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H Biebermann

Publications and source records attributed to H Biebermann.

14 recordsLinked to original sources
PubMed2000

Constitutively activating TSH-receptor mutations as a molecular cause of non-autoimmune hyperthyroidism in childhood.

BACKGROUND: The glycoprotein hormone TSH (thyroid-stimulating hormone) and its receptor, the TSH-receptor (TSHR), play a crucial role in thyroid growth and function. Constitutively activating germline mutations within the TSHR gene were identified in patients with sporadic or familial non-autoimmune hyperthyroidism. Inheritance of these mutations is autosomal dominant. PATIENTS AND METHODS: We investigated two patients with neonatal onset of non-autoimmune hyperthyroidism and two families in whom the child and one parent are affected. RESULTS: Hyperthyroidism was difficult to treat in all of these patients and was complicated by premature craniosynostosis. Sequencing of all exons of the TSHR gene in one family with hyperthyroidism revealed a mutation in exon 10 (T6321), which was first identified in toxic adenomas and found to constitutively activate the TSHR. In the other family, we identified a new mutation in the first membrane spanning segment (G431S). In both patients with sporadic hyperthyroidism, a heterozygous mutation in exon 9 (S281N) was detected. The functional characterization of S281N and G431S demonstrated that both mutants were constitutively active. Therefore, these mutations are the molecular cause of non-autoimmune hyperthyroidism in the patients. CONCLUSIONS: For patients suffering from non-autoimmune hyperthyroidism, screening for mutations and their functional characterization is recommended. In case of an ineffective hyperthyroidism treatment, thyroidectomy should be performed to prevent lengthy anti-thyroid drug treatment and complications like premature craniosynostosis.

Child↗
PubMed2000

Molecular pathogenesis of neonatal hypothyroidism.

In patients with congenital hypothyroidism (CH), the autosomal recessive inheritance of mutations of thyroid peroxidase, thyroglobulin and the NIS and pendrin genes encoding for sodium iodide transporters has been identified. CH due to thyroid dysgenesis was considered to be a sporadic disease, but recently, inheritable defects of thyroid development have been described. The autosomal recessive inheritance of mutations of the thyroid-stimulating hormone receptor gene was recognized in patients with CH and thyroid hypoplasia, while autosomal dominant mutations of the Pax-8 gene were described in patients with thyroid dysgenesis. In addition, analysis of mutations of the beta-thyrotropin gene has resulted in a new understanding of the pathogenesis of central CH. Molecular genetic studies in patients with CH detected by newborn screening will provide the information necessary for genetic counselling and may help to explain the less favourable outcome present in 5-10% of the patients.

Carrier Proteins↗
PubMed1999

Alterations of neonatal thyroid function.

Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations.

Congenital Hypothyroidism↗
PubMed1999

Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene.

Isolated TSH deficiency leading to hypothyroidism seems to be a rare condition, escaping the diagnosis by neonatal screening programs, which are based on the primary determination of TSH. This is the first report of a case with an autosomal recessive TSH defect caused by a homozygous mutation of the betaTSH gene that was diagnosed in the early neonatal period. Hypothyroidism in the first child of apparently unrelated parents was suspected because of the classical symptoms of congenital hypothyroidism, which were fully expressed already on the 11th day of life. Routine neonatal TSH-screening on the 4th day of life had been normal, but subsequent determination of serum thyroid hormone levels revealed almost undetectable levels and thyroid hormone substitution was immediately started. Because there was no indication for other pituitary hormone deficiencies, sequence analysis of the betaTSH gene was initiated. A homozygous T deletion in codon 105 was found resulting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift. This altered betaTSH is a biologically inactive peptide. Because of the early development of severe symptoms, it is possible that this altered TSH suppresses the physiologic constitutive activity of the unliganded TSH receptor. Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded, that symptoms of hypothyroidism in the neonatal period should result always in an immediate comprehensive work-up of thyroid function including molecular genetic studies irrespective of the screening result.

Congenital Hypothyroidism↗
PubMed1998

V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms.

