Human Genetics

, 118:348

Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1

  • Helmut Grasberger
  • Martine Vaxillaire
  • Silvana Pannain
  • John C. Beck
  • Aviva Mimouni-Bloch
  • Vincent Vatin
  • Gilbert Vassart
  • Philippe Froguel
  • Samuel Refetoff
Original Investigation

Abstract

Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe form by thyroid gland hypoplasia. We recently identified six extended kindreds with autosomal dominant RTSH, only one of which was linked to a mutation in the PAX8 candidate gene. Genome wide scans conducted in two of the remaining five families revealed independently significant linkage to chromosome 15q25.3–26.1, with maximum multipoint LOD scores of 8.51 and 4.31. Linkage to this novel locus was replicated (P<0.01) in each of the three remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3 cM/2.9 Mb interval. Thus, we report the first locus for congenital nongoitrous hypothyroidism identified by a genome wide screening approach.

Keywords

Hypothyroidism; thyrotropin; thyroid stimulating hormone; genetic linkage 

Supplementary material

439_2005_36_MOESM1_ESM.pdf (129 kb)
Supplementary material

References

  1. Abramowicz MJ, Duprez L, Parma J, Vassart G, Heinrichs C (1997) Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest 99:3018–3024PubMedCrossRefGoogle Scholar
  2. Calaciura F, Miscio G, Coco A, Leonardi D, Cisternino C, Regalbuto C, Bozzali M, Maiorana R, Ranieri A, Carta A, Buscema M, Trischitta V, Sava L, Tassi V (2002) Genetics of specific phenotypes of congenital hypothyroidism: a population-based approach. Thyroid 12:945–951PubMedCrossRefGoogle Scholar
  3. Castanet M, Polak M, Bonaiti-Pellie C, Lyonnet S, Czernichow P, Leger J (2001) Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 86:2009–2014PubMedCrossRefGoogle Scholar
  4. Congdon T, Nguyen LQ, Nogueira CR, Habiby RL, Medeiros-Neto G, Kopp P (2001) A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. J Clin Endocrinol Metab 86:3962–3967PubMedCrossRefGoogle Scholar
  5. De Felice M, Di Lauro R (2004) Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev 25:722–746PubMedCrossRefGoogle Scholar
  6. de Sanctis L, Corrias A, Romagnolo D, Di Palma T, Biava A, Borgarello G, Gianino P, Silvestro L, Zannini M, Dianzani I (2004) Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype variability. J Clin Endocrinol Metab 89:5669–5674PubMedCrossRefGoogle Scholar
  7. Fisher DA (1983) Second international conference on neonatal thyroid screening: progress report. J Pediatr 102:653–654PubMedCrossRefGoogle Scholar
  8. Grasberger H, Mimouni-Bloch A, Vantyghem C-M, Van Vliet G, Abramowicz M, Metzger DL, Abdullatif H, Rydlewski C, Macchia PE, Scherberg NH, Van Sande J, Mimouni M, Weiss RE, Vassart G, Refetoff S (2005a) Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci. J Clin Endocrinol Metab 90:4025–4034CrossRefGoogle Scholar
  9. Grasberger H, Ringkananont U, Lefrancois P, Abramowicz M, Vassart G, Refetoff S (2005b) Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity. Mol Endocrinol 19:1779–1791CrossRefGoogle Scholar
  10. Komatsu M, Takahashi T, Takahashi I, Nakamura M, Takada G (2001) Thyroid dysgenesis caused by PAX8 mutation: the hypermutability with CpG dinucleotides at codon 31. J Pediatr 139:597–599PubMedCrossRefGoogle Scholar
  11. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363PubMedGoogle Scholar
  12. Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247PubMedCrossRefGoogle Scholar
  13. Lathrop GM, Lalouel JM (1984) Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 36:460–465PubMedGoogle Scholar
  14. Leger J, Marinovic D, Garel C, Bonaiti-Pellie C, Polak M, Czernichow P (2002) Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J Clin Endocrinol Metab 87:575–580PubMedCrossRefGoogle Scholar
  15. Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Gruters A, Busslinger M, Di Lauro R (1998) PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nat Genet 19: 83–86PubMedCrossRefGoogle Scholar
  16. Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, Weill J, Dina C, Froguel P (2004) A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes 53:803–811PubMedCrossRefGoogle Scholar
  17. Moreno JC, Pauws E, van Kampen AH, Jedlickova M, de Vijlder JJ, Ris-Stalpers C (2001) Cloning of tissue-specific genes using serial analysis of gene expression and a novel computational substraction approach. Genomics 75:70–76PubMedCrossRefGoogle Scholar
  18. Perry R, Heinrichs C, Bourdoux P, Khoury K, Szots F, Dussault JH, Vassart G, Van Vliet G (2002) Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab 87:4072–4077PubMedCrossRefGoogle Scholar
  19. Refetoff S (2003) Resistance to thyrotropin. J Endocrinol Invest 26:770–779PubMedGoogle Scholar
  20. Schaffer AA, Gupta SK, Shriram K, Cottingham RW Jr (1994) Avoiding recomputation in linkage analysis. Hum Hered 44:225–237PubMedCrossRefGoogle Scholar
  21. Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1337PubMedGoogle Scholar
  22. Sunthornthepvarakul T, Gottschalk ME, Hayashi Y, Refetoff S (1995) Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 332: 155–160CrossRefGoogle Scholar
  23. Tonacchera M, Perri A, De Marco G, Agretti P, Banco ME, Di Cosmo C, Grasso L, Vitti P, Chiovato L, Pinchera A (2004) Low prevalence of thyrotropin receptor mutations in a large series of subjects with sporadic and familial nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab 89:5787–5793PubMedCrossRefGoogle Scholar
  24. Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J, Costagliola S, Vassart G (2001) Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J Clin Endocrinol Metab 86:234–238PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Helmut Grasberger
    • 1
  • Martine Vaxillaire
    • 4
  • Silvana Pannain
    • 1
  • John C. Beck
    • 5
  • Aviva Mimouni-Bloch
    • 6
  • Vincent Vatin
    • 4
  • Gilbert Vassart
    • 7
  • Philippe Froguel
    • 4
    • 8
  • Samuel Refetoff
    • 1
    • 2
    • 3
  1. 1.Department of MedicineThe University of ChicagoChicagoUSA
  2. 2.Department of PediatricsThe University of ChicagoChicagoUSA
  3. 3.Department of Committee on GeneticsThe University of ChicagoChicagoUSA
  4. 4.Institute of Biology and Pasteur InstituteCNRS UMR 8090LilleFrance
  5. 5.Howard Hughes Medical Institute and the Department of PediatricsUniversity of Iowa Ames CityUSA
  6. 6.Schneider Children’s Medical CenterSackler School of MedicinePetah-TiqvaIsrael
  7. 7.IRIBHM and Department of GeneticsUniversite Libre de BruxellesBrusselsBelgium
  8. 8.Imperial College Genome Centre and Section of Genomic MedicineImperial College LondonLondonUnited Kingdom

Personalised recommendations