J Parma

Publications (53)377.14 Total impact

• Article: The G Protein–coupled Receptor Family and One of Its Members, the TSH Receptora

  G. VASSART, F. DESARNAUD, L. DUPREZ, D. EGGERICKX, O. LABBÉ, F. LIBERT, C. MOLLEREAU, J. PARMA, R. PASCHKE, M. TONACCHERA, P. VANDERHAEGHEN, J. VAN SANDE, J. DUMONT, M. PARMENTIER
  Annals of the New York Academy of Sciences 12/2006; 766(1):23 - 30. · 3.15 Impact Factor
• Article: Prevalence of germline mutations in the TSH receptor gene as a cause of juvenile thyrotoxicosis.

  L Lavard, B Brock Jacobsen, H Perrild, G Vassart, J Parma
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  ABSTRACT: To ascertain the prevalence of germline mutations in the TSH receptor gene as a cause of juvenile thyrotoxicosis (JT) in non-autoimmune patients. TSH receptor gene mutations are not seen in autoimmune-active patients. In a nationwide study on JT, 123 patients were re-examined 10 y (range 4 to 21 y) after diagnosis. Two patients with toxic adenoma were excluded. In 25 patients, no TPO, TG or TSH-R antibodies were found. In 17 patients, DNA material was available for TSH receptor gene analysis. The entire TSH receptor gene was sequenced in five patients. TSH receptor "hot spots" for mutations in exon 9 and 10 were sequenced in the remaining 12 patients. A TSH receptor gene germline mutation was identified in only one patient of a total number of 121 patients with JT, of which 17 patients were presumed to have non-autoimmune JT by the lack of thyroid autoantibodies. In Denmark the prevalence of germline mutations in the TSH receptor gene is one in 121 patients with JT (0.8%; 95% CI: 0.02-4.6%) and one in 17 patients with presumed non-autoimmune JT (6%; 95% CI: 5.88% (0.15-28.69)).
  Acta Paediatrica 10/2004; 93(9):1192-4. · 2.07 Impact Factor
• Article: Predictive factors for pancreatic cancer in patients with chronic pancreatitis in association with K-ras gene mutation.

  M Arvanitakis, J-L Van Laethem, J Parma, V De Maertelaer, M Delhaye, J Devière
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  ABSTRACT: Chronic pancreatitis is considered to be a predisposing factor for pancreatic ductal adenocarcinoma (PAC). The purpose of this study was to examine the prognostic value of a finding of mutated (K- ras) gene in predicting the development of PAC in patients with chronic pancreatitis. The pancreatic duct brushings of 146 patients with chronic pancreatitis were examined in order to identify K- ras gene mutations. A total of 112 patients were followed up (median duration 42 months) using clinical evaluation, serum CA19 - 9 levels, and imaging studies. One or more K- ras mutations were found in 57 of the 146 patients with chronic pancreatitis (39 %). Patients harboring K- ras mutations had a higher incidence of persistent alcohol consumption ( P = 0.041) and of prior rupture of the main pancreatic duct ( P = 0.040). A finding of nuclear atypia in brushing cytology was also more common in patients with K- ras mutation ( P = 0.048). Out of the 112 patients who were followed up, PAC occurred in four of the 44 patients who had a K- ras mutation, but in none of the 68 patients with the wild genotype ( P = 0.022). PAC occurred in three of the 25 patients who did not have pancreatic calcifications ( P = 0.034) and in four of the 54 patients who had demonstrated exocrine insufficiency, but in none of the 58 patients with preserved exocrine function ( P = 0.051). Using stepwise logistic regression, the absence of calcifications, the presence of exocrine insufficiency, and the presence of K- ras mutation were identified as independent predictive factors for cancer development in all patients with chronic pancreatitis. K- ras gene mutations occur in chronic pancreatitis and are associated with evolution towards PAC. The absence of pancreatic calcifications and the presence of exocrine insufficiency were identified as additional predictive factors for the development of PAC.
  Endoscopy 07/2004; 36(6):535-42. · 5.21 Impact Factor
• Article: TSH receptor and disease

  M. Tonacchera, J. Van Sande, J. Parma, L. Duprez, F. Cetani, S. Costagliola, J. E. Dumont, G. Vassart
  Clinical Endocrinology 10/2003; 44(6):621 - 633. · 3.17 Impact Factor
• Source

  Available from: eje.org

  Article: Oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in the Japanese population.

