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Molecular Analysis of the Rare In(Lu) Blood Type: Toward Decoding the Phenotypic Outcome of Haploinsufficiency for the Transcription Factor KLF 1
Author(s) -
Helias Virginie,
Saison Carole,
Peyrard Thierry,
Vera Eliane,
Prehu Claude,
Cartron JeanPierre,
Arnaud Lionel
Publication year - 2013
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.22218
Subject(s) - haploinsufficiency , biology , transactivation , transcription factor , missense mutation , microbiology and biotechnology , genetics , phenotype , immunology , gene
KLF1 encodes an erythroid transcription factor, whose essential function in erythropoiesis has been demonstrated by extensive studies in mouse models. The first reported mutations in human KLF1 were found in individuals with a rare and asymptomatic blood type called I n( L u). Here, we show that KLF 1 haploinsufficiency is responsible for the I n( L u) blood type, after redefining this peculiar blood type using flow cytometry to quantify the levels of BCAM and CD 44 on red blood cells. We found 10 (seven novel) heterozygous KLF1 mutations responsible for the I n( L u) blood type. Although most were obligate loss‐of‐function mutations due to the truncation of the DNA ‐binding domain of KLF 1, three were missense mutations that were located in its DNA ‐binding domain and impaired the transactivation capacity of KLF1 in vitro. We further showed that the levels of the hemoglobin variants H b F and H b A 2 were increased in the I n( L u) blood type, albeit differently. The levels of the membrane glycoproteins BCAM and CD 44 were also differently reduced on I n( L u) red blood cells. This biochemical and genetic analysis of the I n( L u) blood type tackles the phenotypic outcome of haploinsufficiency for a transcription factor.