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TBX5 mutations in Non‐Holt‐Oram Syndrome (HOS) malformed hearts
Author(s) -
ReamonBuettner Stella Marie,
Borlak Juergen
Publication year - 2004
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9255
Subject(s) - missense mutation , biology , mutation , somatic cell , heart disease , genetics , heart development , homeobox protein nkx 2.5 , gene , transcription factor , medicine , embryonic stem cell , homeobox
Abstract The T‐box transcription factor Tbx5 is important in mammalian cardiac development. Mutations in the human TBX5 gene cause Holt‐Oram syndrome (HOS), a disorder characterized by heart and upper limb deformities. To determine the role of TBX5 in non‐HOS patients with complex cardiac malformations, we analyzed 68 explanted hearts from unrelated patients with various cardiac abnormalities including atrial (ASD), ventricular (VSD) and atrioventricular septal defects (AVSD). Direct sequencing detected nine mutations in diseased cardiac tissues of patients, eight of which are novel. Six mutations would affect amino acids in the T‐domain, and one (c.236C>T, p.Ala79Val) is within the recently identified nuclear localization signal (NLS1) region. Further, mutations were found in patients with ASD and AVSD, but not with VSD; and mutations were absent in normal heart tissue of same patients, thus indicating somatic origin. Our results suggest a possible role of somatically occurring TBX5 mutations in congenital heart disease. We show for the first time TBX5 mutations in non‐HOS associated cardiac malformations and we identified a novel missense mutation that would impact nuclear localization of TBX5. © 2004 Wiley‐Liss, Inc.