Alternative titles; symbols
SNOMEDCT: 115824003;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.13 | Blood group--Lutheran inhibitor | 111150 | Autosomal dominant | 3 | KLF1 | 600599 |
A number sign (#) is used with this entry because the Lutheran inhibitor (INLU) blood group phenotype of the Lutheran blood group (111200) results from heterozygous mutation in the KLF1 gene (600599) on chromosome 19p13.
The Lutheran inhibitor blood group phenotype (In(Lu)) is characterized phenotypically by the apparent absence of the Lu antigen (BCAM; 612773) on red blood cells during serologic tests, i.e., Lu(a-b-). Since it is inherited as an autosomal dominant trait, it was initially postulated to result from an inhibitor of the Lu antigen. However, Singleton et al. (2008) found that the phenotype results from a mutation in the transcription factor KLF1 that regulates expression of the BCAM gene.
The Lu-null phenotype, or autosomal recessive true Lu(a-b-) (247420), is caused by homozygous or compound heterozygous inactivating mutations in the BCAM gene.
By flow cytometry, Helias et al. (2013) demonstrated that the majority of red blood cells from individuals with the In(Lu) blood type completely lacked BCAM reactivity, although a small proportion showed some BCAM reactivity, suggesting weak expression of Lu(b). In addition, In(Lu) blood cells also showed low expression of CD44 (107269) compared to controls. These flow cytometric parameters allowed distinction of In(Lu) from recessive true Lu-null cells, or Lu(a-b-), that is caused by inactivating mutations in the BCAM gene. All 10 samples of In(Lu) carried heterozygous loss-of-function mutations in the KLF1 gene (see, e.g., 600599.0007-600599.0009). Helias et al. (2013) also found that In(Lu) individuals had increased levels of fetal hemoglobin (HbF) (mean of 2.14%) compared to controls (mean less than 1.0%), and slightly increased levels of HbA2 (141850). Finally, 9 In(Lu) individuals who were heterozygous for the P1 allele (607922.0007) did not express the P1 antigen (see 111400), whereas 1 who was homozygous for the P1 allele expressed only weak P1. These findings suggested that the expression of P1 is suppressed in the In(Lu) blood type. Helias et al. (2013) concluded that the KLF1 haploinsufficiency has different effects on the expression of different erythroid proteins, likely reflecting the variable dependence of their respective genes on the KLF1 transcription factor.
Race and Sanger (1975) described a dominant, independently segregating suppressor affecting the expression of Lutheran gene, which has been termed the Lutheran inhibitor, symbolized In(Lu). It influences the Lutheran, Auberger (see 111200), I (110800), and P (111400) blood group systems. The Auberger system belongs to the Lutheran system (Daniels et al., 1991).
Gibson (1976) described 2 families and confirmed the fact that In(Lu) also inhibits the full expression of the P1 antigen.
Shaw et al. (1984) found that the dominant inhibitor of Lutheran antigens, In(Lu), is the usual cause of the Lutheran null phenotype in southeast England where they studied the families of 41 probands and found no proven case of the recessive background, LuLu. The only suggestion of linkage was with Rh (maximum lod = 1.169 in males at theta 0.1). Previously, INLU and CD44 (or MDU3; 107269) were thought to be the same. Telen (1992), however, knew of no evidence for this.
Rowe et al. (1992) investigated the families of 11 Lu-null probands to determine which of the 3 known genetic backgrounds, dominant, recessive (247420), or X-linked recessive (309050), was responsible for their Lu-null phenotype. In 10 of the 11 families, the Lu-null phenotype was caused by the dominant suppressor gene INLU. The family data permitted them to demonstrate for the first time independence of the INLU and LU genes. They also demonstrated suppression of the P1 antigen by the INLU gene. Close linkage of INLU and HLA was excluded.
Karamatic Crew et al. (2007) noted that the autosomal dominant Lu(a-b-) is more common than autosomal recessive Lu(a-b-) (247420).
Singleton et al. (2008) identified 9 different heterozygous loss-of-function mutations in the KLF1 gene (see, e.g., 600599.0001-600599.0004) in 21 of 24 persons with the autosomal dominant In(Lu) phenotype. The individuals had no reported pathology, indicating that 1 functional KLF1 allele is sufficient to sustain human erythropoiesis.
