Detection of the first gross CDC73 germline deletion in an HPT-JT syndrome family

Authors

  • Alberto Cascón,

    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
    Search for more papers by this author
  • Carlos Vázquez Huarte-Mendicoa,

    1. Genetic Unit, Hospital Materno-Infantil, Las Palmas de Gran Canaria, Spain
    Search for more papers by this author
  • L. Javier Leandro-García,

    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Rocío Letón,

    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Javier Suela,

    1. Molecular Cytogenetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Alfredo Santana,

    1. Genetic Unit, Hospital Materno-Infantil, Las Palmas de Gran Canaria, Spain
    2. Research Unit, Hospital de Gran Canaria Dr. Negrín, Las Palmas GC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Tenerife, Spain
    Search for more papers by this author
  • Mauro Boronat Costa,

    1. Endocrinology Service, Complejo Hospitalario Universitario Materno Insular, Las Palmas de Gran Canaria, Spain
    Search for more papers by this author
  • Iñaki Comino-Méndez,

    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Iñigo Landa,

    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Lydia Sánchez,

    1. Histology and Immunohistochemistry Core Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Cristina Rodríguez-Antona,

    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
    Search for more papers by this author
  • Juan C. Cigudosa,

    1. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
    2. Molecular Cytogenetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    Search for more papers by this author
  • Mercedes Robledo

    Corresponding author
    1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
    • Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme. Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain
    Search for more papers by this author

Abstract

Hereditary primary hyperparathyroidism (HPT) may develop as a solitary endocrinopathy (FIHP) or as part of multiple endocrine neoplasia Type 1, multiple endocrine neoplasia Type 2A, or hereditary HPT-jaw tumor syndrome. Inactivating germline mutations of the tumor suppressor gene CDC73 account for 14 and 50% of all FIHP and HPT-JT patients, respectively, and have also been found in almost 20% of apparently sporadic parathyroid carcinoma patients. Although more than 60 independent germline mutations have been described, to date no rearrangement affecting the CDC73 locus has been identified. By means of multiplex-PCR we found a large germline deletion affecting the whole gene in a two-generation HPT-JT family. Subsequently array-CGH and specific PCR analysis determined that the mutation spanned ∼ 547 kb, and included four additional genes:TROVE2, GLRX2, B3GALT2, and UCHL5. Although no clear mutation-specific phenotype was found associated to the presence of the mutation, further studies are needed to assess whether the loss of the neighboring genes could modify the phenotype of carriers. There was complete absence of nuclear staining in the two HPT-JT-related tumors available. The finding of the first rearrangement affecting the CDC73 gene warrants screening for this tumor suppressor gene inactivation mechanism not only in high-risk CDC73 point mutation-negative HPT-JT families, but also in FIHP patients. © 2011 Wiley-Liss, Inc.

Ancillary