Biomedical subjects

Annette Grüters

Publications and source records attributed to Annette Grüters.

At least 19 recordsLinked to original sources

PubMed2006

Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci.

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases.

Adult↗

PubMed2006

A role for beta-melanocyte-stimulating hormone in human body-weight regulation.

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.

Amino Acid Sequence↗

PubMed2006

Arteries define the position of the thyroid gland during its developmental relocalisation.

During vertebrate development, the thyroid gland undergoes a unique relocalisation from its site of induction to a distant species-specific position in the cervical mesenchyme. We have analysed thyroid morphogenesis in wild-type and mutant zebrafish and mice, and find that localisation of growing thyroid tissue along the anteroposterior axis in zebrafish is linked to the development of the ventral aorta. In grafting experiments, ectopic vascular cells influence the localisation of thyroid tissue cell non-autonomously, showing that vessels provide guidance cues in zebrafish thyroid morphogenesis. In mouse thyroid development, the midline primordium bifurcates and two lobes relocalise cranially along the bilateral pair of carotid arteries. In hedgehog-deficient mice, thyroid tissue always develops along the ectopically and asymmetrically positioned carotid arteries, suggesting that, in mice (as in zebrafish), co-developing major arteries define the position of the thyroid. The similarity between zebrafish and mouse mutant phenotypes further indicates that thyroid relocalisation involves two morphogenetic phases, and that variation in the second phase accounts for species-specific differences in thyroid morphology. Moreover, the involvement of vessels in thyroid relocalisation sheds new light on the interpretation of congenital thyroid defects in humans.

Animals↗

PubMed2005

Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart- Willi syndrome.

CONTEXT: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS), central or peripheral, remains unexplained. OBJECTIVES: The objectives of this study were to investigate the cause of hypogonadism in PWS and determine whether human chorionic gonadotropin (hCG) treatment can restore pubertal development. DESIGN: This was a clinical follow-up study, divided into two samples, over a duration of 1.5 and 4.5 yr. PATIENTS: Eight male infants and six peripubertal boys (age at start of observation, 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied. INTERVENTION: hCG (500-1500 U twice weekly) was given from age 13.5 yr to the present. MAIN OUTCOME MEASURES: Serum FSH, LH, inhibin B, and testosterone levels and pubertal development were the main outcome measures. RESULTS: Infants with PWS presented normal LH (2.3 +/- 0.7 U/liter) and testosterone (2.5 +/- 0.9 nmol/liter) levels (mean +/- sem at 5 months) compared with the reference range. However, two thirds of the boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr, 72 +/- 17 pg/ml), whereas FSH secretion increased (9.9 +/- 2.6 U/liter). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 +/- 2 nmol/liter) and reduced FSH (at 16 yr, 1.1 +/- 0.9 U/liter) levels. Testicular volume (5.6 +/- 1 ml) and inhibin B (26.5 +/- 11.9 pg/ml) remained low. CONCLUSION: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B and high FSH) hypogonadism, suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization.

Child↗

PubMed2005

MC4R oligomerizes independently of extracellular cysteine residues.

The melanocortin 4 receptor (MC4R) plays an essential role in weight regulation. Recently we could show that the MC4R is able to form receptor dimers. In the present study we investigated the role of extracellular cysteine residues and the structure of the third extracellular loop for receptor dimerization. None of the four extracellular cysteine residues nor the structure of the third extracellular loop play a role for MC4R-MC4R interaction as all investigated mutants display the same dimerization pattern as the wild-type receptor. Therefore for MC4R dimerization structures of the transmembrane-spanning helices are more likely to be involved.

Amino Acid Sequence↗

PubMed2005

Impaired glucose tolerance and type 2 diabetes mellitus: a new field for pediatrics in Europe.

