRS. None were found to have duplications of either GRB10 or IGFBP1. The hypothesis that sub-microscopic duplications including GRB10 and IGFBP1 is a cause of SRS remains a possibility and warrants further investigation. Importantly, in contrast to current thinking, our results suggest that imprinted genes may not underlie the SRS phenotype, and we propose an alternative hypothesis to explain the occurrence of maternal UPD 7 seen in some cases of SRS.

Abnormalities, Multiple↗
PubMed1999

Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.

Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and is characterized by hypoplasia or absence of the terminal portions of the index to little fingers, usually with absence of the nails. The thumbs may be of normal length but are often flattened and occasionally are bifid. The feet are similarly but less severely affected. We have performed a genomewide linkage analysis of three families with BDB, two English and one Portugese. The two English families show linkage to the same region on chromosome 9 (combined multipoint maximum LOD score 8.69 with marker D9S257). The 16-cM disease interval is defined by recombinations with markers D9S1680 and D9S1786. These two families share an identical disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provides strong evidence that the English families have the same ancestral mutation, which reduces the disease interval to <12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, we excluded linkage to this region, a result indicating that BDB is genetically heterogeneous. Reflecting this, there were atypical clinical features in this family, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enable a refined classification of BDB and identify a novel locus for digit morphogenesis in 9q22.

Chromosomes, Human, Pair 9↗
PubMed1999

A 28-kb deletion spanning D15S63 (PW71) in five families: a rare neutral variant?

Methylation analysis with probe PW71 (D15S63) is an established procedure to test patients suspected of having Prader-Willi syndrome or Angelman syndrome. Using this test, we have identified a 28-kb deletion spanning D15S63 in five independent families. Sequence analysis revealed identical breakpoints in all the families. The haplotype data are compatible with a common ancestral origin of the deletion in at least two families. The deletion was not found in 1, 000 unrelated controls. Although the deletion maps within the imprinting-center region, neither maternal nor paternal inheritance of the deletion appears to affect imprinting in proximal 15q. We conclude that the deletion is a rare neutral variant that can lead to false-positive results in the PW71-methylation test.

Adolescent↗
PubMed1999

Localisation of a gene for transient neonatal diabetes mellitus to an 18.72 cR3000 (approximately 5.4 Mb) interval on chromosome 6q.

Transient neonatal diabetes mellitus (TNDM) is a rare condition which presents with intrauterine growth retardation, dehydration, and failure to thrive. The condition spontaneously resolves before 1 year of age but predisposes patients to type 2 diabetes later in life. We have previously shown that, in some cases, TNDM is associated with paternal uniparental disomy (UPD) of chromosome 6 and suggested that an imprinted gene responsible for TNDM lies within a region of chromosome 6q. By analysing three families, two with duplications (family A and patient C) and one with several affected subjects with normal karyotypes (family B), we have further defined the TNDM critical region. In patient A, polymorphic microsatellite repeat analysis identified a duplicated region of chromosome 6, flanked by markers D6S472 and D6S311. This region was identified on the Sanger Centre's chromosome 6 radiation hybrid map (http://www.sanger.ac.uk/HGP/Chr6) and spanned approximately 60 cR3000. Using markers within the region, 418 unique P1 derived artificial chromosomes (PACs) have been isolated and used to localise the distal breakpoints of the two duplications. Linkage analysis of the familial case with a normal karyotype identified a recombination within the critical region. This recombination has been identified on the radiation hybrid map and defines the proximal end of the region of interest. We therefore propose that an imprinted gene for TNDM lies within an 18.72 cR3000 (approximately 5.4 Mb) interval on chromosome 6q24.1-q24.3 between markers D6S1699 and D6S1010.

Chromosome Mapping↗
PubMed1999

Anterior chamber eye anomalies, redundant skin and syndactyly--a new syndrome associated with breakpoints at 2q37.2 and 7q36.3.

