The Site of the Molecular Defect in the Thyroid Gland of the hyt/hyt Mouse: Abnormalities in the TSH Receptor-G Protein Complex
The hyt/hyt mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T 4 , elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the hyt/hyt thyroid gland along with these biochemical...
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| Veröffentlicht in: | Thyroid (New York, N.Y.) N.Y.), 1991, Vol.1 (3), p.257-266 |
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| creator | Stein, S A Zakarija, M McKenzie, J M Shanklin, D R Palnitkar, M B Adams, P M |
| description | The
hyt/hyt
mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T
4
, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the
hyt/hyt
thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the
hyt/hyt
thyroid gland. In order to evaluate the potential site of the defect in the
hyt/hyt
mouse, we have studied the
hyt/hyt
gland and
hyt/hyt
TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of
hyt/hyt
serum in the McKenzie bioassay, this reduced responsiveness to TSH in the
hyt/hyt
mouse is not due to reduced bioactivity of
hyt/hyt
TSH or a major structural abnormality in the
hyt/hyt
TSH molecule. In comparison to
hyt/
+ euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the
hyt/hyt
mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However,
hyt/hyt
cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE
1
, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the
hyt/hyt
thyroid gland. Specifically, these findings suggest that the
hyt/hyt
mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the
hyt/hyt
gland makes T
3
and T
4
but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both
hyt/hyt
and euthyroid
hyt/
+ littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland may underlie the significant decrease in thyroid hormone production by the
hyt/hyt
mouse. |
| doi_str_mv | 10.1089/thy.1991.1.257 |
| format | Article |
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hyt/hyt
mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T
4
, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the
hyt/hyt
thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the
hyt/hyt
thyroid gland. In order to evaluate the potential site of the defect in the
hyt/hyt
mouse, we have studied the
hyt/hyt
gland and
hyt/hyt
TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of
hyt/hyt
serum in the McKenzie bioassay, this reduced responsiveness to TSH in the
hyt/hyt
mouse is not due to reduced bioactivity of
hyt/hyt
TSH or a major structural abnormality in the
hyt/hyt
TSH molecule. In comparison to
hyt/
+ euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the
hyt/hyt
mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However,
hyt/hyt
cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE
1
, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the
hyt/hyt
thyroid gland. Specifically, these findings suggest that the
hyt/hyt
mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the
hyt/hyt
gland makes T
3
and T
4
but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both
hyt/hyt
and euthyroid
hyt/
+ littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland may underlie the significant decrease in thyroid hormone production by the
hyt/hyt
mouse.</description><identifier>ISSN: 1050-7256</identifier><identifier>EISSN: 1557-9077</identifier><identifier>DOI: 10.1089/thy.1991.1.257</identifier><identifier>PMID: 1668617</identifier><language>eng</language><publisher>United States</publisher><subject>Adenylyl Cyclases - metabolism ; Animals ; Base Sequence ; Blotting, Northern ; Cyclic AMP - biosynthesis ; GTP-Binding Proteins - physiology ; Hypothyroidism - genetics ; Mice ; Mice, Inbred Strains ; Molecular Sequence Data ; Nucleic Acid Hybridization ; Receptors, Thyrotropin - physiology ; RNA, Messenger - analysis ; Thyroglobulin - blood ; Thyroid Gland - metabolism ; Thyrotropin - blood</subject><ispartof>Thyroid (New York, N.Y.), 1991, Vol.1 (3), p.257-266</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c250t-36775c2d2c1cd92980f6eba6a7c1921697fd23e9bd4f176573b95f0dd513b1193</citedby><cites>FETCH-LOGICAL-c250t-36775c2d2c1cd92980f6eba6a7c1921697fd23e9bd4f176573b95f0dd513b1193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.liebertpub.com/doi/epdf/10.1089/thy.1991.1.257$$EPDF$$P50$$Gmaryannliebert$$H</linktopdf><linktohtml>$$Uhttps://www.liebertpub.com/doi/full/10.1089/thy.1991.1.257$$EHTML$$P50$$Gmaryannliebert$$H</linktohtml><link.rule.ids>314,776,780,3029,4010,21702,27900,27901,27902,55266,55278</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1668617$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stein, S