OBJECTIVE: Several studies have shown that obese children and adolescence seem to have an increased risk to develop a disturbed glucose metabolism as already known for obese adults. This might result in the same disastrous outcomes of cardiovascular diseases as it has been shown for adult obese patients. The most sensitive measurement for detecting changes in glucose metabolism in obese children seems to be an oral glucose tolerance test (OGGT) which is not practical for all daily outpatient clinics. DESIGN: Cross-sectional study. SUBJECTS AND MEASUREMENTS: We therefore made a preselection from a cohort of 491 subjects according to the American Diabetes Association (ADA) criteria for the diagnosis of diabetes. In the selected high-risk subgroup (n = 102) of obese pediatric subjects, we measured the prevalence of impaired glucose tolerance (IGT) by OGTT. RESULTS: We diagnosed six patients with type 2 diabetes and 37 patients with impaired glucose tolerance. In addition, we found a close correlation of IGT to disturbances of triglyceride and cholesterol parameters. This prevalence was comparable to a similar study group that was screened without preselection. CONCLUSIONS: These prevalence data further underline the need to diagnose children with obesity-associated risk factors in terms of an insulin resistance syndrome. The preselection of a high-risk subgroup by ADA criteria might be a practical approach.

Adolescent↗

PubMed2004

Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in liver, heart and kidney.

To assess interference with endocrine regulation of the thyroid axis, rats (female, ovariectomised) were treated for 12 weeks with the suspected endocrine active compounds (EAC) or endocrine disrupters (ED) 4-nonylphenol (NP), octyl-methoxycinnamate (OMC) and 4-methylbenzylidene-camphor (4-MBC) as well as 17beta-estradiol (E2) and 5alpha-androstane-3beta,17beta-diol (Adiol) on the background of a soy-free or soy-containing diet, and endpoints relevant for regulation via the thyroid axis were measured. Thyrotropin (TSH) and thyroid hormone (T4, T3) serum levels were altered, but not in a way consistent with known mechanisms of feedback regulation of the thyroid axis. In the liver, malic enzyme (ME) activity was significantly increased by E2 and Adiol, slightly by OMC and MBC and decreased by soy, whereas type I 5'-deiodinase (5'DI) was decreased by all treatments. This may be due rather to the estrogenic effect of the ED, as there is no obvious correlation with T4 or T3 serum levels. None of the substances inhibited thyroid peroxidase (TPO) in vitro, except for NP. In general, several endocrine active compounds disrupt the endocrine feedback regulation of the thyroid axis. However, there was no uniform, obvious pattern in the effects of those ED tested, but each compound elicited its own spectrum of alterations, arguing for multiple targets of interference with the complex network of thyroid hormone action and metabolism.

Animals↗

PubMed2004

Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity -- a problem that is no longer restricted to minority groups.

BACKGROUND: The incidence of childhood obesity and type 2 diabetes is an increasing problem in Europe. We determined the prevalence of impaired glucose regulation in a predominantly Caucasian cohort of 491 children and adolescents with obesity. METHODS: Fasting glucose and insulin levels were determined in all 491 subjects. Patients with an abnormal fasting glucose or with additional risk factors (positive family history of type 2 diabetes, acanthosis nigricans, hyperlipidemia; n=102) underwent an oral glucose tolerance test (OGTT; 1.75 g glucose/kg body weight). Homeostasis model assessment was used to estimate insulin resistance in all subjects. The insulin sensitivity index was determined in those subjects who underwent an OGTT. Screening for mutations in the melanocortin 4 receptor (MC4R) gene and the coding region of the brain-derived neutrophic factor (BDNF) in 37 patients with an impaired glucose tolerance was performed by WAVE analysis. RESULTS: Out of the total of 491 patients, 12 had an abnormal fasting glucose level. Of the 102 patients who underwent an OGTT, 37 had impaired glucose tolerance; 6 out of the 102 patients were diagnosed with type 2 diabetes. Eighty-eight per cent of patients with abnormal glucose tolerance and 66% of patients with type 2 diabetes were Caucasian. Insulin resistance indices correlated well with the degree of abnormal glucose tolerance. Using the screening algorithm for type 2 diabetes as advocated by the American Diabetes Association, 68% of patients with impaired glucose tolerance and 66% of patients with type 2 diabetes would have been missed. No abnormalities in the MC4R and BDNF genes were detected. CONCLUSIONS: Impaired glucose tolerance and type 2 diabetes are far more common in obese European children of Caucasian origin than previously thought. Using fasting glucose levels as the main screening tool appears to be insufficient in detecting these children.