We report a 34-year-old female with a de novo balanced reciprocal translocation involving 2q37.2 and 7q36.3. She has a unique combination of multiple congenital malformations that include redundant skin, complete tissue syndactyly of the hands and feet, hirsutism, polycystic ovaries and bilateral anterior chamber eye anomalies. Her son has inherited the unbalanced product (46,XY,der(2) t(2;7)(q37.2;q36.3). He has a similar clinical picture with additional features including complex congenital heart disease, post axial polydactyly, hypotonia and global developmental delay. The breakpoints may indicate the location of the gene(s) responsible for this unique combination of features.

Abnormalities, Multiple↗
PubMed1998

Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus.

Transient neonatal diabetes mellitus occurs in growth-retarded infants, has an incidence of 1 in 400000 live births and has been associated with both paternal uniparental disomy of chromosome 6 and paternal duplications of 6q. We analysed samples from our cohort of patients with transient neonatal diabetes mellitus for uniparental disomy of chromosome 6 using polymorphic microsatellite repeat analysis. We report here the fifth case of paternal uniparental disomy of chromosome 6 associated with classic transient neonatal diabetes mellitus and estimate that uniparental disomy of chromosome 6 accounts for approximately one fifth of cases of transient neonatal diabetes mellitus.

Chromosomes, Human, Pair 6↗
PubMed1998

Distal 6p deletion syndrome: a report of a case with anterior chamber eye anomaly and review of published reports.

We describe a 32 year old male with a distal 6p24.3-->pter deletion. He has specific developmental anomalies of the anterior chamber of the eye and a cleft uvula which is consistent with the recent localisation of genes for iris development and orofacial clefting to distal 6p. In addition he has progressive sensorineural deafness and this may localise a gene for deafness to this region. We conclude that a refined distal 6p deletion syndrome exists and includes a characteristic facial appearance with hypertelorism, downward slanting palpebral fissures, tented mouth, smooth philtrum, palatal malformation, ear anomalies, anterior chamber eye defects, progressive sensorineural deafness, cardiac defects, abdominal herniae, small external genitalia, and motor and speech delay.

Abnormalities, Multiple↗
PubMed1997

Coloboma, mental retardation, hypogonadism, and obesity: critical review of the so-called Biemond syndrome type 2, updated nosology, and delineation of three "new" syndromes.

Biemond syndrome type 2 (BS2) is classically regarded as a recessively inherited condition (MIM 210350) comprising mental retardation, coloboma, obesity, polydactyly, hypogonadism, hydrocephalus, and facial dysostosis. Clinically, the disorder is closely related to Bardet-Biedl syndrome. Few cases have been reported, most of them before 1970. We present clinical data on three mentally retarded sporadic cases with coloboma, obesity, and hypogenitalism (in two of them), fitting as first glance a diagnosis of BS2. A review documents striking clinical variability among the patients said to have BS2. We propose a new nosology of those cases and delineate several new clinical forms. Purported BS2 cases may be divided into: (1) Bardet-Biedl syndrome with fortuitous coloboma or aniridia, (2) BS2 sensu stricto, a recessively inherited syndrome of sexual infantilism, short stature, coloboma, and preaxial polydactyly without obesity, only known from the original report, (3) a "new" dominantly inherited form of colobomatous microphthalmia occasionally associated with obesity, hypogonadism, and mental retardation, to which our observations belong. (4) cytogenetically proven Rubinstein-Taybi syndrome (one case), (5) an unclassifiable, early lethal familial syndrome resembling Buntinx-Majewski syndrome, and (6) a "new" coloboma-zygodactyly-clefting syndrome. The latter two syndromes may result from chromosomal anomaly.

Abnormalities, Multiple↗
PubMed1997

A small intraexonic deletion within the dystrophin gene suggests a possible mechanism of mutagenesis.

A case of Duchenne muscular dystrophy is described with an unusual mutation consisting of a 17-bp deletion within exon 47 of the dystrophin gene. The sequences on either side of the deletion have a high degree of intrastrand base complementarity. It is hypothesised that the mechanism generating the deletion may have been the formation of hairpin loop structure in a single strand of DNA followed by enzymatic degradation at unpaired regions within the loop.

