Biomedical subjects

Peter Kopp

Publications and source records attributed to Peter Kopp.

15 recordsLinked to original sources

PubMed2006

Goitrous congenital hypothyroidism and hearing impairment associated with mutations in the TPO and SLC26A4/PDS genes.

CONTEXT: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses. CASE REPORT: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected. METHODS: We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro. RESULTS: Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro. CONCLUSIONS: These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.

Congenital Hypothyroidism↗

PubMed2005

Radiotherapy planning for lung cancer: slow CTs allow the drawing of tighter margins.

BACKGROUND AND PURPOSE: Evaluation of the use of planning CTs with slow revolution time (4s/slice; 'slow CTs') in the planning procedure of radiotherapy for lung cancer patients in comparison to commonly used 'fast' planning CTs; impact on margin assessment of planning target volume (PTV) design. PATIENTS AND METHODS: Eighteen lung cancer patients (six upper, lower lobe and central tumors, respectively) have been scanned each by three series of slow CTs and one fast CT (spiral CT). Patients have been freely breathing. The largest transversal tumor diameters in slow and fast CTs have been measured. Tumor edge positions have been determined for six spatial directions in all slices of the three slow CT series. RESULTS: Slow CTs show larger dimensions of the visible tumor than fast CTs. The median difference of the diameter for all tumors is 2mm (range 0-4mm). Slow CTs deliver constant depictions of lung tumors within a range of 1.6mm in all directions. This margin is considered to be sufficient to compensate for tumor movements by respiration and cardiovascular motions (internal margin). A margin of 7 mm added to the GTV of a single slow CT series to draw the PTV is proposed. CONCLUSIONS: Slow planning CTs show larger, but highly constant depictions of lung tumors in comparison to conventional fast CT scanning, yielding an integral delineation of almost all positions of the moving tumors. Thus the use of slow planning CTs enables the drawing of tighter margins in external beam treatment planning of lung cancer.

Aged↗

PubMed2005

Naturally occurring mutations in the thyroglobulin gene.

Thyroglobulin (Tg) is a large glycoprotein dimer secreted into the follicular lumen. It serves as the matrix for the synthesis of thyroxine (T4) and triiodothyronine (T3), and the storage of thyroid hormone and iodide. In response to demand for thyroid hormone secretion, Tg is internalized into the follicular cell and digested in lysosomes. Subsequently, the thyronines T4 (approximately 80%) and T3 (approximately 20%) are released into the blood stream. Biallelic mutations in the Tg gene have been identified in several animal species and human patients presenting with goiter and overt or compensated hypothyroidism. In untreated patients, goiters are often remarkably large and display continuous growth. In most instances, the affected individuals have related parents and are homozygous for inactivating mutations in the Tg gene. More rarely, compound heterozygous mutations lead to a loss of function of both alleles. Molecular analyses indicate that at least some of these alterations result in a secretory defect and an endoplasmic reticulum storage disease (ERSD). This review discusses the nature and consequences of naturally occurring Tg gene mutations in humans and several animal species. Recent recommendations for the nomenclature of mutations have led to different numbering systems, an aspect that is discussed in order to clarify discrepancies between different publications.

Animals↗

PubMed2005

Thyroid carcinoma.

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Biomarkers, Tumor↗

PubMed2004

Quantitative trait loci associated with elevated thyroid-stimulating hormone in the Wistar-Kyoto rat.

Thyroid hormones are essential for the regulation of developmental and physiological processes. The genetic factors underlying naturally occurring variability in mammalian thyroid function are, however, only partially understood. Genetic control of thyroid function can be studied with animal models such as the inbred Wistar-Kyoto (WKY) rat strain. Previous studies established that WKY rats have elevated TSH, slightly elevated total T3, and normal total T4 levels compared with Wistar controls. The present study confirmed a persistent 24-h elevation of TSH in WKY rats compared with the Fisher 344 (F344) rat, another inbred strain. Acute T3 challenge (25 microg/100 g body weight ip) suppressed serum TSH and T4 levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY x F344 F2 population identified one highly significant locus on chromosome 6 (LOD=11.7, TSH-1) and one suggestive locus on chromosome 5 (LOD=2.3, TSH-2). The confidence interval of TSH-1 contains the TSH receptor and type 2 deiodinase genes, and TSH-2 contains the type 1 deiodinase gene. The WKY alleles of each gene contain sequence alterations, but additional studies are indicated to identify the specific gene or genes responsible for altered regulation of the thyroid axis. These findings suggest that one or more genetic alterations within the TSH-1 locus significantly contribute to the altered thyroid function tests of the WKY rat.