In red blood cell samples from 10 probands with the dominant In(Lu) phenotype, Helias et al. (2013) identified 10 different heterozygous loss-of-function mutations in the KLF1 gene (see, e.g., 600599.0001-600599.0002 and 600599.0007-600599.0009).
In(Lu) was originally postulated to result from inheritance of a gene that inhibited or suppressed the Lutheran antigen gene (Gibson, 1976). The findings of Singleton et al. (2008) indicated that the lack of expression of the Lu antigen in this phenotype results from decreased transcription of erythroid-specific genes associated with red blood cell maturation. Although individuals with the In(Lu) phenotype serologically type as Lu(a-b-), further adsorption and elution techniques may show the presence of very weak Lutheran antigen expression.
In South Wales, Rowe et al. (1992) found a frequency of 0.0002 for the Lu(a-b-) phenotype.
Contreras, M., Tippett, P. The Lu(a-b-) syndrome and an apparent upset of P1 inheritance. Vox Sang. 27: 369-371, 1974. [PubMed: 4416594] [Full Text: https://doi.org/10.1111/j.1423-0410.1974.tb02429.x]
Daniels, G. L., Le Pennec, P. Y., Rouger, P., Salmon, C., Tippett, P. The red cell antigens Au(a) and Au(b) belong to the Lutheran system. Vox Sang. 60: 191-192, 1991. [PubMed: 1862644] [Full Text: https://doi.org/10.1111/j.1423-0410.1991.tb00903.x]
Gibson, T. Two kindred with the rare dominant inhibitor of the Lutheran and P1 red cell antigens. Hum. Hered. 26: 171-174, 1976. [PubMed: 955641] [Full Text: https://doi.org/10.1159/000152801]
Helias, V., Saison, C., Peyrard, T., Vera, E., Prehu, C., Cartron, J.-P., Arnaud, L. Molecular analysis of the rare In(Lu) blood type: toward decoding the phenotypic outcome of haploinsufficiency for the transcription factor KLF1. Hum. Mutat. 34: 221-228, 2013. [PubMed: 23125034] [Full Text: https://doi.org/10.1002/humu.22218]
Karamatic Crew, V., Mallinson, G., Green, C., Poole, J., Uchikawa, M., Tani, Y., Geisen, C., Oldenburg, J., Daniels, G. Different inactivating mutations in the LU genes of three individuals with the Lutheran-null phenotype. Transfusion 47: 492-498, 2007. [PubMed: 17319831] [Full Text: https://doi.org/10.1111/j.1537-2995.2006.01141.x]
Race, R. R., Sanger, R. Blood Groups in Man. (6th ed.) Oxford: Blackwell Sci. Publ. (pub.) 1975. Pp. 267-272.
Rowe, G. P., Gale, S. A., Daniels, G. L., Green, C. A., Tippett, P. A study on Lu-null families in South Wales. Ann. Hum. Genet. 56: 267-272, 1992. [PubMed: 1449238] [Full Text: https://doi.org/10.1111/j.1469-1809.1992.tb01151.x]
Shaw, M. A., Leak, M. R., Daniels, G. L., Tippett, P. The rare Lutheran blood group phenotype Lu(a-b-): a genetic study. Ann. Hum. Genet. 48: 229-237, 1984. [PubMed: 6465841] [Full Text: https://doi.org/10.1111/j.1469-1809.1984.tb01019.x]
Singleton, B. K., Burton, N. M., Green, C., Brady, R. L., Anstee, D. J. Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype. Blood 112: 2081-2088, 2008. [PubMed: 18487511] [Full Text: https://doi.org/10.1182/blood-2008-03-145672]
Taliano, V., Guevin, R.-M., Tippett, P. The genetics of a dominant inhibitor of the Lutheran antigens. Vox Sang. 24: 42-47, 1973. [PubMed: 4682512] [Full Text: https://doi.org/10.1111/j.1423-0410.1973.tb03855.x]
Telen, M. J. Personal Communication. Durham, N. C. 12/30/1992.