Acanthosis Nigricans↗

PubMed2004

Molecular genetic defects in congenital hypothyroidism.

Recently molecular genetic defects in some cases of congenital hypothyroidism (CH) as well as of rare cases of central hypothyroidism have been identified. These studies have led to the description of so far unexplained forms of these disorders. In some patients with CH early diagnosis by newborn screening and early treatment was not able to lead to a normal mental development. This could subsequently be explained by molecular defects of transcription factors (FOXE-1/FKHL15, NKX2.1) which are important not only for the embryonic development of the thyroid gland but also for other organs including the central nervous system (CNS). These findings will help in understanding the critical role of thyroid hormones in the pre-and postnatal CNS development. However, many questions regarding the molecular defects and their consequences in the majority of patients with CH still remain open and will be addressed in this article.

Animals↗

PubMed2004

[Characteristic features of autoimmune thyroid disease in children].

The present review discusses in detail the most important problems of autoimmune thyroid disease in children and adolescents. There is a low incidence of autoimmune thyroid disorders in children and adolescents, the most important being Hashimoto's thyroiditis. Painless thyroid enlargement and delayed development are essential symptoms. Patients suffering from hypothyroidism or goitre should be treated with 1-thyroxin. The aim of treatment is to normalise metabolism and TSH levels. Graves' disease in children and adolescents is uncommon, and clinical features may be subtle. Typical eye symptoms are very often not present. Compared to older patients, the duration of symptoms is usually longer and the degree of hyperthyroidism more pronounced. This is why children require more time to achieve remission after anti-thyroid drug treatment. As already indicated, surgery is usually preferred to radioiodine.

Adolescent↗

PubMed2003

Neonatal thyroid disorders.

Congenital hypothyroidism is the most prevalent endocrine disorder in the newborn and affects 1 in 3000-4000 newborns. Screening for congenital hypothyroidism is a major achievement of paediatrics because early diagnosis and treatment have resulted in normal development in nearly all cases. The cause of congenital hypothyroidism in the majority of newborns is unknown. However, in some patients the molecular basis of their congenital hypothyroidism has recently been clarified. In patients with congenital hypothyroidism and a normally developed thyroid gland, the autosomal recessive inheritance of loss-of-function mutations of genes encoding for the thyroid peroxidase gene, the sodium-iodide symporter gene and the pendrin gene have been identified. The autosomal recessive inheritance of loss-of-function mutations of the thyroid stimulating hormone (TSH) receptor as well as the dominant inheritance of mutations encoding for transcription factors have been identified in patients with defective thyroid development. Furthermore, it has become evident that in some patients with persistent mental retardation and neurological symptoms, defects of the transcription factor NKX2.1, which is expressed in the thyroid gland as well as in the CNS during embryonic development, cause both defective thyroid and CNS development resulting in persistent neurological and mental defects despite early diagnosis and treatment. Central hypothyroidism is a rare disease with an estimated frequency of not more than 1 in 50000 newborns. Central hypothyroidism can be due to recessive inheritance of loss-of-function mutations of the TSH-beta gene and to developmental defects of the hypothalamus or pituitary. In contrast to the previous assumption that isolated TSH deficiency will not lead to impaired mental development, identification of the molecular defects in central hypothyroidism has clearly demonstrated that some of these patients will have impaired mental development. Clarification of the molecular defects of thyroid development will help to explain the differences in outcome in patients with congenital hypothyroidism and to develop new diagnostic and therapeutic strategies to ensure adequate counselling and care for these patients.

Animals↗

PubMed2003

Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4-10.