  V Vanvooren, S Uchino, L Duprez, M J Costa, J Vandekerckhove, J Parma, G Vassart, J E Dumont, J Van Sande, S Noguchi
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  ABSTRACT: Constitutively activating mutations of the thyrotropin receptor (TSHR) have been found in the majority of autonomously functioning thyroid nodules (AFTNs) in European patients. The reported frequency of these mutations varies among reports but amounts to 50-80%. To date, only one such mutation responsible for AFTNs has been identified in the Japanese population and the pathogenic role of such mutations in Japanese AFTNs has been questioned. In the present study, we evaluated the frequency of activating mutations in the TSHR and G(alpha)s in 10 Japanese AFTNs. Genomic DNA was extracted from fresh frozen tissue. The TSHR and the almost entire sequence of the gene coding for the alpha subunit of Gs have been amplified and sequenced. In sequence analysis, four mutations in the TSHR (T632A, I486M, M453T and L512R) were found. To complete our analysis, we searched mutations in the gene coding for the alpha subunit of Gs, in the samples negative for TSHR mutations. In one case a mutation (R201H) affecting GTPase activity was found. If we focus on the solitary nodules, we obtain the same mutation proportion as in European patients (70%). The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions.
  European Journal of Endocrinology 10/2002; 147(3):287-91. · 3.42 Impact Factor
• Article: [Medical genetics service].

  G Vassart, M Abramowicz, P Cochaux, L Duprez, H el Housni, F Hayez, P Heimann, J Parma, E Vamos, N Van Regemorter
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  ABSTRACT: Created in 1987, the department of medical genetics finds its origins in molecular endocrinology research which had developed from the seventies at the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM) of the Faculty of Medicine. After its fusion with the Center of Human Genetics of the ULB, in 1992, the department is composed of three units: the lab of molecular genetics and oncology, the lab of cytogenetics and a clinical genetics unit. One thousand consultations of genetic counseling and more than 15,000 molecular or cytogenetic diagnostic procedures are performed annually. The development of the clinical activities was paralleled by a very active research activity, resulting in a series of "firsts". Amongst the main results are: the identification of the first mutations responsible for congenital hypothyroidism; the molecular cloning of the TSH receptor and of a series of "orphan" G protein-coupled receptors; the identification of a novel neuropeptide, nociceptin, by the first example of "reverse pharmacology"; the identification of olfactory receptors on the sperm of mammals, including man; the identification in molecular terms of the mechanisms responsible for acquired and hereditary hyperthyroidisms; the identification of the chemokine receptor CCR5 as the major coreceptor of HIV-1, and of the prevalent mutation of CCR5 conferring resistance to HIV to about 1% of the European population.
  Revue medicale de Bruxelles 02/2002; 23 Suppl 2:63-7.
• Article: A familial case of congenital hypothyroidism caused by a homozygous mutation of the thyrotropin receptor gene.

  P Bretones, L Duprez, J Parma, M David, G Vassart, P Rodien
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  ABSTRACT: Most of the time congenital hypothyroidism appears as a sporadic disease. In addition to the rare defects in hormonosynthesis associated with goiters, the causes of congenital hypothyroidism include agenesis and ectopy of the thyroid gland. The study of some familial cases has allowed the identification of a few genes responsible for congenital hypothyroidism. We report here a familial case of congenital hypothyroidism, transmitted as a recessive trait, and caused by a homozygous mutation in the thyrotropin receptor (TSH-R). The initial diagnosis of thyroid agenesis, based on the absence of tracer uptake on scintiscan, was incorrect, because ultrasound examination identified severely hypoplastic thyroid tissue in the cervical region.
  Thyroid 11/2001; 11(10):977-80. · 4.79 Impact Factor
• Source

  Available from: Claude Massart

  Article: Mutation analysis of the Epac--Rap1 signaling pathway in cold thyroid follicular adenomas.

