Search PubMed⌕ Search

Biomedical subjects

J J de Vijlder

Publications and source records attributed to J J de Vijlder.

At least 19 recordsLinked to original sources
PubMed2001

[From gene to disease; POU1F1- and PROP1-mutations in pituitary hormone deficiency].

Multiple pituitary hormone deficiency can be caused by mutations in at least three pituitary transcription factors: POU1F1 (formerly called PIT1), PROP1 or HESX1. The role of the various pituitary transcription factors in pituitary ontogeny has been elucidated in part for the mouse. In humans, mutations in POU1F1 result in a total deficiency of growth hormone and prolactin, and a variable deficiency of TSH. Cases of mutations in PROP1 exhibit the same deficiencies, with additional deficiencies of gonadotrophins and a variable deficiency of ACTH. In the Netherlands, cases of multiple pituitary hormone deficiency are not only detected on the basis of the classical signs and symptoms of pituitary deficiency, but also by means of screening on congenital hypothyroidism with an incidence of approximately 1:20,000.

Animals↗
PubMed2001

Heterogeneity in polyadenylation cleavage sites in mammalian mRNA sequences: implications for SAGE analysis.

The analysis of a human thyroid serial analysis of gene expression (SAGE) library shows the presence of an abundant SAGE tag corresponding to the mRNA of thyroglobulin (TG). Additional, less abundant tags are present that can not be linked to any other known gene, but show considerable homology to the wild-type TG tag. To determine whether these tags represent TG mRNA molecules with alternative cleavage, 3'-RACE clones were sequenced. The results show that the three putative TG SAGE tags can be attributed to TG transcripts and reflect the use of alternative polyadenylation cleavage sites downstream of a single polyadenylation signal in vivo. By screening more than 300 000 sequences corresponding to human, mouse and rat transcripts for this phenomenon we show that a considerable percentage of mRNA transcripts (44% human, 22% mouse and 22% rat) show cleavage site heterogeneity. When analyzing SAGE-generated expression data, this phenomenon should be considered, since, according to our calculations, 2.8% of human transcripts show two or more different SAGE tags corresponding to a single gene because of alternative cleavage site selection. Both experimental and in silico data show that the selection of the specific cleavage site for poly(A) addition using a given polyadenylation signal is more variable than was previously thought.

Animals↗
PubMed2001

Absence of activating mutations in ras and gsp oncogenes in a cohort of nine patients with sporadic pediatric thyroid tumors.

BACKGROUND: Characterization of the genetic background of pediatric thyroid carcinomas could aid in distinguishing between differently staged tumors with respect to treatment and prognosis. Two known genetic factors associated with thyroid carcinoma, the proto-oncogenes gsp and ras were investigated. PROCEDURE: DNA was extracted from paraffin sections from both tumor and normal thyroid tissue of nine patients (ages 9-16 years). Of these patients, eight were diagnosed with papillary carcinoma and one with follicular adenoma. The coding exons of gsp and the three known ras genes (H, K, and N-ras) were screened for mutations using SSCP-analysis. RESULTS: There were no mutations present in the ras and gsp proto-oncogenes hot spots, however, LOH of H-ras (chromosome location 11p15.5) was found in tumor tissue from one patient and a homozygous mutation in exon 12 of gsp causing a Pro-->Ser conversion was present in the thyroid tumor tissue from another patient. Two silent polymorphisms were detected, H-ras exon1, 86T-->C and gsp exon 5, 81T-->C. CONCLUSIONS: Our results indicate that the ras/gsp mutations found are probably late events in the tumorigenesis representing general oncogenic stress. In conclusion, it seems that ras/gsp activation is not a factor in the mechanism causing sporadic thyroid carcinoma in children.

Adolescent↗
PubMed2001

Cloning of tissue-specific genes using serial analysis of gene expression and a novel computational substraction approach.

