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BERNARDO WAJCHENBERG,
MEYER KNOBEL,
NANCY J. COX,
LESLIE J. DEGROOT and
GERALDO MEDEIROS-NETO
Thyroid Study Unit, Department of Medicine (A.M., L.J.D.), and the Howard Hughes Medical Institute (N.J.C.,), University of Chicago Chicago, Illinois 60637
The Thyroid Laboratory, Hospital das Clinicas, University of Sao Paulo Medical School (A.-E.C.B., M.K., G.M.-N.) Sao Paulo, Brazil
Address all correspondence and requests for reprints to: Geraldo Medeiros-Neto, M.D., Laboratorio de Tireoide, Hospital das Clinicas, Caixa Postal 8091, 05403 Sao Paulo, Brazil.
We have conducted biochemical and genetic studies in five unrelated families (denoted A, C, R, P, and G), which included nine goitrous subjects (five borderline euthyroid and four hypothyroid) with complete (n = 6) or partial (n = 3) thyroid peroxidase (TPO) deficiency. Thyroid tissue was obtained from four subjects, respectively, in families A, C, and R. No iodide organification or iodide incorporation into protein was present in families A and C. The two affected siblings in family R had a low normal tissue thyroperoxidase activity. Using a 0.8-kilobase (kb) cDNA clone (pM5) encoding 30% of the cDNA of human TPO gene down-stream from basepair 730 and four restriction enzymes (TaqI, PstI, BglI, and BglII), we were unable to find any polymorphisms in family A. In another family (C) blood samples were obtained from only two family members, and consequently, it was not possible to determine linkage. DNA from families G, P, and C showed biallelic polymorphisms when digested with BglII, at 8.7 and 8.5 kb. In family R we detected two biallelic polymorphisms at 9.0 and 8.5 kb, and the 9.0-kb bands were clearly larger than 8.7-kb bands found in the other subjects. Also, there was an absence of a 4.0- to 3.9-kb band that may represent a partial gene deletion. With PstI-restricted DNA a possible deletion of 5.5-kb band was also present in affected siblings of family R. The logarithm of odds (Lod) score analyzed from the family with inbreeding (R) was compatible with linkage of disease and the TPO gene (Lod = 2.08). When this method was used with families G and P, the Lod score was inconsistent with linkage between disease and the TPO gene. These data suggest that the cause of TPO deficiency in these families is heterogeneous. However, the restriction fragment length polymorphism pattern of BglII-restricted DNA in the R family strongly suggests that a partial TPO gene deletion has occurred in this family.
* This work was supported by CNPq (Brazil) Grant 40.5991-88.6/CL/FV/PQ, USPHS Grants DK-13377 and DK-27384, March of Dimes Birth Defects Foundation Grant 1-1166, the Boots Co., the Klabin and Irmaos Co. (Sao Paulo), and the David Wiener Research Fund. This paper was presented in part at the International Symposium on Thyroperoxidase and Thyroid Autoimmunity, Marseille, France, June 1990.
t Recipient of a fellowship from Fundacao Faculdade de Medicina at the Thyroid Study Unit, University of Chicago (Prof. Leslie J. DeGroot, M.D.) during 1989.
Received June 11, 1990.
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