The symptoms of severe early-onset obesity, adrenal insufficiency, and red hair define the proopiomelanocortin (POMC) deficiency syndrome as described so far in two children with complete loss-of-function mutations of the human POMC gene. In POMC deficiency, obesity reflects the lack of POMC-derived peptides as ligands at the melanocortin (MC) MC4 and MC3 receptors, which are expressed in the hypothalamic leptin-melanocortin pathway of body weight regulation. Hypocortisolism and alteration of pigmentation are caused by the lack of POMC-derived peptides at the adrenal MC2 receptor and the skin MC1 receptor, respectively. Here we describe three new cases of complete loss-of-function mutations of the POMC gene. Patients were diagnosed based on the clinical trials of red hair, adrenal insufficiency, and early-onset severe obesity. One previously described translation initiation mutation (C3804A) as well as one new nonsense (A6851T) and two new frame-shift mutations (6996del and 7100 + 2G) were found in homozygosity or compound heterozygosity. The heterozygous parents were found to have high normal or mildly elevated body weight, suggesting a dosage effect of the POMC gene product on weight regulation. To compensate for the lack of hypothalamic melanocortin function, we initiated a trial in the two previously published patients with intranasal ACTH4-10, a melanocortin fragment for which an anorexic effect has been described recently. During 3 months with increasing doses of ACTH4-10, no change of body weight or metabolic rate was observed, suggesting that at least in these two POMC-deficient patients ACTH4-10 is without any compensatory effect. In the same two patients, further investigation revealed a mildly elevated TSH. However, a 1-yr treatment with thyroid hormone did not result in a significant reduction of body weight.

Adrenocorticotropic Hormone↗

PubMed2003

Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization.

Mutations in the melanocortin-4 receptor (MC4R) gene are the most frequent monogenic causes of severe obesity. Most mutations have been described as heterozygous with loss of function, suggesting that haploinsufficiency is the most likely mechanism of dominant inheritance. We detected a heterozygous mutation, D90N, in a patient with severe early-onset obesity. Functional characterization of the mutant receptor revealed normal cell-surface expression and binding properties but loss of signal transduction activity. In coexpression studies of wild-type (WT)-MC4R and D90N, the mutant receptor had a dominant-negative effect on WT-receptor function. Further investigation of this effect with sandwich enzyme-linked immunosorbent assays and fluorescence resonance energy transfer studies showed that the WT-MC4R and the D90N mutant form homodimers and heterodimers. We hypothesize that the dominant-negative effect of the D90N mutation is caused by a functionally altered WT-MC4R/D90N receptor heterodimer. These findings necessitate the reinvestigation of other heterozygous MC4R missense mutations to discriminate between haploinsufficiency and a dominant-negative effect. The finding of receptor dimerization highlights a more complex hypothalamic signaling network governing the regulation of body weight.

Age of Onset↗

PubMed2002

Mutations in TITF-1 are associated with benign hereditary chorea.

Benign hereditary chorea (BHC) (MIM 118700) is an autosomal dominant movement disorder. The early onset of symptoms (usually before the age of 5 years) and the observation that in some BHC families the symptoms tend to decrease in adulthood suggests that the disorder results from a developmental disturbance of the brain. In contrast to Huntington disease (MIM 143100), BHC is non-progressive and patients have normal or slightly below normal intelligence. There is considerable inter- and intrafamilial variability, including dysarthria, axial dystonia and gait disturbances. Previously, we identified a locus for BHC on chromosome 14 and subsequently identified additional independent families linked to the same locus. Recombination analysis of all chromosome 14-linked families resulted initially in a reduction of the critical interval for the BHC gene to 8.4 cM between markers D14S49 and D14S278. More detailed analysis of the critical region in a small BHC family revealed a de novo deletion of 1.2 Mb harboring the TITF-1 gene, a homeodomain-containing transcription factor essential for the organogenesis of the lung, thyroid and the basal ganglia. Here we report evidence that mutations in TITF-1 are associated with BHC.

