title: Detection of the first gross CDC73 germline deletion in an HPT-JT syndrome family.
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.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.forename: Carlos Vázquez
authors.initials: CV
authors.lastname: Huarte-Mendicoa
authors.forename: L
authors.initials: L
authors.lastname: Javier Leandro-García
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Javier
authors.initials: J
authors.lastname: Suela
authors.forename: Alfredo
authors.initials: A
authors.lastname: Santana
authors.forename: Mauro Boronat
authors.initials: MB
authors.lastname: Costa
authors.forename: Iñaki
authors.initials: I
authors.lastname: Comino-Méndez
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Lydia
authors.initials: L
authors.lastname: Sánchez
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007573:Jaw Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010282:Parathyroid Neoplasms / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins