Biomedical subjects

Heiko Krude

Publications and source records attributed to Heiko Krude.

12 recordsLinked to original sources

PubMed2004

Childhood obesity.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Child↗

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↗

PubMed2003

Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor inactivation in patients with obesity.

By screening patients with severe early onset obesity for mutations within the melanocortin 4 receptor (MC4R) gene, we have identified a missense mutation (C271R) that occurs homozygous in two siblings with obesity. In-depth functional characterization of C271R revealed a right-shifted concentration response curve due to lower affinity to natural and synthetic MC4R agonists and a reduced cell surface expression. Cys-271 is located in the third extracellular loop. Here, we provide evidence that Cys-271 forms an intra-loop disulfide bond with Cys-277. Unexpectedly, we found that loss of receptor function is not only caused by the disruption of this disulfide bridge. Our data strongly support a new mechanism in which the receptor malfunction in the C271R mutant is induced by formation of a functionally disastrous disulfide bridge between Cys-277 and a third Cys residue at position 279. Mutational and chemical disruption of this improper disulfide bond was able to restore normal receptor potency. By demonstrating that a loss of a disulfide bond-participating Cys residue can favor a functionally disastrous disulfide bond, we now add a new mechanism of how Cys residues can be involved in G-protein-coupled receptor malfunction.

Adolescent↗

PubMed2003

Mutations in the human proopiomelanocortin gene.

The melanocortin peptides and their receptors represent one of the most complex systems in human endocrinology. Hormonal regulation includes pigmentation, weight maintenance, adrenal function, and exocrine gland secretion via endocrine, paracrine, autocrine, and neurocrine action of melanocortin peptides at five different but homologous melanocortin receptors. Genetic relevance of the melanocortin system for human physiology was initially shown by mutations in the different melanocortin receptor genes, first described in the melanocortin-2 receptor gene in 1993 as one reason for congenital hypocortisolism. Because all ligands within the melanocortin systems are derived from one single precursor hormone, proopiomelanocortin (POMC), a genetic defect in the POMC gene could have been expected to affect all functional components of the melanocortin system. Accordingly, patients with a complete defect of the POMC gene product due to homozygous or compound heterozygous loss of function mutations were shown to be affected mainly by red hair, early-onset obesity, and congenital hypocortisolism. No further obvious clinical problems were described in these patients, suggesting that no additional function of the melanocortin system has escaped recognition. However, whether partial loss of function mutations in the POMC gene might lead to more circumscribed phenotypes, especially common obesity, remains an open question.

Animals↗

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

Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation.

We report on a 25-year-old patient with isolated mitochondrial complex III deficiency and a new heteroplasmic mutation (T14849C) in the cytochrome b gene. He suffered from septo-optic dysplasia, retinitis pigmentosa, exercise intolerance, hypertrophic cardiomyopathy, and rhabdomyolysis. A HESX1 mutation was excluded as a cause of his septo-optic dysplasia. Low alpha-tocopherol concentrations in his muscles and an elevated urinary leukotriene E(4) excretion indicate increased production of reactive oxygen species.

Adult↗

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↗

PubMedDate not supplied

Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.

Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.

Child↗