3' Untranslated Regions↗

PubMed2004

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism.

Congenital hypothyroidism affects about 1:3000-1:4000 infants. Screening programs now permit early recognition and treatment, thus avoiding the disastrous consequences of thyroid hormone deficiency on brain development. In about 85%, congenital hypothyroidism is associated with developmental defects referred to as thyroid dysgenesis. They include thyroid (hemi)agenesis, ectopic tissue and thyroid hypoplasia. Thyroid dysgenesis is usually sporadic; in only 2% it occurs in a familial fashion. It can be caused by mutations in transcription factors that are essential for the development and function of thyroid follicular cells. Thyroid hypoplasia can also result from resistance to TSH at the level of the thyrocytes. Defects in the steps required for thyroid hormone synthesis within thyroid follicular cells are referred to as dyshormonogenesis and account for about 10-15% of congenital hypothyroidism. In contrast to thyroid dysgenesis, affected patients typically present with goitrous enlargement of the thyroid. The defects leading to dyshormonogenesis typically display a recessive mode of inheritance. Careful clinical, biochemical and molecular analyses of patients with syndromic and non-syndromic forms of thyroid dysgenesis and dyshormonogenesis have significantly enhanced our understanding of the wide spectrum of pathogenetic mechanisms underlying congenital hypothyroidism and provide unique insights into the (patho)physiology of thyroid development and hormone synthesis.

Animals↗

PubMed2004

Functional characterization of pendrin in a polarized cell system. Evidence for pendrin-mediated apical iodide efflux.

Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in beta-intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendred's syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendred's syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.

Adenoviridae↗

PubMed2004

Longitudinal associations of age, anthropometric and lifestyle factors with serum total insulin-like growth factor-I and IGF binding protein-3 levels in Black and White men: the CARDIA Male Hormone Study.

Although several studies have assessed cross-sectional correlates of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3), there are no longitudinal studies of the correlates of long-term changes in these measures. We examined the 8-year longitudinal associations of age, body mass index (BMI), waist circumference, physical activity, number of cigarettes smoked per day, and alcohol intake with serum total IGF-I and IGFBP-3 concentrations in 622 Black and 796 White male participants of the Coronary Artery Risk Development in Young Adults Study who were ages 20 to 34 years at the time of the first IGF measurement. In generalized estimating equation analyses, IGF-I decreased by 5.6 and 5.9 ng/mL per year increase in age for Black and White men, respectively (P< 0.0001), and there was an age-related decline in IGFBP-3 that was stronger in Whites (P < 0.0001) than Blacks (P = 0.21). Average IGF-I (beta = -17.51 ng/mL) and IGFBP-3 (beta = -355.4 ng/mL) levels across all three exams were lower in Blacks than Whites (P < 0.0001). Increased BMI was associated with decreased IGF-I (P < 0.0002), but was not associated with IGFBP-3. There were no meaningful associations with waist circumference. Increased physical activity was associated with a decrease in IGFBP-3 (P < 0.05), but was not associated with IGF-I. In White men, there were weak inverse associations between the number of cigarettes smoked per day with IGF-I (P=0.15) and with IGFBP-3 (P = 0.19), and in Black men, increased alcohol intake was associated with a decrease in IGF-I (P = 0.011). In conclusion, these results support an age-related decline and Black-White difference in serum IGF-I and IGFBP-3 levels. Importantly, they suggest that IGF-I and/or IGFBP-3 levels could be influenced by changes in BMI, and perhaps by physical activity, alcohol intake, and cigarette smoking.

Adult↗

PubMed2003

Men with acquired hypogonadotropic hypogonadism treated with testosterone may be fertile.