Loss-of-function mutations in the V2 vasopressin receptor (AVPR2) gene have been identified as a molecular basis for X-linked nephrogenic diabetes insipidus (NDI). Herein, we describe a novel deletion mutation at nucleotide position 102 (delG102) found in a Russian family resulting in a frameshift and a truncated receptor protein. Furthermore, we analyzed the AVPR2 gene of two other unrelated boys with NDI from our patient clientele. These patients showed previously described mutations (R137H, R181C). In-depth characterization of the three mutant AVPR2s by a combination of functional and immunological techniques permitted further insight into molecular mechanisms leading to receptor dysfunction. Premature truncation of the AVPR2 (delG102) led to a drastically reduced receptor protein expression in transfected COS-7 cells and, as expected, precluded specific AVPR2 functions. As indicated by different ELISA and binding studies, the R137H mutant was almost completely retained in the cell interior. In contrast to previous studies, the few mutant receptors in the plasma membrane displayed a low (2.3-fold above basal) but significant ability to stimulate the Gs/adenylyl cyclase system. In contrast to the latter mutation, the R181C mutant is properly delivered to the cell surface but the mutation interferes with high affinity vasopressin binding. Impaired ligand binding is reflected in an about 100-fold shift of the concentration-response curve toward higher vasopressin concentrations with only slightly reduced agonist potency.

Amino Acid Sequence↗
PubMed1998

Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.

Sequential cleavage of the precursor protein pre-pro-opiomelanocortin (POMC) generates the melanocortin peptides adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) alpha, beta and gamma as well as the opioid-receptor ligand beta-endorphin. While a few cases of isolated ACTH deficiency have been reported (OMIM 201400), an inherited POMC defect has not been described so far. Recent studies in animal models elucidated a central role of alpha-MSH in the regulation of food intake by activation of the brain melanocortin-4-receptor (MC4-R; refs 3-5) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus, led to the proposal of an association of POMC with human obesity. The dual role of alpha-MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity, alteration in pigmentation and ACTH deficiency. The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes. Patient 1 was found to be a compound heterozygote for two mutations in exon 3 (G7013T, C7133delta) which interfere with appropriate synthesis of ACTH and alpha-MSH. Patient 2 was homozygous for a mutation in exon 2 (C3804A) which abolishes POMC translation. These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early-onset obesity, adrenal insufficiency and red hair pigmentation.

Adrenal Insufficiency↗
PubMed1998

A conserved tyrosine residue (Y601) in transmembrane domain 5 of the human thyrotropin receptor serves as a molecular switch to determine G-protein coupling.

In the human thyroid, the wild-type thyrotropin receptor (TSHR) couples to adenylyl cyclase and phospholipase C and constitutively increases intracellular cAMP levels. The first human TSHR sequence submitted differs from subsequently cloned wild-type receptors by an exchange of a conserved Y residue within transmembrane domain 5 (TM5) for an H residue. We did not detect the Y601H mutant in 263 European individuals, but confirmed the homozygous occurrence of TSHR-Y601. Expression of TSHR-Y601H in COS-7 cells revealed a loss of constitutive cAMP production and selective lack of TSH-induced phosphoinositide hydrolysis, whereas agonist-induced cAMP formation remained unaltered. Analysis of several mutant receptors (Y601A, Y601D, Y601F, Y601K, Y601P, Y601S, Y601W, Y601Delta) did not show restoration of constitutive activity and dual signaling, thus suggesting a functional role of a properly spaced hydroxyl group at position 601. Molecular modeling revealed that the formation of a hydrogen bond between the hydroxyl group of Y601 in TM5 and the carbonyl oxygen of A623 in the peptide backbone of TM6 is critical for the receptor to adopt active conformations that impart wild-type signaling properties. Our findings indicate that multiple active receptor states underlie coupling of a G-protein-coupled receptor to different G-proteins.

Animals↗
PubMed1998

Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor.

