Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy.
The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.
Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, 2010, Australia.
Edwin P
EP
Kirk
Margaret
M
Sunde
Mauro W
MW
Costa
Scott A
SA
Rankin
Orit
O
Wolstein
M Leticia
ML
Castro
Tanya L
TL
Butler
Changbaig
C
Hyun
Guanglan
G
Guo
Robyn
R
Otway
Joel P
JP
Mackay
Leigh B
LB
Waddell
Andrew D
AD
Cole
Christopher
C
Hayward
Anne
A
Keogh
Peter
P
Macdonald
Lyn
L
Griffiths
Diane
D
Fatkin
Gary F
GF
Sholler
Aaron M
AM
Zorn
Michael P
MP
Feneley
David S
DS
Winlaw
Richard P
RP
Harvey
D000293:Adolescent; D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D006321:Heart; D006330:Heart Defects, Congenital / Q000235:genetics*; D006343:Heart Septal Defects / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D020825:T-Box Domain Proteins / Q000235:genetics*
D018389:Codon, Nonsense; D020825:T-Box Domain Proteins; C420984:TBX20 protein, human