Men with acquired hypogonadotropic hypogonadism treated with testosterone are generally assumed to be infertile. The finding of two such patients with unexpected fertility and normal sperm counts prompted an evaluation of spermatogenesis in additional men with this condition. Case records were initially searched and one similar case with fertility was found. Subsequently, 12 consecutive men with acquired hypogonadotropic hypogonadism were evaluated for gonadal function and sperm production while receiving testosterone. In five of the cases with proven spermatogenesis, exon 10 of the FSH receptor was sequenced to look for activating mutations. The original three cases and four of the subsequent 12 men had sperm concentrations > or = 15 million/ml. Two additional men had concentrations of 1 million/ml and six were azoospermic. Residual LH and FSH levels were slightly higher in those with maintained spermatogenesis prior to testosterone replacement. No activating mutations were found in exon 10 of the FSH receptor in the five cases studied. We conclude that men with acquired hypogonadotropic hypogonadism being treated with testosterone should not be assumed to be sterile, as we have found that more than half have been shown to have persistent spermatogenesis with more than one-third having sperm concentrations > or = 15 million/ml. This may be related to fact that gonadotropin levels in such patients are present, albeit low. Semen analyses in such men should be routinely carried out so that they can be appropriately counseled regarding potential fertility.

Acromegaly↗

PubMed2003

Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of Prophet of Pit-1 presenting as constitutional growth delay.

Combined pituitary hormone deficiency (CPHD) is characterized by impaired production of GH and one or more of the other anterior pituitary hormones. Prophet of Pit-1 (PROP-1), one of the pituitary specific homeodomain transcription factors, is involved in the differentiation of the anterior pituitary cells (somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs), and PROP-1 gene mutations may interfere with the development of these cells, resulting in CPHD. We performed molecular analyses of the PROP-1 gene in two siblings, born to consanguineous parents, who presented with short stature. The index patient, a boy, was initially diagnosed with constitutional growth delay based on familial short stature, low parental target height, normal GH secretion, and imaging of the pituitary gland. On follow-up, auxological data and pubertal delay prompted a thorough reevaluation, which documented GH, TSH, and gonadotropin deficiencies. Direct sequencing of the PROP-1 gene revealed a novel homozygous transition 296G-->A in exon 2 in the two affected siblings. The mutation substitutes a highly conserved arginine by a glutamine at codon 99 (R99Q) in the second helix of the DNA-binding domain of the PROP-1 protein. Compared with wild-type PROP-1, R99Q displays a significant decrease in DNA binding on a paired box response element (PRDQ9) and trans-activation of a luciferase reporter gene. The findings emphasize the importance of repeated evaluations and illustrate that patients with CPHD associated with PROP-1 mutations present with a phenotypic spectrum, suggesting that the consequences of distinct PROP-1 mutations may be diverse and/or that additional factors, such as modifier genes, may have an impact on their expressivity.

Adolescent↗

PubMed2002

Pheno- and genotypic properties of streptococci of serological group B of canine and feline origin.

In the present study streptococci of serological group B isolated from canines (n=48) and felines (n=7) were comparatively investigated with group B streptococci from humans and bovines for cultural, biochemical and serological properties for antibiotic resistancies and by molecular analysis. An identification was performed with group B-specific antiserum, biochemical reactions, by PCR amplification and subsequent endonuclease digestion of the 16S rRNA gene and by amplification of species-specific parts of the 16S rDNA the 16S-23S rDNA intergenic spacer region and the CAMP factor gene cfb. Phenotypic similarities of group B streptococci of canine and feline origin with group B streptococci from humans and differences to group B streptococci of bovine origin could be observed in lactose fermentation, serotype patterns, pigmentation, growth properties of the bacteria in fluid medium and soft agar, hemagglutination reactions and in minocycline and tetracycline resistance. A negative hyaluronidase plate test, a hylB amplicon with a size of 4.6 kb and an insertion sequence 1548 could be observed among canine, feline and human group B streptococci of serotype III. The remaining hyaluronidase positive strains, also including all isolates of bovine origin, had a hylB gene with a size of 3.3 kb. Further genotypic differences could be observed in the occurrence of the genes lmb and scpB which appeared generally among canine, feline and human group B streptococci, but less pronounced among bovine isolates of this species. According to the presented data group B streptococci of canine and feline origin seemed to be more related to human than to bovine isolates of this species possibly indicating some epidemiological relation.

Adhesins, Bacterial↗

PubMed2002

Cloning of the cat TSH receptor and evidence against an autoimmune etiology of feline hyperthyroidism.

