Alternative titles; symbols
HGNC Approved Gene Symbol: XK
SNOMEDCT: 234411007;
Cytogenetic location: Xp21.1 Genomic coordinates (GRCh38) : X:37,685,791-37,732,130 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp21.1 | McLeod syndrome | 300842 | X-linked | 3 |
The XK gene encodes a putative membrane transporter that is expressed ubiquitously, but found mainly in nervous tissue, heart, and red blood cells. In red blood cells XK is covalently linked to Kell glycoprotein (613883) through a disulfide bond, forming a complex on the cell surface. There is a correlation between expression of Kell and XK; thus, XK levels are reduced when Kell is absent and vice versa (summary by Dubielecka et al., 2011).
Ho et al. (1994) assembled a cosmid contig of 360 kb that encompassed the XK locus and, by screening DNA from patients with radiolabeled whole cosmids, detected a 50-kb deletion. Two transcription units were identified within this deletion. The mRNA expression pattern of one of them, designated XK, correlated closely with the McLeod phenotype (MCLDS; 300842). Two unrelated patients with no deletions or rearrangements detected on pulsed field gel electrophoresis and Southern blot analysis were examined for the presence of point mutations. The strategy involved direct sequence analysis of PCR products derived from genomic DNA samples that were isolated from patients' leukocytes. In 1 patient, a mutation was found in the donor splice site of intron 2, and in the second, a mutation in the acceptor splice site of intron 2. The predicted protein product of XK is composed of 444 amino acids with a calculated molecular weight of 50,913 daltons. The protein shared structural characteristics with membrane transport proteins of prokaryotes and eukaryotes. The neurologic abnormalities in McLeod syndrome correlate well with the high levels of expression of XK in the brain. Striatal degeneration with the development of chorea in McLeod syndrome can probably be explained thereby. Late-onset muscular dystrophy and cardiomyopathy also correlate well with a high expression of XK in skeletal and cardiac muscle.
Stanfield and Horvitz (2000) found that the 458-amino acid Ced8 transmembrane protein of C. elegans is weakly similar to the human XK protein. The Ced8 and XK proteins share 19% amino acid identity, have similar hydropathy plots, and both contain 10 hydrophobic predicted membrane-spanning segments. The authors showed that loss-of-function mutations in the Ced8 gene lead to the late appearance of cell corpses during embryonic development in C. elegans. Ced8 functions downstream of or in parallel to the regulatory cell death gene Ced9 and may function as a cell death effector downstream of the caspase encoded by the programmed cell death killer gene Ced3. Stanfield and Horvitz (2000) suggested that in Ced8 mutants, embryonic programmed cell death probably initiates normally but proceeds slowly. The Ced8 protein appeared to be localized to the plasma membrane.
The XK gene contains 3 exons (Ho et al., 1994).
Marsh (1977) showed that the XK locus, which controls synthesis of the Kell blood group 'precursor substance' (Kx), is X-linked. The XK locus is inactivated by lyonization.
The XK and Xg (314700) loci are closely linked (Densen et al., 1981). Marsh (1978) reported a total lod score of 3.426 for theta of 0.0.
Ho et al. (1992) constructed a long-range restriction map of Xp21, encompassing the gene loci for McLeod and chronic granulomatous disease (CGD; 306400). Multiple CpG islands were found clustered in a 700-kb region. Using a new marker, DXS709, they limited the McLeod syndrome region to a 150- to 380-kb segment. Within this interval, 2 CpG-rich islands that may represent candidate sites for the McLeod gene were identified.
Ho et al. (1994) identified the XK gene on chromosome Xp21.1.
XK is located close to the genes responsible for chronic granulomatous disease (CYBB; 300481) and Duchenne muscular dystrophy (DMD; 300377) on the X chromosome (summary by Jung et al., 2007).
The Kell precursor substance becomes evident in persons homozygous for a 'silent' allele at the Kell locus (K0). In such cases, none of the Kell antigens can be detected but a strong Kx reaction is demonstrable with both red and white cells. Such persons are clinically and hematologically normal. The McLeod phenotype is caused by an X-linked mutation leading to lack of Kx substance (summary by Marsh, 1978).
Jung et al. (2007) stated that the KX antigen, formerly KEL15, had been regrouped into the new antigen system 019 (XK019001).
Variant alleles at the XK locus determine synthesis of permutations of Kx antigenicity on white and red cells. Absence of Kx antigen on red cells is associated with the McLeod phenomenon in the Kell system (see 110900), i.e., they react little or not at all with various antisera in the Kell system. (It was first discovered by Allen et al. (1961) in a blood donor named Hugh McLeod.) Absence of leukocyte Kx antigen is associated with X-linked chronic granulomatous disease (summary by Marsh, 1977). In 1970, Mr. McLeod's red cells were noted to be acanthocytic in the absence of abetalipoproteinemia. Mr. McLeod had normal white cell Kx. He did have a compensated hemolytic state (Wimer et al., 1976). Evidence for X-linkage of XK is provided by mosaicism for both acanthocytosis and red cell Kx in heterozygous females. The mother of the original proband was heterozygous. The observations showed that some blood group antigens are important to both structure and function of cell membranes. Structural and/or functional significance of several other blood group antigens is known. For example, absence of Rh antigens (Rh null) is associated with changes in red cell shape (see 111700) and lack of Duffy antigen (see 613665) leads to inability of the tertian malaria parasite to penetrate red cells (see 110700).