A paradigm of molecular medicine is the identification of functionally specialized genes in the search of defects responsible for human disease. To identify novel genes relevant for thyroid physiology, we applied serial analysis of gene expression (SAGE) and identified 4260 tag sequences that did not match any known gene present in the GenBank database ("no-match" tags). These no-match tags represent still uncharacterized transcripts. Most of them are expected to correspond to housekeeping genes and only a few to genes with a tissue-restricted pattern of expression. To pinpoint the best candidates for tissue-specificity in a large series of tags, we used a computer-based approach. We compared the relative abundance of 80 no match tags in our thyroid SAGE library with the expression level in 14 other SAGE libraries derived from 9 different human tissues. Based on the expression data, we developed the "tissue preferential expression" (TPE) algorithm to discriminate tags expressed specifically in the thyroid. We then selected four tags as preferentially expressed in thyroid. Results were validated by RT-PCR and northern blot on multiple-tissue RNA samples. Finally, the screening of a thyroid cDNA library with expressed sequence tag (EST) sequences related to the selected tags allowed the isolation of four novel thyroid-specific cDNAs. We demonstrate that the computational substraction of SAGE tags by the proposed TPE algorithm is a rapid and reliable way to expedite the cloning of tissue-specific genes through the combined use of SAGE and EST databases.

Algorithms↗
PubMed2001

Serum thyroglobulin and urinary iodine concentration are the most appropriate indicators of iodine status and thyroid function under conditions of increasing iodine supply in schoolchildren in Benin.

Iodine deficiency control programs have greatly reduced iodine deficiency disorders worldwide. For monitoring changes in iodine status, different indicators may be used. The aim of this study was to evaluate the suitability of indicators of iodine status and thyroid function, thyroglobulin (Tg), thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in serum, thyroid volume and urinary iodine concentration, in iodine-deficient schoolchildren under conditions of increasing iodine supply. The study was established as a double-blind, placebo-controlled oral administration of a single dose of iodized oil to schoolchildren (7-10 y old), living in an iodine-deficient area of Benin, with an observation period of 10 mo. However, 3-4 mo after supplementation, iodized salt became available in the area. The study population therefore comprised an iodized oil-supplemented group and a nonsupplemented group, both of which had variable, uncontrolled intakes of iodized salt during the last 6 mo of the study. Initial mean serum concentrations of TSH and FT4 were within the normal range, whereas serum Tg concentration, urinary iodine concentration and thyroid volume were indicative of moderate-to-severe iodine deficiency. At the end of the study, all indicators had improved significantly, except thyroid volume, which had decreased only in the supplemented group. The supplemented group also still had significantly lower serum Tg and higher urinary iodine concentrations than the nonsupplemented group. Serum Tg and urinary iodine concentrations are the indicators most influenced by a changing iodine supply. Current normal reference ranges of serum concentrations of TSH and FT4 are too wide for detecting iodine deficiency in this age group.

Anthropometry↗
PubMed2001

Maternal isodisomy for chromosome 2p causing severe congenital hypothyroidism.

Severe congenital hypothyroidism (CH) due to a total iodide organification defect (TIOD) is usually due to mutations in the thyroid peroxidase (TPO) gene located at chromosome 2p25. A homozygous deletion [DeltaT2512 (codon 808)] in exon 14 was identified in a patient with classical TIOD. The transmission pattern of the TPO gene in this family was anomalous; the mother was heterozygous for the deletion; and the mutation was absent in the father. Polymorphic short tandem repeat (STR) markers confirmed paternity and demonstrated on chromosome 2 that the propositus was homozygous for most markers on chromosome 2p and that these were identical to one of the maternal 2p homologs. A normal karyotype was found in the propositus, his parents and sister. We conclude that the homozygosity in the patient is due to partial maternal isodisomy of the short arm of chromosome 2, carrying a defective TPO gene. The patient, born small for gestational age, develops and grows well and appears healthy (while being treated with thyroxine) and has a normal phenotype except for a unilateral preauricular skin tag. This shows that partial maternal isodisomy for chromosome 2p (2pter - 2p12) is compatible with a minimal influence on normal development.

Base Sequence↗
PubMed2001

Plasma thyrotropin bioactivity in Down's syndrome children with subclinical hypothyroidism.