A</creatorcontrib><creatorcontrib>Zakarija, M</creatorcontrib><creatorcontrib>McKenzie, J M</creatorcontrib><creatorcontrib>Shanklin, D R</creatorcontrib><creatorcontrib>Palnitkar, M B</creatorcontrib><creatorcontrib>Adams, P M</creatorcontrib><title>The Site of the Molecular Defect in the Thyroid Gland of the hyt/hyt Mouse: Abnormalities in the TSH Receptor-G Protein Complex</title><title>Thyroid (New York, N.Y.)</title><addtitle>Thyroid</addtitle><description>The
hyt/hyt
mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T
4
, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the
hyt/hyt
thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the
hyt/hyt
thyroid gland. In order to evaluate the potential site of the defect in the
hyt/hyt
mouse, we have studied the
hyt/hyt
gland and
hyt/hyt
TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of
hyt/hyt
serum in the McKenzie bioassay, this reduced responsiveness to TSH in the
hyt/hyt
mouse is not due to reduced bioactivity of
hyt/hyt
TSH or a major structural abnormality in the
hyt/hyt
TSH molecule. In comparison to
hyt/
+ euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the
hyt/hyt
mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However,
hyt/hyt
cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE
1
, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the
hyt/hyt
thyroid gland. Specifically, these findings suggest that the
hyt/hyt
mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the
hyt/hyt
gland makes T
3
and T
4
but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both
hyt/hyt
and euthyroid
hyt/
+ littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland may underlie the significant decrease in thyroid hormone production by the
hyt/hyt
mouse.</description><subject>Adenylyl Cyclases - metabolism</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Blotting, Northern</subject><subject>Cyclic AMP - biosynthesis</subject><subject>GTP-Binding Proteins - physiology</subject><subject>Hypothyroidism - genetics</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Molecular Sequence Data</subject><subject>Nucleic Acid Hybridization</subject><subject>Receptors, Thyrotropin - physiology</subject><subject>RNA, Messenger - analysis</subject><subject>Thyroglobulin - blood</subject><subject>Thyroid Gland - metabolism</subject><subject>Thyrotropin - blood</subject><issn>1050-7256</issn><issn>1557-9077</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkM9P2zAUx62JiXVs192QfOKW1M_Bds2tKqxM6rRpdGcrsV_UoCQutivR0_51XArjyMHy0_v-kP0h5BuwEthMT9NmX4LWUELJhfpAJiCEKjRT6iTPTLBCcSE_kc8x3jMGcqaqU3IKUs4kqAn5t94gvesSUt_SlOefvke76-tAr7FFm2g3Pu_Xm33wnaPLvh7dq3mzT9N8cmgX8YrOm9GHoe671GH8H7y7pX_Q4jb5UCzp7-ATZmnhh22Pj1_Ix7buI359uc_I3-8368Vtsfq1_LGYrwrLBUtFJZUSljtuwTrN9Yy1Epta1sqC5iC1ah2vUDfusgUlhaoaLVrmnICqAdDVGbk49m6Df9hhTGboosU-_wbz443iSnEQPBvLo9EGH2PA1mxDN9Rhb4CZA3GTiZsDcQMmE8-B85fmXTOge7MfEWf98qgftvU49h02GNJ7tU91dI3x</recordid><startdate>1991</startdate><enddate>1991</enddate><creator>Stein, S A</creator><creator>Zakarija, M</creator><creator>McKenzie, J M</creator><creator>Shanklin, D R</creator><creator>Palnitkar, M B</creator><creator>Adams, P M</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>1991</creationdate><title>The Site of the Molecular Defect in the Thyroid Gland of the hyt/hyt Mouse: Abnormalities in the TSH Receptor-G Protein Complex</title><author>Stein, S A ; Zakarija, M ; McKenzie, J M ; Shanklin, D R ; Palnitkar, M B ; Adams, P M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c250t-36775c2d2c1cd92980f6eba6a7c1921697fd23e9bd4f176573b95f0dd513b1193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Adenylyl Cyclases - metabolism</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Blotting, Northern</topic><topic>Cyclic AMP - biosynthesis</topic><topic>GTP-Binding Proteins - physiology</topic><topic>Hypothyroidism - genetics</topic><topic>Mice</topic><topic>Mice, Inbred Strains</topic><topic>Molecular Sequence Data</topic><topic>Nucleic Acid Hybridization</topic><topic>Receptors, Thyrotropin - physiology</topic><topic>RNA, Messenger - analysis</topic><topic>Thyroglobulin - blood</topic><topic>Thyroid Gland - metabolism</topic><topic>Thyrotropin - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stein, S A</creatorcontrib><creatorcontrib>Zakarija, M</creatorcontrib><creatorcontrib>McKenzie, J M</creatorcontrib><creatorcontrib>Shanklin, D R</creatorcontrib><creatorcontrib>Palnitkar, M B</creatorcontrib><creatorcontrib>Adams, P M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Thyroid (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stein, S A</au><au>Zakarija, M</au><au>McKenzie, J M</au><au>Shanklin, D R</au><au>Palnitkar, M B</au><au>Adams, P M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Site of the Molecular Defect in the Thyroid Gland of the hyt/hyt Mouse: Abnormalities in the TSH Receptor-G Protein Complex</atitle><jtitle>Thyroid (New York, N.Y.)</jtitle><addtitle>Thyroid</addtitle><date>1991</date><risdate>1991</risdate><volume>1</volume><issue>3</issue><spage>257</spage><epage>266</epage><pages>257-266</pages><issn>1050-7256</issn><eissn>1557-9077</eissn><abstract>The
hyt/hyt
mouse has a severe and pervasive primary inherited hypothyroidism with significantly depressed serum T
4
, elevated serum and pituitary TSH, and reduced thyroid gland iodide uptake. Previous ultrastructural and histologic analysis of the
hyt/hyt
thyroid gland along with these biochemical abnormalities support an inherited defect in TSH responsiveness of the
hyt/hyt
thyroid gland. In order to evaluate the potential site of the defect in the
hyt/hyt
mouse, we have studied the
hyt/hyt
gland and
hyt/hyt
TSH from a biochemical and molecular standpoint. Based on demonstrated bioactivity of
hyt/hyt
serum in the McKenzie bioassay, this reduced responsiveness to TSH in the
hyt/hyt
mouse is not due to reduced bioactivity of
hyt/hyt
TSH or a major structural abnormality in the
hyt/hyt
TSH molecule. In comparison to
hyt/
+ euthyroid littermates and +/+ BALB/cBY progenitor strain mice, the
hyt/hyt
mouse demonstrates a twofold reduction in thyroid gland basal cAMP and a markedly diminished response of adenylyl cyclase to exogenous TSH. However,
hyt/hyt
cAMP production is equivalent to the euthyroid mice after stimulation of thyroid glands by forskolin, cholera toxin, PGE
1
, and isoproterenol. These results support a defect in the TSH-G protein-adenylyl cyclase system in the
hyt/hyt
thyroid gland. Specifically, these findings suggest that the
hyt/hyt
mouse has a defect in TSH responsivity due to an inherited defect in the thyroid gland TSH receptor molecule. Since the
hyt/hyt
gland makes T
3
and T
4
but at diminished levels, the proposed defect in the TSH receptor would still impart partial function. Both
hyt/hyt
and euthyroid
hyt/
+ littermates make TSH receptor mRNAs of 5500 and 2400 base pairs. This suggests that the receptor defect does not represent a major structural abnormality of the gene. The receptor defect could represent a reduction in receptor number, receptor-TSH affinity, or TSH receptor-G protein coupling. The specificity of this effect on adenylyl cyclase-cAMP is shown by the reduction of TSH-cAMP regulated thyroid peroxidase (TPO) and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland. Given the importance of TPO and thyroglobulin in normal thyroid hormone synthesis, the reductions in TPO and thyroglobulin mRNAs in the
hyt/hyt
thyroid gland may underlie the significant decrease in thyroid hormone production by the
hyt/hyt
mouse.</abstract><cop>United States</cop><pmid>1668617</pmid><doi>10.1089/thy.1991.1.257</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1050-7256 |
| ispartof | Thyroid (New York, N.Y.), 1991, Vol.1 (3), p.257-266 |
| issn | 1050-7256 1557-9077 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72772152 |
| source | Mary Ann Liebert Online Subscription; MEDLINE |
| subjects | Adenylyl Cyclases - metabolism Animals Base Sequence Blotting, Northern Cyclic AMP - biosynthesis GTP-Binding Proteins - physiology Hypothyroidism - genetics Mice Mice, Inbred Strains Molecular Sequence Data Nucleic Acid Hybridization Receptors, Thyrotropin - physiology RNA, Messenger - analysis Thyroglobulin - blood Thyroid Gland - metabolism Thyrotropin - blood |
| title | The Site of the Molecular Defect in the Thyroid Gland of the hyt/hyt Mouse: Abnormalities in the TSH Receptor-G Protein Complex |
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