Amino Acid Sequence↗

PubMed2002

Long-term consequences of congenital hypothyroidism in the era of screening programmes.

Newborn screening for congenital hypothyroidism (CH), is one of the major achievements of medicine because early diagnosis and treatment has resulted in normal development in the vast majority of cases. However, all studies on outcome report up to 10% of patients with residual problems regarding mental development and neurological symptoms despite early diagnosis. Factors clearly associated with a less favourable outcome are late onset and an inadequate dosage of thyroid hormone substitution, a poor social-economic environment and compliance problems, while the impact of severity of CH at diagnosis on outcome is not completely settled, although most studies demonstrate a correlation between severity of hypothyroidism and poorer outcome. More recently in a few cases the molecular basis of CH has been clarified. It has become evident that, in some patients with persistent mental retardation and neurological symptoms, defects in transcription factors which are expressed in the thyroid gland as well as in the central nervous system (CNS) during embryonic development cause both defective thyroid and CNS development. The clarification of further molecular defects which affect the thyroid gland and brain development will help us to understand the poor outcome of patients with CH in the era of newborn screening and these diagnostic advances will ensure adequate counselling and care for these patients.

Congenital Abnormalities↗

PubMed2002

Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency.

The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1, we investigated the human NKX2-1 gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C2519A, C1302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the NKX2-1 gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with NKX2-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.

Adolescent↗

PubMed2002

Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus.

By screening patients with X-linked nephrogenic diabetes insipidus (NDI) for mutations within the V(2) vasopressin receptor (AVPR2) gene, we have identified six novel and two recurrent mutations. Additionally, one patient revealed a genomic deletion of 3.2 kb encompassing most of the AVPR2 gene and the last exon/3'-region of C1 gene, which is in close proximity to the AVPR2 locus. In-depth characterization of the mutant AVPR2s by a combination of functional and immunological techniques allowed to gain further insight into molecular mechanisms leading to the receptor dysfunction. Aiming at the functional reconstitution of mutant G protein-coupled receptors, several strategies of potential therapeutic usefulness have been tested. Because the functional rescue of truncated receptors is most challenging, we addressed this issue by applying an aminoglycoside approach. Here, we demonstrate that the misreading capacity of the aminoglycoside antibiotic geneticin was sufficient to restore function of mutant AVPR2s harboring premature stop codons in an in vitro expression system.

Amino Acid Sequence↗

PubMed2002

Congenital central hypothyroidism due to homozygous thyrotropin beta 313 Delta T mutation is caused by a Founder effect.

Neonatal TSH screening has been a major achievement for the early detection and treatment of primary congenital hypothyroidism. It nevertheless fails to reveal cases of central hypothyroidism caused by TSH levels in the low normal range. In the last 10 yr, homozygous mutations in the TSHbeta-subunit gene have been recognized as a cause of central hypothyroidism with isolated TSH deficiency. The most frequent TSHbeta mutation 313DeltaT (C105V) has been described in six apparently unrelated families. We investigated the frequency and possible monophyletic origin of the different TSHbeta 313DeltaT alleles of the three affected families. Haplotype analysis of five polymorphic single-nucleotide polymorphism loci in the TSHbeta region revealed the presence of seven different haplotypes in the general population. In all six parental lines, the mutation occurred on the same haplotype. Extending the haplotype by two flanking microsatellite markers led to a mutational age estimate of about 150 generations. In 500 unrelated individuals from the general population, we did not detect any TSHbeta 313DeltaT allele, suggesting a population heterozygote carrier frequency less than 1:170 with more than 95% probability. Accordingly, the disease risk in the general population because of homozygosity is low. Our data suggest a monophyletic origin of the TSHbeta 313DeltaT mutation from a common ancestor and no significant population prevalence. Therefore, identification and genetic counseling of heterozygous carriers in affected families seems to be more advisable than population-wide neonatal T(4) screening programs for an early detection of this rare condition.

Alleles↗