The pituitary hormone thyrotropin stimulates the function, expression of differentiation and growth of thyrocytes by cyclic AMP-dependent mechanisms. Tissue hyperplasia and hyperthyroidism are therefore expected to result when activation of the adenylyl cyclase-cAMP cascade is unregulated. This is observed in several situations, including when somatic mutations impair the GTPase activity of the G protein Gsa (ref 6, 7). Such a mechanism is probably responsible for the development of a minority of monoclonal hyperfunctioning thyroid adenomas. Here we identify somatic mutations in the carboxy-terminal portion of the third cytoplasmic loop of the thyrotropin receptor in three out of eleven hyperfunctioning thyroid adenomas. These mutations are restricted to tumour tissue and involve two different residues (aspartic acid at position 619 to glycine in two cases, and alanine at position 623 to isoleucine in one case). The mutant receptors confer constitutive activation of adenylyl cyclase when tested by transfection in COS cells. This shows that G-protein-coupled receptors are susceptible to constitutive activation by spontaneous somatic mutations and may thus behave as proto-oncogenes.

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Thyroid peroxidase (TPO) is the key enzyme in the synthesis ofthyroid hormones, and the TPO defects are believed to be the most prevalent causes of the inborn errors of thyroid metabolism. We investigated an adopted boy with iodide organification defect, who presented with florid hypothyroidism at the age of4 mo, poorly complied with thyroxine treatment, and developed a compressive goiter necessitating partial resection at the age of 12 yr.Biochemical studies revealed the absence ofTPO activity in the resected tissue. Genomic DNA studies identified a 4 basepair insertion in the eighth exon of the TPO gene, and showed that the patient was homozygous for this frameshift mutation. The direct genetic diagnosis of this mutation can be made by digestion of polymerase chain reaction products with NaeI restriction enzyme. This will help assessing its prevalence among the heterogenous genetic group of TPO defects. (J. Clin. Invest. 1992. 90:1200-1204.) Key words: alternative splicing.

The single-nucleotide polymorphisms at position +896 or +1196 in the TLR-4 gene is associated with systemic inflammatory hyporesponsiveness to inhaled lipopolysaccharide.

A case of congenital goiter with defective thyroglobulin synthesis has been studied in molecular terms. The patient is the fifth of a kindred of six, three of which have a goiter. The parents are first cousins. Segregation of thyroglobulin alleles in the family was studied by Southern blotting with a probe revealing a diallelic restriction fragment length polymorphism (RFLP). The results demonstrated that the three affected siblings were homozygous for the RFLP. Northern blotting analysis of the goiter RNA with a thyroglobulin probe suggested that thyroglobulin mRNA size was slightly reduced. Polymerase chain reaction amplification of the 8.5-kb thyroglobulin mRNA as overlapping cDNA fragments demonstrated that a 200-bp segment was missing from the 5' region of the goiter mRNA. Subcloning and sequencing of the cDNA fragments, and of the patient genomic DNA amplified from this region, revealed that exon 4 is missing from the major thyroglobulin transcript in the goiter, and that this aberrant splicing is due to a C to G transversion at position minus 3 in the acceptor splice site of intron 3. The presence in exon 4 of a putative donor tyrosine residue (Tyrosine n' 130) involved in thyroid hormone formation provides a coherent explanation to the hypothyroid status of the patient. (J. Clin. Invest. 1991. 88:1901-1905

The presence of ETV6 deletions was investigated in 215 chilof t(5;12) 10 and was subsequently found to be fused to a dren with acute lymphoblastic leukemia (ALL) using the loss number of different partners as a result of various leukemiaof heterozygosity (LOH) approach. We used four intragenic or associated translocations. [11][12][13] In pediatric B lineage ALL, juxtagenic microsatellite markers to detect allelic deletions. In t(12;21)(p13;q22), which leads to the formation of a ETV6- region of deletion that did not include ETV6 was found near

Medullary carcinoma of the breast is an epithelial malignant proliferation that shares many characteristics (macroscopic, microscopic, epidemiologic, and prognostic) with lymphoepithelioma-like carcinomas of various sites. The authors hypothesized that they could also share the same etiologic agent, the Epstein-Barr virus (EBV). Epstein-Barr virus, a virus of the herpesvirus family, is to be associated with lymphoepithelioma-like carcinomas of the nasopharynx, stomach, lung, thymus, and salivary gland. Therefore, the authors looked for the virus in a series of 10 medullary carcinomas of the breast. Using immunohistochemistry, in situ hybridization and polymerase chain reaction, this investigation failed to show evidence of EBV. Similar negative results have been reported in lymphoepithelioma-like carcinomas arising in the skin and in the uterine cervix, which like the breast do not originate in the foregut. These results suggest that the pathogenesis of these tumors is not unique, implicating probably different etiopathogenic entities.

New-onset diabetes after transplantation (NODAT) is a serious and frequent complication in transplant recipients. Whether NODAT shares the same susceptibility genes as type 2 diabetes is unknown. In this multicenter study, we genotyped 1076 white patients without diabetes at transplantation for 11 polymorphisms that associate with type 2 diabetes. We defined NODAT as a fasting plasma glucose Ն126 mg/dl on at least two occasions or de novo hypoglycemic therapy. We compared clinical and genetic factors between patients who developed NODAT within 6 mo of transplantation (n ϭ 118; incidence 11%) and patients without diabetes (n ϭ 958). In multivariate analysis, NODAT significantly associated with the following characteristics: TCF7L2 polymorphism (odds ratio [OR] 1.60 per each T allele; P ϭ 0.002), age (OR 1.03 per year; P Ͻ 0.001), body mass index at transplantation (OR 1.09 per unit; P Ͻ 0.001), tacrolimus use (OR 2.26; P Ͻ 0.001), and the occurrence of a corticoid-treated acute rejection episode (OR 2.78; P Ͻ 0.001). In summary, our data show that the TCF7L2 rs7903146 polymorphism, a known risk factor for type 2 diabetes in the general population, also associates with NODAT.