Gain of function mutations in the TSH receptor (TSHR) have been identified as the molecular basis for congenital and acquired forms of autonomous thyroid function. Herein, we report the molecular characterization of a case of severe congenital hyperthyroidism with a history of hyperthyroidism in the paternal aunt and the paternal grandmother, who were both found to be heterozygous for a mutation (R528H) located in exon 10 of the TSHR gene. Functional expression of the mutant TSHR-R528H in COS-7 cells, however, did not result in constitutive activity of the TSHR. Subsequent analysis of exons 1-9 led to the detection of an additional heterozygous mutation (S281N) in the patient, but not in other family members. Interestingly, the latter mutation is located in the extracellular domain of the TSHR, and functional studies revealed a marked increase in basal cAMP levels when the mutant receptor was expressed in COS-7 cells. To address the question of whether both mutations were present on the same allele, a double mutant TSHR (S281N/R528H) was generated and characterized. These functional studies in conjunction with RT-PCR analysis of thyroid tissue obtained from subtotal thyroidectomy performed at the age of 6 yr revealed that the patient bears two distinct mutations on different alleles: the familial paternal R528H mutation to be regarded as a polymorphism and a de novo mutation (S281N) on the maternal allele accounting for the clinical picture. Thus, the main conclusions to be drawn from this case are 1) a search for mutations in cases of congenital nonautoimmune hyperthyroidism should not remain restricted to exon 10 of the TSHR gene, because germ-line gain of function mutations of the TSH receptor can be located outside of the transmembrane core of the receptor; and 2) this case illustrates the necessity for careful functional characterization of any novel mutation before a causal relationship to hyperthyroidism can be established.

Alleles↗
PubMed1997

Congenital hyperthyroidism.

Congenital hyperthyroidism is a very rare disease. But, for each affected child it has to be considered as a serious condition because of the negative impact of hyperthyroidism on fetal and postnatal development. If the manifestation occurs during fetal life tachycardia, cardiac arrhythmia, growth retardation and, most significant, prematurity are the consequences. Postnatal signs of hyperthyroidism are irritability, tachycardia, hypertension, poor weight gain and thyroid enlargement. Even cardiac failure may occur if hyperthyroidism is severe and treatment not adequate which explains the high early mortality rate of 16%. The main complication of persistent hyperthyroidism in the neonatal period and during infancy is craniosynostosis. Severe developmental delay or even mental retardation can be the consequence of inadequate high T4-levels during fetal and neonatal life. Congenital hyperthyroidism was first recognized in infants born to mothers with Graves' disease. The description of transplacental passage of the maternal thyroid stimulating antibodies elucidated the molecular mechanism in this major group of patients with "autoimmune congenital hyperthyroidism". In contrast to this transient, self-limited character of "autoimmune congenital hyperthyroidism", due to the clearance of maternal antibodies from the infant's circulation, some cases of persistent congenital hyperthyroidism without signs of thyroid autoimmunity have been recognized. Activating mutations in the thyroid-stimulating hormone receptor were described recently as the underlying molecular pathogenesis in this group of "non-immune congenital hyperthyroidism". Therefore the possibility of a molecular differential diagnosis of both groups of congenital hyperthyroidism now exists and opens the opportunity of optimal treatment for each patient.

Autoimmune Diseases↗
PubMed1997

Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism.

The pathogenesis of congenital hypothyroidism due to thyroid dysgenesis is still unknown. A point mutation in the TSH receptor (TSHR) of the hypothyroid hyt/hyt mouse invoked the TSHR as a candidate gene for congenital hypothyroidism. Therefore, we screened for mutations in the TSHR gene in patients with congenital hypothyroidism and hypoplasia of the gland. In one girl detected in neonatal screening with the confirmed diagnosis of permanent congenital hypothyroidism with reduced thyroid volume, two novel mutations in the TSHR gene were identified. Single strand conformational polymorphism and subsequent DNA sequencing studies of a fragment of the TSHR gene showed that the patient is a compound heterozygote for 2 loss of function mutations in exon 10 of the TSHR gene. In the mutant maternal allele, 18 nucleotides (positions 1217-1234) are deleted, and 4 novel bp are inserted, resulting in a frame-shift and premature termination of the coding sequence. Transfection studies showed that this truncated TSHR was trapped intracellularly and completely lacked cell surface expression. The paternal gene harbors a missense mutation at nucleotide position 1170, leading to the exchange of the highly conserved C-390 for a W residue. This alteration resulted in a drastic loss of affinity and potency of TSH acting at the mutant compared to the wild-type receptor. In contrast to the published loss of function mutations of the TSHR leading to euthyroid hyperthyrotropinemia, the two new mutations lead to persistent congenital hypothyroidism and defective organ development. Further studies will have to analyze to what extent TSHR mutations are involved in the pathogenesis of congenital hypothyroidism as opposed to other genetic or environmental factors.

Amino Acid Sequence↗
PubMed1996

The gene for the thyrotropin receptor (TSHR) as a candidate gene for congenital hypothyroidism with thyroid dysgenesis.