OBJECTIVE: Subclinical hypothyroidism occurs in a number of children with Down's syndrome (DS). The reason for the mildly elevated plasma thyrotropin (TSH) concentrations is not known. The present study investigated whether decreased TSH bioactivity plays a role in this phenomenon. DESIGN: A retrospective study of plasma specimens from DS children with mildly elevated plasma TSH concentrations and thyroid hormone levels within the reference range, using a TSH receptor-adenylate cyclase mediated bioassay. METHODS: Strain JP26 Chinese hamster ovary (CHO) cells, stable transfected with the human TSH receptor, were incubated with unfractionated plasma (1/10 diluted in hypotonic incubation medium) of 10 DS children with subclinical hypothyroidism and nine euthyroid children with insulin-dependent diabetes mellitus as controls. cAMP released in the incubation medium was measured by RIA. Mock-transfected CHO cells were used to correct for non-specific CHO response. WHO Second International Reference Preparation of human TSH was dissolved and diluted in pooled normal human plasma and simultaneously bioassayed to match patient and control results. RESULTS: Plasma TSH levels were slightly increased in DS (mean +/- S.D., 6.5+/-1.3 mU/l, reference range 0.4-4.0 mU/l). Plasma TSH levels for controls (1.3+/-0.4 mU/l) were within the reference range. Plasma thyroid hormone levels in patients and controls were normal, plasma TSH binding inhibitory immunoglobulin and thyroid peroxidase antibodies were negative. cAMP levels (corrected for non-specific CHO response) in DS patients (18.4+/-3.9 pmol/well) and in controls (14.3+/-1.3 pmol/well) did not significantly differ from cAMP levels generated by patient-TSH equivalent TSH standards (16.3+/-0.9 pmol/well). CONCLUSIONS: The present results demonstrate normal TSH bioactivity in plasma of DS children, indicating that subclinical hypothyroidism in these patients is of primary (thyroidal) origin.

Adolescent↗
PubMed2001

Neonatal thyroxine supplementation in very preterm children: developmental outcome evaluated at early school age.

OBJECTIVE: Transient hypothyroxinemia in very premature infants is associated with developmental problems. A randomized, placebo-controlled trial of thyroxine (T(4)) supplementation was conducted in a group of 200 infants <30 weeks' gestation. T(4) supplementation improved mental outcome at 2 years old in children of 25/26 weeks' gestation only. The effect of T(4) supplementation beyond 2 years of age is unknown. We present the effects of neonatal T(4) supplementation on outcome at early school age. METHODS: Standardized measurements were used to assess cognitive, behavioral, and motor outcome, as well as a qualitative assessment of neurologic functioning. Survivors of the T(4) trial were assessed at the age of 5.7 years. RESULTS: Ninety-nine percent of the 157 survivors participated. Outcome on all domains was comparable between the T(4) group and placebo group. In children <27 weeks' gestation, a 10 IQ point difference was found in favor of the T(4) group, whereas in children of 29 weeks' gestation, a difference of 15 IQ points was found in favor of the placebo group. Teachers' reports showed less behavioral problems in the T(4)-treated children of 25/26 weeks' gestation, but more behavioral problems in the T(4)-treated children of 27 weeks' gestation. Differences in motor outcome and neurologic outcome were in favor of the T(4)-treated children <29 weeks' gestation, but not of the T(4)-treated children of 29 weeks' gestation. CONCLUSIONS: We found benefits of T(4) supplementation for children <29 weeks' gestation, and especially in children of 25/26 weeks' gestation. However, in children of 29 weeks' gestation T(4) supplementation is associated with more developmental problems.

Child↗
PubMed2001

Up to date with human thyroglobulin.