McLeod syndrome was first described by Allen et al. (1961) in a Harvard dental student, Hugh McLeod. Danek et al. (2001) demonstrated that this individual had a 13-bp deletion in exon 3 of the XK gene (314850.0006).
The mutation in the New Zealand family that helped to clarify the X-linked pattern of inheritance (Symmans et al., 1979) was shown by Bertelson et al. (1988) to be a deletion; the exact size and position of the deletion was further defined by Ho et al. (1994).
Danek et al. (2001) analyzed the mutations and clinical findings of 22 men, aged 27 to 72 years, with McLeod neuroacanthocytosis. Fifteen different XK mutations were found, 9 of which were novel, including the 1 present in the blood donor whose name was given to this disorder. All of the mutations predicted absence or truncation of the XK protein.
In a patient with McLeod syndrome (MCLDS; 300842), Ho et al. (1994) identified a change in the invariant dinucleotide of the 5-prime donor splice site of intron 2 from GT to AT.
In a patient with McLeod syndrome (MCLDS; 300842), Ho et al. (1994) observed a change in the invariant dinucleotide at the 3-prime splice acceptor site from AG to AA.
In a female with McLeod syndrome (MCLDS; 300842), Ho et al. (1996) demonstrated a novel 1-bp deletion in exon 2 of the XK gene at codon 90, creating a frameshift that results in premature termination of translation and elimination of 80% of the predicted XK protein. The mutation was found in a 51-year-old woman who presented with cognitive impairment, chorea tics, and areflexia due to an axonal peripheral neuropathy. This woman had marked skewing of X inactivation. The authors pointed out the similarity of the clinical features in advanced cases of McLeod syndrome to those of choreoacanthocytosis (200150).
In a 50-year-old Japanese man with McLeod syndrome (MCLDS; 300842), Hanaoka et al. (1999) found deletion of a single base, T, at nucleotide 1095 of the XK gene (codon 320), which was predicted to cause a premature stop codon at amino acid 408. His 82-year-old mother was heterozygous for the mutation and had no neuromuscular symptoms and normal serum creatine kinase levels. The man had noticed slowly progressive muscular atrophy, weakness in the lower limbs, and gait disturbance since the age of 45. At the age of 26, he had been hospitalized for depression, and high levels of serum transaminase and creatine kinase were noted.
Of 15 different mutations identified in the XK gene by Danek et al. (2001) in 22 men with McLeod neuroacanthocytosis (MCLDS; 300842), only one was a missense mutation: a 962T-C transition in exon 3 resulting in a cys294-to-arg (C294R) substitution.
In Hugh McLeod, the original propositus (Allen et al., 1961) for whom the 'McLeod phenotype' (MCLDS; 300842) is named, Danek et al. (2001) demonstrated a 13-bp deletion (1020-1033del) in the XK gene. The mutation resulted in a shift in reading frame, causing the translation machinery to terminate at a downstream, in-frame stop codon. The deletion was initiated in codon 313 and the stop codon was created at codon 336.
Supple et al. (2001) discovered a novel nonsense mutation in the XK gene in a 29-year-old man with a history of elevated creatine kinase and necrotizing myopathy. Prominent red cell acanthocytosis in association with reduced Kell antigen expression was present. Investigation of the patient's XK gene revealed a novel TGG-to-TAG transition at nucleotide 1023 in exon 3 that resulted in an in-frame stop codon, trp314-to-ter (W314X), and predicted a truncated XK protein of 313 amino acids, compared with the 444 amino acids in the normal XK protein. The mutation was not found in the patient's mother or sister, indicating that it was a de novo mutation. His myopathy had initially been labeled polymyositis and treated with immunosuppressive therapy. Subsequently the diagnosis of McLeod syndrome (MCLDS; 300842) was suggested on the basis of prominent acanthocytosis, mild compensated hemolysis, persistent elevation of creatine kinase, and excessive sweating without neuromuscular symptoms.
In a family with McLeod syndrome (MCLDS; 300842) who originated from the German-speaking part of Switzerland, Jung et al. (2001) identified a C-to-T transition at nucleotide 977 of the XK gene, resulting in a gln299-to-ter (Q299X) mutation. Among 7 affected males, 5 manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only 2 presented with chorea. Positron emission tomography (PET) and magnetic resonance volumetry revealed reduced striatal 2-fluoro-2-deoxyglucose uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, in the female carriers a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal 2-fluoro-2-deoxyglucose uptake without structural abnormalities. The authors suggested that patients with psychiatric signs or symptoms segregating in an X-linked manner should be examined for acanthocytosis and Kell/Kx blood group serology.
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