Algorithms↗
PubMed1997

A new alpha 1-antitrypsin mutation, Thr-Met 85, (PI Zbristol) associated with novel electrophoretic properties.

A new AAT allele (PI Zbristol) has been discovered in a woman with an obstetric history of three perinatal deaths from fulminant liver disease and no living offspring. She and her father were both PI M1Zbristol heterozygotes. The Zbristol protein is active as a proteinase inhibitor but appeared to be deficient in the plasma to about the same degree as the S protein in MS heterozygotes. It focuses on the basic side of Z and lacks the normal pattern of secondary isoforms associated with the commonly occurring AAT variants and migrates faster than normal on an SDS electrophoresis gel. The Zbristol mutation was found to be a C to T transition at codon 85 changing ACG (Thr) to ATG (Met). This disrupts the N-glycosylation site starting at Asn 83 preventing glycosylation at residue 83 in the PI Zbristol protein and explains the protein isoelectric focusing and SDS gel electrophoresis results. An analysis of haplotypes in the propositus and her father indicated that the Zbristol mutation occurred on the common M1(Val 213) genetic background. The new mutation also led to the generation of an NlaIII restriction endonuclease recognition site. Cell lines from two offspring tested for the presence of this NlaIII site revealed that one had the variant and the other did not. Thus, the relationship between Zbristol and fulminant liver disease in the offspring is unclear.

Amino Acid Substitution↗
PubMed1997

Aetiopathology and genetic basis of neonatal diabetes.

A British Paediatric Association Surveillance Unit* study of neonatal diabetes determined a national incidence of 1 in 400,000 live births. Additional cases of transient neonatal diabetes were collected retrospectively. Most cases were of low birthweight at term: none had evidence of an autoimmune aetiopathogenesis. The median requirement for exogenous insulin treatment was three months. A significant number of cases developed type 2 diabetes in later life. Three of the 11 cases were found to have paternal uniparental isodisomy of chromosome 6. A further patient carried an unbalanced duplication of 6q 22-23, inherited from the father, which localised a potentially imprinted gene for diabetes to this region. The fact that low birthweight predisposes to type 2 diabetes in later life is well established, but a genetic defect that may relate both to intrauterine growth failure and the development of type 2 diabetes in later life has now been identified.

Aneuploidy↗
PubMed1997

Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS. We have investigated the molecular pathology of 106 sporadic BWS cases; 17% (14/83) of informative cases had uniparental disomy (UPD) for chromosome 11p15.5. In each case UPD appeared to result from a postzygotic event resulting in mosaicism for segmental paternal isodisomy. The critical region for isodisomy was refined to a 25 cM interval between D11S861 and D11S2071 which contained the IGF2, H19, and p57(KIP2) genes. In three cases isodisomy for 11q markers was detected but this did not extend further than 11q13-q21 suggesting that complete chromosome 11 disomy may not produce a BWS phenotype. The allele specific methylation status of the H19 gene was investigated in 80 sporadic BWS cases. All 13 cases with UPD tested displayed hypermethylation consistent with an excess of paternal H19 alleles. In addition, five of 63 (8%) cases with normal biparental inheritance had H19 hypermethylation consistent with an "imprinting centre" mutation (ICM) or "imprinting error" (IE) lesion. The phenotype of patients with putative ICM/IE mutations was variable and overlapped with that of non-UPD sporadic BWS cases with normal H19 methylation. However, exomphalos was significantly (p < 0.05) more common in the latter group. These findings may indicate differential effects on the expression of imprinted genes in chromosome 11p15 according to the precise molecular pathology. Analysis of H19 methylation is useful for the diagnosis of both UPD or altered imprinting in BWS and shows that a variety of molecular mechanisms may cause relaxation of IGF2 imprinting in BWS.

Aneuploidy↗