Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland

被引:169
作者
Abramowicz, MJ
Duprez, L
Parma, J
Vassart, G
Heinrichs, C
机构
[1] HOP UNIV ENFANTS REINE FABIOLA,DEPT PEDIAT,B-1020 BRUSSELS,BELGIUM
[2] FREE UNIV BRUSSELS,INST RECH INTERDISCIPLINAIRE BIOL HUMAINE & NUCL,B-1070 BRUSSELS,BELGIUM
关键词
thyrotropin receptor; congenital hypothyroidism; thyroglobulin; thyroid agenesis;
D O I
10.1172/JCI119497
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Thyroid gland agenesis is the most common cause of congenital hypothyroidism and is usually sporadic. We investigated a brother and sister from consanguineous parents, ascertained through systematic newborn screening, and initially diagnosed with thyroid agenesis. Careful cervical ultrasonography in both patients revealed a very hypoplastic thyroid gland. By direct sequencing of the thyrotropin receptor gene, we identified the substitution of threonine in place of a highly conserved alanine at position 553, in the fourth predicted transmembrane domain. The mutation was found homozygous in the affected siblings, and heterozygous in both parents and two unaffected siblings. Functional analysis in transfected COS-7 cells showed that it resulted in extremely low expression at the cell surface as compared with the wild-type receptor, in spite of an apparently normal intracellular synthesis. The small amount of mutated receptor expressed at the surface of transfected cells bound thyrotropin with normal affinity and responded in terms of cAMP production, but the in vivo significance of these data from overexpressed receptor in transfected cells is unclear. Of note, blood thyroglobulin was unexpectedly elevated in the patients at the time of diagnosis, a finding that might prove useful in refining etiologies of congenital hypothyroidism.
引用
收藏
页码:3018 / 3024
页数:7
相关论文
共 35 条
  • [1] IDENTIFICATION OF A MUTATION IN THE CODING SEQUENCE OF THE HUMAN THYROID PEROXIDASE GENE CAUSING CONGENITAL GOITER
    ABRAMOWICZ, MJ
    TARGOVNIK, HM
    VARELA, V
    COCHAUX, P
    KRAWIEC, L
    PISAREV, MA
    PROPATO, FVE
    JUVENAL, G
    CHESTER, HA
    VASSART, G
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (04) : 1200 - 1204
  • [2] INHERITED PRIMARY HYPOTHYROIDISM IN MICE
    BEAMER, WG
    EICHER, EM
    MALTAIS, LJ
    SOUTHARD, JL
    [J]. SCIENCE, 1981, 212 (4490) : 61 - 63
  • [4] BIBERMANN H, 1996, 10 INT C END
  • [5] CLONED, STABLY EXPRESSED PARATHYROID-HORMONE (PTH)/PTH-RELATED PEPTIDE RECEPTORS ACTIVATE MULTIPLE MESSENGER SIGNALS AND BIOLOGICAL RESPONSES IN LLC-PK1 KIDNEY-CELLS
    BRINGHURST, FR
    JUPPNER, H
    GUO, J
    URENA, P
    POTTS, JT
    KRONENBERG, HM
    ABOUSAMRA, AB
    SEGRE, GV
    [J]. ENDOCRINOLOGY, 1993, 132 (05) : 2090 - 2098
  • [6] DETERMINATION OF THYROID VOLUME BY ULTRASOUND FROM THE NEONATAL-PERIOD TO LATE ADOLESCENCE
    CHANOINE, JP
    TOPPET, V
    LAGASSE, R
    SPEHL, M
    DELANGE, F
    [J]. EUROPEAN JOURNAL OF PEDIATRICS, 1991, 150 (06) : 395 - 399
  • [7] Evidence for negative cooperativity among human thyrotropin receptors overexpressed in mammalian cells
    Chazenbalk, GD
    Kakinuma, A
    Jaume, JC
    McLachlan, SM
    Rapoport, B
    [J]. ENDOCRINOLOGY, 1996, 137 (11) : 4586 - 4591
  • [8] CONGENITAL HYPOTHYROIDISM ASSOCIATED WITH THYROTROPIN UNRESPONSIVENESS AND THYROID CELL-MEMBRANE ALTERATIONS
    CODACCIONI, JL
    CARAYON, P
    MICHELBECHET, M
    FOUCAULT, F
    LEFORT, G
    PIERRON, H
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1980, 50 (05) : 932 - 937
  • [9] PLASMA THYROGLOBULIN MEASUREMENTS HELP DETERMINE THE TYPE OF THYROID DEFECT IN CONGENITAL HYPOTHYROIDISM
    CZERNICHOW, P
    SCHLUMBERGER, M
    POMAREDE, R
    FRAGU, P
    [J]. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1983, 56 (02) : 242 - 245
  • [10] THYROID-SPECIFIC GENE-EXPRESSION
    DAMANTE, G
    DILAURO, R
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1994, 1218 (03): : 255 - 266