The coding region of the human thyroglobulin (TG) mRNA has been resequenced, and comparison with the TG sequence originally published in 1987 showed many variations. All of the variations were validated in 20--40 other alleles, and this resulted in the revision of 41 nucleotide positions. This review presents the revised wild-type human TG sequence, including all known exon/exon boundaries and additional data on the TG mRNA population, concerning alternative splicing and variability of the polyadenylation cleavage site. The amino acid sequence derived shows one additional, 12 changed, and 10 polymorphic residues. Protein characteristics, such as acceptor and donor tyrosine residues, N-glycosylation sites, cysteine-rich repeats, the proposed receptor domain, and antigenic epitopes, are included, and their relationship to the revised sequence is discussed. Furthermore, all reported TG mutations causing dyshormonogenesis in humans and animals are designated in the nucleotide and amino acid sequences. This up-to-date profile of the human TG molecule presents the features of importance for its complex role in thyroid hormonogenesis, and is the basis for future studies on the structure--function relationship.

Alternative Splicing↗
PubMed2000

Serial analysis of gene expression as a tool to assess the human thyroid expression profile and to identify novel thyroidal genes.

The assessment of the expression profile of normal human thyroid tissue using serial analysis of gene expression (SAGE) generated a collection of 10,994 sequence transcripts (tags). Each tag represented a messenger RNA transcript, and, in total, 6099 different tags could be distinguished. The presence and abundance of thyroid-specific transcripts showed the overall expression profile to be from a normal thyroid cell. The expression level of several transcripts was confirmed on Northern blot. Seventy percent of tags could not be attributed to a known human gene and, therefore, possibly correspond to novel genes putatively involved in thyroid function. The tag sequence generated by the SAGE technique can be used to further characterize these novel genes. In this way, application of the SAGE technique to thyroid tissue gives insight in the expression profile of a normal thyroid gland and provides the information to characterize novel genes involved in thyroid pathology, such as congenital hypothyroidism and thyroid neoplasia.

Base Sequence↗
PubMed2000

Changes in plasma thyroid hormone levels after a single dose of triiodothyronine in premature infants of less than 30 weeks gestational age.

OBJECTIVE: Evaluation of thyroid hormone response to a single administration of triiodothyronine (T3) early postnatally to premature infants of <30 weeks gestational age. DESIGN: A prospective clinical trial with historical control. METHODS: Ten infants born <28 weeks gestational age and ten infants born between 28 and 30 weeks gestational age were given 0.5 microg/kg T3 intravenously at 12 h after birth. The infants <28 weeks gestational age were also treated with thyroxine (T4; 8 microg/kg, once daily) during the first 6 weeks of life. Premature infants from a previous trial served as a matched historical control group. Analysis of variance for repeated measurements was performed. RESULTS: For the infants <28-30 weeks gestational age mean plasma T3 concentrations were significantly higher in the T3-treated group (P=0.027) for at least 2 weeks, whereas mean plasma levels of T4, free T4 and TSH were comparable. For the infants <28 weeks gestational age plasma T3 levels were also significantly different after correction for gestational age (P=0.0002), with either comparable or higher values in the T3-treated infants up to 56 days after injection of T3. Mean plasma free T4 levels were lower during the first 3 days and higher or comparable thereafter (P=0.0014), and TSH suppression was more evident in the T3-treated infants (P=0.003). CONCLUSION: A single administration of T3 to premature infants <30 weeks gestational age early postnatally results in a sustained increase of plasma T3 levels during the first weeks of life. In infants of 28-30 weeks gestational age this occurs without change in plasma free T4 levels, whereas in infants <28 weeks gestational age a transient decrease of plasma free T4 was present. The increase in plasma T3 is possibly caused by a T3-induced increase of type I deiodinase activity.

Blood Pressure↗
PubMed1999

The screening for mutations in the thyroglobulin cDNA from six patients with congenital hypothyroidism.

