Mild Congenital Primary Hypothyroidism in a Turkish Family Caused by a Homozygous Missense Thyrotropin Receptor (TSHR) Gene Mutation (A593 V)

Abstract

Congenital primary hypothyroidism (CH) occurs in 1 of 4000 births. The majority of the cases are due to agenesis or dysgenesis of the thyroid gland, which can be caused by mutations in genes encoding for transcriptional factors that are responsible for the development of the thyroid gland. It is also known that the thyrotropin receptor (TSHR), a G-protein coupled receptor, is involved in late stages of thyroid organogenesis. Thus, mutations in the TSHR gene can cause congenital hypothyroidism. However, the clinical spectrum of thyroid abnormalities due to mutant TSHRs is wide and ranges from severe hypoplasia to an almost normal sized and structured thyroid gland. So far, 23 distinct loss-of-function mutations in the TSHR gene have been reported, occurring in families of different ethnic backgrounds and geographical areas. Here we report on a Turkish kindred in which two children were diagnosed to have very mild congenital primary hypothyroidism and one child had subclinical hypothyroidism. A novel homozygous missense mutation in codon 593 (A593 V) of the TSHR gene was identified in the affected individuals as the underlying molecular defect. This mutation substitutes a non-polar amino acid (alanine) with a non-polar amino acid (valine), so that only a minimal impairment of the TSHR function is expected. Indeed, the molecular finding is in agreement with the observed mild phenotype of the affected individuals. Our conclusion is that in mild primary hypothyroidism or subclinical hypothyroidism, mutations in the TSHR gene have to be considered as the molecular cause, especially in patients who have no detectable thyroid autoantibodies and have thyroid glands of normal size and in normal location.

Key words

Thyrotropin receptor - missense mutation - primary hypothyroidism

References

• 1 Abramowicz M J, Duprez L, Parma J, Vassart G, Heinrichs C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland.  J Clin Invest. 1997;  99 3018-3024
• 2 Alberti L, Proverbio M, Costagliola S, Romoli R, Boldrighini B, Vigone M, Weber G, Chiumello G, Beck-Peccoz P, Persani L. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism.  J Clin Endocrinol Metab. 2002;  87 2549-2555
• 3 Biebermann H, Schöneberg T, Krude H, Schultz G, Gudermann T, Grüters A. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistant congenital hypothyroidism.  J Clin Endocrinol Metab. 1997;  82 3471-3480
• 4 Biebermann H, Schöneberg T, Schulz A, Krause G, Gruters A, Schultz G, Gudermann T. A conserved tyrosine residue (Y601) in transmembrane domain 5 of the human thyrotropin receptor serves as a molecular switch to determine G- protein coupling.  FASEB J. 1998;  12 1461-1471
• 5 Bretones P, Duprez L, Parma J, David M, Vassart G, Rodien P. A familial case of congenital hypothyroidism caused by a homozygous mutation of the thyrotropin receptor gene.  Thyroid. 2001;  11 977-980
• 6 Clifton-Bligh R J, Gregory J W, Ludgate M, John R, Persani L, Asteria C, Beck-Peccoz P, Chatterjee V KK. Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH.  J Clin Endocrinol Metab. 1997;  82 1094-1100
• 7 De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms.  Endocr Rev. 2004;  25 722-746
• 8 De Roux N, Misrahi M, Brouner R, Houang M, Carel J C, Granier M, Le Bouc Y, Ghinea N, Boumedienne A, Toublanc J E, Milgrom E. Four families with loss of function mutations of the thyrotropin receptor.  J Clin Endocrinol Metab. 1996;  81 4229-4235
• 9 Gagné N, Parma J, Deal C, Vassart G, Van Vliet G. Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities?.  J Clin Endocrinol Metab. 1998;  83 1771-1775
• 10 Jordan N, Williams N, Gregory J, Evans C, Ludgate M. The W546 X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population.  J Clin Endocrinol Metab. 2003;  88 1002-1005
• 11 Libert F, Lefort A, Gerald C, Parmentier M, Perret J, Ludgate M, Dumont J E, Vassart G. Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies.  Biochem Biophys Res Commun. 1989;  165 1250-1255
• 12 Misrahi M, Loosfelt H, Atger M, Sar S, Guiochon-Mantel A, Milgrom E. Cloning, sequencing and expression of human TSH receptor.  Biochem Biophys Res Commun. 1990;  166 394-403
• 13 Nagashima T, Murakami M, Onigata K, Morimura T, Nagashima K, Masatomo M, Morikawa A. Novel inactivating missense mutation in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin.  Thyroid. 2001;  11 551-559
• 14 Nagayama Y, Kaufman K D, Seto P, Rapoport B. Molecular cloning, sequence and functional expression of the cDNA for human thyrotropin receptor.  Biochem Biophys Res Commun. 1989;  165 1184-1190
• 15 Park S-M, Clifton-Bligh R J, Betts P, Chatterjee V KK. Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor.  Clin Endocrinol. 2004;  60 220-227
• 16 Richter-Unruh A, Hauffa B, Pfarr N, Pohlenz J. Congenital primary hypothyroidism in a Turkish family due to a homozygous nonsense mutation (R609 X) in the thyrotropin receptor (TSHR) gene.  Thyroid. 2004;  14 93-96
• 17 Russo D, Betterle C, Arturi F, Chiefari E, Girelli M E, Filetti S. A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH.  J Clin Endocrinol Metab. 2000;  85 4238-4242
• 18 Sunthornthepvarakul T, Gottschalk M E, Hayashi Y, Refetoff S. Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene.  N Engl J Med. 1995;  332 155-160
• 19 Tiosano D, Pannain S, Vassart G, Parma J, Gershoni-Baruch R, Mandel H, Lotan R, Zaharan Y, Pery M, Weiss R E, Refetoff S, Hochberg Z E. The hypothyroidism in an Inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.  Thyroid. 1999;  9 887-894
• 20 Tonacchera M, Agretti P, De Marco G, Perri A, Pinchera A, Vitti P, Chiovato L. Thyroid resistance to TSH complicated by autoimmune thyroiditis.  J Clin Endocrinol Metab. 2001;  86 4543-4546
• 21 Tonacchera M, Agretti P, Pinchera A, Rosellini V, Perri A, Collecchi P, Vitti P, Chiovato L. Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene.  J Clin Endocrinol Metab. 2000;  85 1001-1008
• 22 Tonacchera M, Perri A, De Marco G, Agretti P, Banco M E, Di Cosmo C, Grasso L, Vitti P, Chiovato L, Pinchera A. Low prevalence of thyrotropin receptor mutations in a large series of subjects with sporadic and familial nonautoimmune subclinical hypothyroidism.  J Clin Endocrinol Metab. 2004;  89 5787-5793
• 23 Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G. Somatic and germline mutations of the TSH receptor gene in thyroid diseases.  J Clin Endocrinol Metab. 1995;  80 2577-2585
• 24 Xie J, Pannain S, Pohlenz J, Weiss R E, Moltz K, Morlot M, Asteria C, Persani L, Beck-Peccoz P, Parma J, Vassart G, Refetoff S. Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH.  J Clin Endocrinol Metab. 1997;  82 3933-3940