Cats are the only nonhuman mammalian species with a high incidence of hyperthyroidism, and a better understanding of the pathogenesis of feline hyperthyroidism is of clinical relevance for veterinary medicine. The etiology of this disease in cats remains controversial. Both an intrinsic autonomy of growth and function of follicular cells as well as an autoimmune-related mechanism have been proposed. To explore the role of the autologous TSH receptor (TSHR) in the pathogenesis of hyperthyroidism in cats, we cloned the coding sequence of the feline TSHR by RT-PCR. The open reading frame consists of 2292 nucleotides and encodes a 763-amino acid protein, one amino acid less than the human TSHR. Species comparison reveals that the cat TSHR is most closely related to the canine TSHR, with 96% identity and 97% similarity in amino acid sequence. cAMP accumulation, inositol phosphate production, and TSH binding were similar in the feline TSHR, compared with the human receptor. Analogous to the human TSHR, the cat TSHR also displays basal constitutive activity. To test the possibility that hyperthyroid cats develop antibodies that stimulate the autologous receptor, transfected cells expressing the feline TSHR were treated with sera or purified IgG obtained from 16 hyperthyroid cats. There was no increase in cAMP-dependent luciferase activity in the hyperthyroid cats, suggesting the absence of stimulatory autoantibodies. These sera were also negative for TSH-binding inhibitory Igs in an RRA. At least in the animals included in this study, there is no evidence for the presence of circulating thyroid stimulating factors as a mechanism underlying the pathogenesis of feline hyperthyroidism, and the findings support a model involving intrinsic autonomy of thyroid follicular cell growth and function.

Amino Acid Sequence↗

PubMed2002

Perspective: genetic defects in the etiology of congenital hypothyroidism.

Congenital hypothyroidism affects about 1:3000 to 1:4000 infants and may be caused by defects in thyroidal ontogeny or hormone synthesis. The impressive advances in molecular genetics led to the characterization of numerous genes that are essential for normal development and hormone production of the hypothalamic-pituitary-thyroid axis. Mutations in many of these genes now provide a molecular explanation for a subset of the sporadic and familial forms of congenital hypothyroidism. Defects in one of the multiple steps required for normal hormone synthesis account for about 10% of cases with congenital hypothyroidism. They are typically recessive and therefore more common in inbred families. In the vast majority of patients, congenital hypothyroidism is sporadic and associated with thyroid dysgenesis, a spectrum of developmental defects, which includes the absence of detectable thyroid tissue, ectopic tissue, and thyroid hypoplasia. The molecular defects known to date only explain a minority of these cases and include mutations in the paired box transcription factor PAX8, and the thyroid transcription factors TTF1 and TTF2. It is likely that a further subset of patients with thyroid dysgenesis have defects in other transacting proteins or elements of the signaling pathways controlling growth and function of thyrocytes. In other instances, thyroid dysgenesis may be a polygenic disease or have a multifactorial basis. Aside from providing fundamental insights into the ontogeny and the pathophysiology of the thyroid, the characterization of the molecular basis of congenital hypothyroidism may have growing importance for genetic testing and counseling in the future.

Animals↗

PubMed2002

Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene.

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.

Adult↗

PubMed2002

Serum androgen concentrations in young men: a longitudinal analysis of associations with age, obesity, and race. The CARDIA male hormone study.

Serum testosterone concentration appears to be higher in black men than white men, particularly at younger ages. The higher incidence of prostate cancer in blacks has been attributed, at least in part, to this difference. Other factors associated with androgen levels in men include age and obesity. However, most of the studies of adult androgen levels are limited by their cross-sectional design. We conducted longitudinal analyses (Generalized Estimating Equation) of the associations of age, body mass index (BMI), and waist circumference with total and free testosterone and sex hormone-binding globulin (SHBG) concentrations during an 8-year period and compared these hormonal factors between black (n = 483) and white (n = 695) male participants of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. For men ages 24 years and older at the time of the first hormone measurement, increasing age was associated with a statistically significant decrease in serum total and free testosterone and an increase in SHBG (P < 0.05). BMI and waist circumference were inversely associated with total testosterone and SHBG, but only BMI was inversely associated with free testosterone. After adjustment for age and BMI, total testosterone was higher in blacks (0.21 ng/ml; P = 0.028) than whites, an approximately 3% difference. However, after further adjustment for waist circumference, there was no black-white difference (0.05 ng/ml; P = 0.62). These results indicate that the age-associated decrease in circulating testosterone and increase in SHBG begin during the 3rd decade of life, and that increasing obesity, particularly central obesity, is associated with decreasing total testosterone and SHBG. Results also suggest that the previously observed difference in total testosterone between black and white men could be attributed, for the most part, to racial differences in abdominal obesity.

Adolescent↗