The six patients described in this study were clinically diagnosed with congenital hypothyroidism. Based on clinical and pathophysiological parameters, the cause of the thyroid dyshormonogenesis was suspected to be a defect in the synthesis of thyroglobulin, the matrix protein for thyroid hormone synthesis in the thyroid gland. After RNA isolation from six goitrous tissues and control thyroid tissues, RT-PCR was used to amplify 20 overlapping thyroglobulin (TG) cDNA fragments. Two alternative splice transcripts were identified: a transcript with a deletion of nucleotides 177-274 and a transcript with a deletion of nucleotides 3430-3736 that result in frame shifts and the introduction of premature stop codons. Two alternatively spliced transcripts not changing the reading frame were also identified: a transcript containing a deletion of nucleotides 4529-4699 and a transcript with a deletion of nucleotides 7301-7561. All these transcripts were expressed in thyroid tissue of both patients and controls. Nucleotide sequence analysis and comparison to the revised TG sequence (1997) revealed one revision and eight polymorphisms that did not result in amino acid changes and four polymorphisms that did change amino acid codons. In three patients a homozygous mutation was present at nucleotide position 229, causing a glycine to serine amino acid substitution. The clinical description 'thyroglobulin synthesis defect' in this population cannot be explained by major mutations in the coding region of the TG gene. Furthermore, the presence and level of expression of the alternatively spliced transcripts do not co-segregate with thyroid dyshormonogenesis, since in normal thyroid tissue the same alternatively spliced transcripts are present.

Adolescent↗
PubMed1999

Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy.

BACKGROUND: Maternal thyroid function during early pregnancy is an important determinant of early fetal brain development because the fetal thyroid is unable to produce any T4 before 12-14 weeks' gestation. Overt maternal hypothyroidism as seen in severe iodine-deficient areas is associated with severely impaired neurological development of the offspring. At present, it is not known whether low free T4 (fT4) levels during pregnancy in healthy women from iodine sufficient areas may affect fetal neurodevelopment. METHODS: Neurodevelopment was assessed at 10 months of age in a cohort of 220 healthy children, born after uncomplicated pregnancies and deliveries, using the Bayley Scales of Infant Development. Maternal TSH, fT4 and TPO antibody status were assessed at 12 and 32 weeks' gestation. Maternal gestational fT4 concentration was defined as an independent parameter for child development. RESULTS: Children of women with fT4 levels below the 5th (< 9.8 pmol/l, n = 11) and 10th (< 10.4 pmol/l, n = 22) percentiles at 12 weeks' gestation had significantly lower scores on the Bayley Psychomotor Developmental Index (PDI) scale at 10 months of age, compared to children of mothers with higher fT4 values (t test, mean difference: 14.1, 95% confidence interval (CI): 5.9-22 and 7.4, 95% CI: 1.1-13.9, respectively). At 32 weeks' gestation, no significant differences were found. In the group of women with the lowest 10th percentile fT4 concentrations at 12 weeks' gestation, a positive correlation was found between the mothers' fT4 concentration and children's PDI scores (linear regression, R: 0.46, P = 0.03). After correction for confounding variables, a fT4 concentration below the 10th percentile at 12 weeks' gestation was a significant risk factor for impaired psychomotor development (RR): 5.8, 95% CI: 1.3-12.6). CONCLUSIONS: Low maternal plasma fT4 concentrations during early pregnancy may be an important risk factor for impaired infant development.

Antibodies↗
PubMed1999

Thyroid function in very preterm newborns: possible implications.

Thyroid hormones are essential for brain maturation. Very preterm infants, who are at risk of neurodevelopmental disabilities also have low thyroxine (T4) and free thyroxine (FT4) values in the first weeks after birth. This transient hypothyroxinemia may in part be causal to the neurodevelopmental problems. We have carried out a randomized, double-blind, placebo-controlled trial with T4 in 200 infants less than 30 weeks gestation. T4 (or placebo) was given in fixed dose of 8 microg/kg birth weight per day during the first 6 weeks after birth. It resulted in a significant increase of T4, FT4, and reverse triiodothyronine (rT3). Thyrotropin (TSH) secretion was suppressed, and, probably as a result of TSH suppression, triodothyronine (T3) levels were decreased in the T4 group. Mortality was 14% in the T4 group and 21% in the placebo group (NS). No effect was found on morbidity. Heart rate was significantly higher in T4-treated infants less than 28 weeks gestation, but not in T4-treated infants 28 weeks or more, who had the highest FT4 levels. In the study groups as a whole, no clear effect of T4 administration was found on neurodevelopmental outcome. However, there was a strong trend toward improvement of adverse outcome, defined as death or abnormal developmental outcome at 2 years of age. In addition, mental outcome in a subgroup of T4-treated infants less than 27 weeks' gestation was significantly better than in placebo infants of the same age group. In conclusion, this trial does not clearly have conclusive results. New trials of thyroid hormone treatment should be carried out in preterm infants, in order to investigate whether indeed T4 supplementation is required in preterm infants less than 27 or 28 weeks gestation. Addition of T3 to the treatment schedule needs to be considered.

