Genome wide association analysis of a founder population identified TAF3 as a gene for MCHC in humans.
The red blood cell related traits are highly heritable but their genetics are poorly defined. Only 5-10% of the total observed variance is explained by the genetic loci found to date, suggesting that additional loci should be searched using approaches alternative to large meta analysis. GWAS (Genome Wide Association Study) for red blood cell traits in a founder population cohort from Northern Italy identified a new locus for mean corpuscular hemoglobin concentration (MCHC) in the TAF3 gene. The association was replicated in two cohorts (rs1887582, P = 4.25E-09). TAF3 encodes a transcription cofactor that participates in core promoter recognition complex, and is involved in zebrafish and mouse erythropoiesis. We show here that TAF3 is required for transcription of the SPTA1 gene, encoding alpha spectrin, one of the proteins that link the plasma membrane to the actin cytoskeleton. Mutations in SPTA1 are responsible for hereditary spherocytosis, a monogenic disorder of MCHC, as well as for the normal MCHC level. Based on our results, we propose that TAF3 is required for normal erythropoiesis in human and that it might have a role in controlling the ratio between hemoglobin (Hb) and cell volume and in the dynamics of RBC maturation in healthy individuals. Finally, TAF3 represents a potential candidate or a modifier gene for disorders of red cell membrane.
Division of Genetics and Cell Biology, San Raffaele Research Institute and Vita Salute University, Milano, Italy.
Giorgio
G
Pistis
Shawntel U
SU
Okonkwo
Michela
M
Traglia
Cinzia
C
Sala
So-Youn
SY
Shin
Corrado
C
Masciullo
Iwan
I
Buetti
Roberto
R
Massacane
Massimo
M
Mangino
Swee-Lay
SL
Thein
Timothy D
TD
Spector
Santhi
S
Ganesh
Nicola
N
Pirastu
Paolo
P
Gasparini
Nicole
N
Soranzo
Clara
C
Camaschella
Daniel
D
Hart
Michael R
MR
Green
Daniela
D
Toniolo
D000818:Animals; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D004909:Erythrocyte Indices / Q000235:genetics*; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D018703:Founder Effect; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007558:Italy; D020014:K562 Cells; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013049:Spectrin / Q000235:genetics; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID / Q000235:genetics* / Q000378:metabolism
D006454:Hemoglobins; C432689:TAF3 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D013049:Spectrin