According to the central role of the TSH receptor for thyroid function and growth the gene for the TSH receptor is a possible candidate gene for mutations which result in an impairment of thyroid growth and function (Vassart and Dumont 1992). First evidence for the role of TSH receptor defects in the pathogenesis of congenital thyroid disorders was elucidated by the presence of activating germline mutations leading to congenital hyperthyroidism (Duprez et al., 1994). After the finding of partial loss-of-function mutations leading to hyperthyrotropinemia (Sunthornthepvarakul et al., 1995) it was speculated that a more severe phenotype with hypothyroidism and hypoplasia of the gland (thyroid dysgenesis) would be the result, if complete loss-of-function mutations like the isoleucine167 to asparagine mutation would occur in a homozygote or compound heterozygote state. The screening of TSHR gene mutations by SSCP in a well defined cohort of 100 children with congenital hypothyroidism (CH), diagnosed and followed since 1978 in the Childrens Hospital of Berlin, revealed one patient with hypoplasia of the thyroid to be positive for two compound heterozygote inactivating mutations of the TSHR gene, indicating thereby that the clinical approach to define phenotypes of interest could be helpful to understand the fundamental process of thyroid development.

Animals↗
PubMed1996

Screening for mutations of the human thyroid peroxidase gene in patients with congenital hypothyroidism.

While congenital hypothyroidism in 80-90% of the affected individuals is caused by thyroid dysgenesis (athyrosis, ectopy or hypoplasia), hypothyroidism in patients with a thyroid gland of normal position and size can be due to regulatory or enzymatic defects of thyroid hormone biosynthesis. Beside defects of thyroglobulinsynthesis, defects of the sodium-iodide-transporter or the TSH-receptor, a defect of the thyroidperoxidase, the key-enzyme of thyroid hormone biosynthesis, can cause a total iodide organification defect and thereby congenital hypothyroidism. We screened 14 of 103 patients (13.6%) with non familial congenital hypothyroidism and a normally developed thyroid gland detected by the newborn screening program with the PCR-SSCP (single-stranded-conformational-polymorphism) technique for mutations in the exons 2, 8, 9, 10 and 14 of the human thyroperoxidase gene, and in which mutations had been described previously in Dutch and Brazilian families with total organification defects. Most of the previously reported mutations were found in exons 8, 9 and 10 which code for the caralytic part of the enzyme. In two patients a GGCC-duplication in exon 8 was detected leading to a premature stop codon in exon 9. While one patient without neonatal goiter was homozygous for this mutation, the second patient was only heterozygous thus demanding another mutation on the second TPO-allel to explain the phenotype. Since the GGCC duplication is easily demonstrable by a NaeI digestion, because it creates a restriction site for this enzyme, screening for this mutation is indicated since it is easy to perform. In contrast to the perchlorate discharge test molecular genetic studies are less invasive, but as useful in making a definitive diagnosis in the individual patient. Furthermore it is the first feasible step to study the etiology and epidemiology of the so far only putative defects of thyroid hormone biosynthesis leading to congenital hypothyroidism.

Congenital Hypothyroidism↗
PubMed1996

Transient congenital hypothyroidism and hyperthyrotropinemia: normal thyroid function and physical development at the ages of 6-14 years.

Since the introduction of screening programs for congenital hypothyroidism, transient disturbances of thyroid function, especially transient congenital hypothyroidism and hyperthyrotropinemia, mostly due to iodine deficiency or contamination have been observed with variable frequencies. This study was carried out to reevaluate the thyroid function and physical development of 61 schoolchildren with transient congenital hypothyroidism or transient congenital hyperthyrotropinemia. Abnormalities were observed in 3 children. Thyroid function and growth were normal in all children, except 2 with moderately elevated TSH levels at the age of 7.7 and 10 yr in the presence of normal thyroid hormone levels. In 1 child, the TSH elevation was due to an ectopic hemithyroidea; in the other child, an unknown familial cause was suggested. In 1 girl (aged 12 yr), a euthyroid goiter caused by autoimmune thyroiditis was detected. We conclude from our investigation that frequent monitoring of thyroid function in children with transient congenital hypothyroidism or transient congenital hyperthyrotropinemia is not necessary during childhood if, postnatally, thyroid function recovered spontaneously. However, the growth and development of children with neonatal thyroid dysfunction should be followed, and if abnormalities occur, thyroid function tests are essential.

Adolescent↗