Blood Proteins↗
PubMed1999

A premature stopcodon in thyroglobulin messenger RNA results in familial goiter and moderate hypothyroidism.

Impaired thyroglobulin (Tg) synthesis is one of the putative causes for dyshormonogenesis of the thyroid gland. This type of hypothyroidism is characterized by intact iodide trapping, normal organification of iodide, and usually low serum Tg levels in relation to high TSH, and when untreated the patients develop goiter. In thyroid tissue from a 13-yr-old patient suspected of a thyroglobulin synthesis defect, the Tg mRNA was studied. The complete coding region of 8307 bp was directly sequenced and revealed a homozygous point mutation: a C886T transition in exon 7. Upon translation this mutation would result in a stopcodon at amino acid position 277, replacing the arginine residue. A Tg cDNA construct containing the mutation was expressed in rabbit reticulocyte lysate resulting in a truncated protein of 30 kDa. Expression in the presence of microsomal membranes resulted in a gel shift of this Tg molecule, indicating glycosylation ability. Two other siblings had a clinical presentation like the index patient, while their parents were unaffected. Additional restriction fragment length polymorphism analysis of the pedigree verified that the homozygous nonsense mutation cosegregated with the clinical phenotype. Clinically, hypothyroidism was not severe in the affected siblings because the truncated Tg glycoprotein was still capable of thyroid hormonogenesis.

Adolescent↗
PubMed1999

A negative iodine balance is found in healthy neonates compared with neonates with thyroid agenesis.

We studied the effects of the presence or absence of the thyroid gland on the iodine metabolism and excretion in term Dutch newborns by performing a retrospective study of the urinary iodine excretion in 193 term newborns with abnormal congenital hypothyroidism screening results. Thirty-six euthyroid newborns with decreased thyroxine-binding globulin levels were compared with 157 hypothyroid patients, 54 due to thyroid agenesis and 103 due to thyroid dysgenesis. A significant difference in the urinary iodine excretion was observed between the agenesis group (mean: 28 micrograms/24 h) and the euthyroid newborns (mean: 46 micrograms/24 h, P=0.001). In conclusion, healthy, euthyroid, term newborns excreted more iodine in their urine than newborns with thyroid agenesis. These results strongly indicated the existence of a temporarily negative iodine balance: the excretion of iodine prevailed over the intake and the newborn's thyroidal iodine, stored during pregnancy, could be used for thyroxine synthesis in the postnatal period. Since healthy term neonates were able to maintain adequate plasma free thyroxine concentrations under normal TSH stimulation, the prenatally acquired iodine stores could be considered sufficiently high to compensate for the transient postnatal losses.

Female↗
PubMed1998

Placental iodothyronine deiodinase III and II ratios, mRNA expression compared to enzyme activity.

Iodothyronine deiodinases III and II (D3 and D2) specific enzyme activities in human placenta both decrease with gestational age. The relation of the enzyme activities with their respective mRNA expression was investigated by semi-quantitative RT-PCR on human placenta mRNA. To investigate if RT-PCR is a useful tool to detect iodothyronine deiodinase mRNA, several tissues were screened using this technique. In all tissues with iodothyronine deiodinase enzyme activity, the corresponding RT-PCR product is present. Similar to D3 specific enzyme activity, the amount of D3 mRNA in placenta declines with gestational age. The ratios of the D3/D2 enzyme activity and mRNA expression in placenta do not correlate. D3 enzyme activity shows an average 300-fold excess compared to D2 activity. However, semi-quantitative PCR analysis of D3 and D2 mRNA shows a D3/D2 ratio varying from 0.05 to 52. These results suggest that the placental D2 mRNA amplified is not translated into placental D2 enzyme activity.

Female↗