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Inhibin α-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers
  1. C A Longui1,2,
  2. S H V Lemos-Marini4,
  3. B Figueiredo5,
  4. B B Mendonca6,
  5. M Castro7,
  6. R Liberatore, Jr8,
  7. C Watanabe9,
  8. C L P Lancellotti3,
  9. M N Rocha2,
  10. M B Melo2,
  11. O Monte1,
  12. L E P Calliari1,
  13. G Guerra-Junior4,
  14. M T M Baptista4,
  15. L Sbragia-Neto4,
  16. A C Latronico6,
  17. A Moreira7,
  18. A M D Tardelli9,
  19. A Nigri9,
  20. S E Taymans10,
  21. C A Stratakis10
  1. 1Pediatric Endocrinology, Santa Casa de São Paulo, School of Medicine, São Paulo, SP, Brazil
  2. 2Laboratory of Molecular Investigation, Santa Casa de São Paulo, School of Medicine, São Paulo, SP, Brazil
  3. 3Pathology Department, Santa Casa de São Paulo, School of Medicine, São Paulo, SP, Brazil
  4. 4UNICAMP Pediatric Endocrinology Unit, State University of Campinas, Campinas, SP, Brazil
  5. 5Pediatric Endocrinology, Federal University of Paraná, Curitiba, PR, Brazil
  6. 6FMUSP-SP Endocrinology Division, University of Sao Paulo, São Paulo, SP, Brazil
  7. 7Endocrinology Unit, University of São Paulo, Ribeirão Preto, Brazil
  8. 8Pediatric Endocrinology, School of Medicine, São José do Rio Preto, SP, Brazil
  9. 9Pediatric Endocrinology, Catholic University of Sorocaba, Sorocaba, SP, Brazil
  10. 10Section on Endocrinology and Genetics (SEGEN), Developmental Endocrinology Branch (DEB), National Institute of Child Health and Human Development (NICHD), Bethesda, MD, USA
  1. Correspondence to:
 Dr C A Stratakis MD, DSc, Chief
 Section on Endocrinology and Genetics, DEB, NICHD, NIH, Building 10, Room 10N262, 10 Center MSC1862, Bethesda, 20892-1862, USA;


The R337H TP53 mutation is a low-penetrance molecular defect that predisposes to adrenocortical tumour (ACT) formation in Brazilian and possibly other populations. Additional genetic defects may be responsible for the variable expression of ACTs in these cases. The inhibin α-subunit gene (INHA) on 2q33-qter has been implicated in mouse adrenocortical tumourigenesis. We studied 46 pediatric patients with ACTs from Brazil for INHA genetic alterations; 39 of these patients were heterozygous carriers of the R337H TP53 mutation. We first mapped the INHA gene by radiation hybrid analysis and determined 10 linked microsatellite markers in an area flanked by D2S1371 and D2S206 on 2q33-qter. These markers were then used for loss of heterozygozity (LOH) studies in nine paired germline and tumour DNA samples. Mapping placed the INHA gene in close proximity to D2S2848 (SHGC11864) with a log of odds (LOD) score of 5.84. LOH for at least one marker in the region was identified in 8/9 tumours (89%). Six patients were heterozygous for three INHA mutations: one in exon 1, 127C>G, and two in exon 2, 3998G>A and 4088G>A, all leading to amino acid substitutions (P43A, G227R, and A257T, respectively). A257T is located in a conserved INHA region, highly homologous to transforming growth factor-β; both G227R and A257T change polarity, and, in addition, G227R changes the pH. We conclude that these sequence alterations and the detected 2q allelic changes suggest that INHA may be one of the contributing factors needed for ACT formation in pediatric patient carriers of the R337H TP53 mutation.

  • adrenal tumours
  • chromosome 2
  • inhibin α-subunit
  • mutation
  • TP53
  • ACT, adrenocortical tumour
  • LOD, log of odds
  • LOH, loss of heterozygosity
  • MI, microsatellite length instability
  • RH, radiation hybrid
  • TGF-β, transforming growth factor-β

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  • This work was supported by FAPESP (Foundation for Research Support of São Paulo State), grant process #: 99/02275–8.

  • Conflicts of interest: none declared.