  V Vanvooren, A Allgeier, M Nguyen, C Massart, J Parma, J E Dumont, J Van Sande
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  ABSTRACT: The cyclic AMP (cAMP) cascade is the main regulatory pathway in thyrocytes. Whilst activating mutations in the TSH receptor or in the Gs alpha-subunit, which increase cAMP levels, have been shown to be responsible for 80% of the autonomous adenomas, no such mutations have been observed in the other types of thyroid tumors, suggesting that other mechanisms exist. The discovery of Epac ('exchange nucleotide protein directly activated by cAMP'), a novel cAMP-binding protein, which is strongly expressed in the thyroid, raised the possibility of a role for this protein in the generation of the unexplained cold thyroid follicular adenomas. Thus, we investigated whether activating mutations in either Epac or Rap (the downstream target of Epac) could be responsible for the generation of these thyroid nodules. Epac and Rap1 (Rap1A and Rap1B) cDNAs were sequenced in 10 patients. The sequencing of the cDNAs was realized on both strands in the cold nodule and the juxtanodular tissue of each patient. No mutations in either Epac or Rap1 cDNAs were found. For five patients, a polymorphism in Epac at codon 332 (Gly--Ser) was observed. In this report, we show that the cAMP--Epac--Rap1 signaling pathway in the thyroid gland does not play a major role in the generation of cold thyroid follicular adenomas, since no mutations in either Epac or Rap1 could be observed in the 10 nodules studied.
  European Journal of Endocrinology 07/2001; 144(6):605-10. · 3.42 Impact Factor
• Article: [Prevention of hemoglobinopathies in Brussels: a necessity?].

  B Gulbis, F Cotton, V Hansen, A Ferster, M Toppet, P Cochaux, J Parma, G Vassart, P Fondu, F Vertongen
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  ABSTRACT: Haemoglobinopathies are the most frequent genetic diseases in the world. The estimated frequency of carriers in the world is of 200 millions while there is about 300.000 births per year of major forms of haemoglobinopathies. The neonatal screening of haemoglobinopathies performed at the Hospital Erasme on around 80% of births in Brussels since 1994 has demonstrated that the frequency of carriers of an abnormal haemoglobin is around 1.5% while more than 1/2.000 newborns has a major haemoglobinopathy. A strategy must be adopted to manage the haemoglobinopathies in Brussels.
  Revue medicale de Bruxelles 07/2001; 22(3):133-40.
• Article: A rare variant, I852M, of the RET proto-oncogene in a patient with medullary thyroid carcinoma at age 20 years.

  R Demeester, J Parma, P Cochaux, G Vassart, M J Abramowicz
  Human Mutation 05/2001; 17(4):354. · 5.69 Impact Factor
• Article: Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.

  C Vilain, C Rydlewski, L Duprez, C Heinrichs, M Abramowicz, P Malvaux, B Renneboog, J Parma, S Costagliola, G Vassart
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  ABSTRACT: Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.
  Journal of Clinical Endocrinology &amp Metabolism 02/2001; 86(1):234-8. · 6.50 Impact Factor
• Article: Hyperfunctioning malignant thyroid nodule in an 11-year-old girl: pathologic and molecular studies.

  H Mircescu, J Parma, C Huot, C Deal, L L Oligny, G Vassart, G Van Vliet
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  ABSTRACT: We identified a papillary carcinoma in an 11-year-old girl with a hyperfunctioning thyroid nodule. A met453thr mutation in TSHR was found in the nodule but not in normal thyroid tissue or in leukocytes. This case documents that this activating mutation is associated with neoplasia.
  Journal of Pediatrics 11/2000; 137(4):585-7. · 4.11 Impact Factor
• Article: Congenital central isolated hypothyroidism caused by a homozygous mutation in the TSH-beta subunit gene.

  C Heinrichs, J Parma, N H Scherberg, F Delange, G Van Vliet, L Duprez, P Bourdoux, P Bergmann, G Vassart, S Refetoff
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  ABSTRACT: We report a Belgian girl born in 1983 with isolated thyrotropin (TSH) deficiency. Hypothyroidism without goiter was diagnosed at the age of 2 months, with extremely low total thyroxine (T4) at 0.3 microg/dL (4 nmol/L; N[normal]: 5.6-11.4 microg/dL). Basal TSH, only moderately elevated at 14.8 mU/L (N: 0-5.3; competitive radioimmunoassay, RIA), increased to 18.2 mU/L after thyrotropin-releasing hormone (TRH) stimulation, whereas prolactin increased normally. At age 15 years, after withdrawal of levothyroxine (LT4) therapy for 6 weeks, TRH stimulation slightly increased serum TSH using two immunometric assays, from less than 0.03 to 0.07 and from 0.2 to 0.3 (a monoclonal and polyclonal antibody), and from 1.9 to 4.1 mU/L using a polyclonal TSH antibody and iodinated recombinant TSH. Sequencing of the TSH-beta subunit gene revealed a homozygous single nucleotide deletion in codon 105 producing a frame shift that results in a truncated TSH-beta with nonhomologous 9 carboxyterminal amino acids and a loss of the 5 terminal residues. This mutation was previously reported in one Brazilian and two German families. The abnormal, and presumably biologically inactive, TSH can be detected in serum using appropriate antibodies. Its relatively small amount in serum is due to either reduced secretion or rapid degradation. The occurrence of the same mutation in three families of different ethnic origin suggests that this mutation may be prevalent in the population. Common ancestry or de novo mutations in a hot spot cannot be excluded. Finally, we must be aware that neonatal screening of congenital hypothyroidism based on blood spot TSH measurement will not detect this rare but severe genetic defect.
  Thyroid 06/2000; 10(5):387-91. · 4.79 Impact Factor
• Article: Hb Ube-2 [alpha68(E17)Asn-Asp] and Hb Hafnia [beta116(G18)His-->Gln] observed during neonatal screening in Brussels.

  F Cotton, V Hansen, C Lin, J Parma, P Cochaux, E Damis, F Vertongen, B Gulbis
  Hemoglobin 03/2000; 24(1):65-9. · 1.30 Impact Factor
• Article: The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.

  D Tiosano, S Pannain, G Vassart, J Parma, R Gershoni-Baruch, H Mandel, R Lotan, Y Zaharan, M Pery, R E Weiss, S Refetoff, Z Hochberg
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  ABSTRACT: Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.
  Thyroid 10/1999; 9(9):887-94. · 4.79 Impact Factor
• Article: Pathology of the TSH receptor.

  L Duprez, J Parma, J Van Sande, P Rodien, C Sabine, M Abramowicz, J E Dumont, G Vassart
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  ABSTRACT: Gain of function and loss of function mutations of the TSH receptor have been implicated in the pathogenesis of various thyroid diseases. Gain of function mutations, when somatic, are the first cause of autonomous nodules; when germline, they are responsible for hereditary non-autoimmune toxic thyroid hyperplasia and for some cases of sporadic congenital hyperthyroidism. A subset of mutations modifying the receptor selectivity have recently been found to be involved in the pathogenesis of familial gestational hyperthyroidism. These mutations are of great interest for understanding the mechanism of receptor activation. Loss of function mutations of the TSH receptor are responsible for different phenotypes ranging from asymptomatic resistance to TSH to overt congenital hypothyroidism.
  Journal of pediatric endocrinology & metabolism: JPEM 05/1999; 12 Suppl 1:295-302. · 0.88 Impact Factor
• Source

  Available from: endojournals.org

  Article: A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family.

  D H Khoo, J Parma, C Rajasoorya, S C Ho, G Vassart
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  ABSTRACT: Activating mutations of the TSH receptor (TSH-R) have been reported to result in toxic adenomas, multinodular goiters, sporadic neonatal hyperthyroidism, and familial autosomal dominant nonautoimmune hyperthyroidism. To date, all descriptions of such mutations, whether somatic or genomic, have been confined to the Caucasian population. We describe a Chinese family in whom a germline proline to serine substitution in position 639 resulted in familial thyrotoxicosis. This constitutively activating mutation has been previously described in a hyperfunctioning thyroid nodule. The three children in this family developed thyrotoxicosis during childhood; their father was diagnosed as thyrotoxic at the age of 38 yr. Two of the children and the father had mitral valve prolapse (MVP) associated with mitral regurgitation. There was a close temporal relationship between the onset of thyrotoxicosis and the diagnosis of mitral valvular disease in these patients. An increased prevalence of MVP has been reported in Graves' disease and chronic lymphocytic thyroiditis, but the pathophysiological mechanisms linking MVP and autoimmune thyroid disease are still not understood. This is the first report of an association between activating TSH-R mutations and MVP. We postulate that TSH-R activation may increase the clinical expression of MVP in genetically predisposed individuals.
  Journal of Clinical Endocrinology &amp Metabolism 05/1999; 84(4):1459-62. · 6.50 Impact Factor
• Article: Long-term follow-Up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr).

  L Lavard, A Sehested, B Brock Jacobsen, J Muller, H Perrild, U Feldt-Rasmussen, J Parma, G Vassart
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  ABSTRACT: A 18-year clinical follow-up period in a male patient with a germline TSH-R gene mutation (Met453Thr) is described. Nonautoimmune thyrotoxicosis was diagnosed at the age of 7 months. The patient had exophthalmus, failure to thrive, advanced bone age and no goiter. Long-term antithyroid drug treatment (ATD) was necessary during childhood. At the age of 7 years he developed a goiter. Subtotal thyroidectomy was performed at the age of 9 years, followed by repeated ablative radiotherapy at the age of 9.5-13 years due to a toxic multinodular goiter. After 13 years ATD could be discontinued and the patient was euthyroid until 16 years of age, where L-thyroxine substitution had to be started. The exophthalmus diminished, and had disappeared at the age of 18 years, when CT scan of the orbit was performed. Conclusion: TSH-R mutation must be considered in early nonautoimmune thyrotoxicosis. A very aggressive treatment strategy is necessary.
  Hormone Research 02/1999; 51(1):43-6. · 2.48 Impact Factor
• Article: Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin.

  P Rodien, C Brémont, M L Sanson, J Parma, J Van Sande, S Costagliola, J P Luton, G Vassart, L Duprez
  New England Journal of Medicine 01/1999; 339(25):1823-6. · 53.30 Impact Factor
• Article: Relative contribution of Ki-ras gene analysis and brush cytology during ERCP for the diagnosis of biliary and pancreatic diseases.

  J L Van Laethem, V Bourgeois, J Parma, M Delhaye, P Cochaux, T Velu, J Devière, M Cremer
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  ABSTRACT: Ki-ras mutation analysis from material collected during ERCP has been claimed to improve the diagnosis of pancreatic and bile duct carcinomas as compared with conventional cytology. Our aim was to study the relative contribution of both Ki-ras analysis and brush cytology in patients with a significant stricture at ERCP. Brushings were collected in duplicate for both analyses in 142 patients in whom a definitive diagnosis was obtained by histology or a minimal follow-up of 6 months. For pancreatic strictures, sensitivity, specificity, and accuracy of Ki-ras analysis vs. cytology in detecting malignancy were 81% vs. 66%, 72% vs. 100%, and 70% vs. 74%, respectively. For biliary strictures, they were 25% vs. 42%, 100% vs. 100%, and 35% vs. 43%, respectively. The combination of the two methods only marginally increased their sensitivity and accuracy in both types of strictures. Ki-ras analysis is a sensitive method for diagnosing pancreatic but not biliary carcinoma. However, its specificity is lowered by a high frequency of Ki-ras mutations in patients with chronic pancreatitis (25%) who did not manifest cancer development within a 6-month follow-up period. In pancreatic duct strictures, brush cytology appears to be more specific in detecting malignancy; specificity for Ki-ras and cytology are equivalent for the diagnosis of malignant bile duct strictures. Therefore, making a clinical decision on the sole basis of Ki-ras analysis is probably not justified in the majority of the cases.
  Gastrointestinal Endoscopy 07/1998; 47(6):479-85. · 4.88 Impact Factor