RBCC Red Blood Cell Collection

XK (XKR1, XRG1) [Confidence: high (a blood group or CD marker)]
Membrane transport protein XK (Kell complex 37 kDa component; Kx antigen; XK-related protein 1)

hRBCD IPI00020896
IPI00020896 Membrane transport protein XK Membrane transport protein XK membrane n/a n/a 1 n/a n/a n/a 1 1 n/a n/a 1 2 n/a n/a 1 n/a n/a n/a n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight

BGMUT xk
721 xk XK XK reference reference common 8004674 Z32684 Ho et al. 2011-08-09 02:41:50.220 NA

UniProt P51811
ID XK_HUMAN Reviewed; 444 AA.
AC P51811; Q4TTN6; Q8IUK6; Q9UC77;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 24-JAN-2006, sequence version 5.
DT 22-JAN-2014, entry version 111.
DE RecName: Full=Membrane transport protein XK;
DE AltName: Full=Kell complex 37 kDa component;
DE AltName: Full=Kx antigen;
DE AltName: Full=XK-related protein 1;
GN Name=XK; Synonyms=XKR1, XRG1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8004674; DOI=10.1016/0092-8674(94)90136-8;
RA Ho M., Chelly J., Carter N., Danek A., Crocker P., Monaco A.P.;
RT "Isolation of the gene for McLeod syndrome that encodes a novel
RT membrane transport protein.";
RL Cell 77:869-880(1994).
RN [2]
RP SEQUENCE REVISION TO 204-205.
RA Ho M.;
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Huang C.-H., Chen Y.;
RT "A superfamily of XK-related genes (XRG) widely expressed in
RT vertebrates and invertebrates.";
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 1-22, AND LACK OF GLYCOSYLATION.
RX PubMed=7737196; DOI=10.1111/j.1432-1033.1995.tb20342.x;
RA Khamlichi S., Bailly P., Blanchard D., Goossens D., Cartron J.-P.,
RA Bertrand O.;
RT "Purification and partial characterization of the erythrocyte Kx
RT protein deficient in McLeod patients.";
RL Eur. J. Biochem. 228:931-934(1995).
RN [7]
RP SUBUNIT, DISULFIDE BOND, AND MUTAGENESIS OF CYS-347.
RX PubMed=9593744; DOI=10.1074/jbc.273.22.13950;
RA Russo D., Redman C., Lee S.;
RT "Association of XK and Kell blood group proteins.";
RL J. Biol. Chem. 273:13950-13956(1998).
RN [8]
RP VARIANT MLS ARG-294.
RX PubMed=11761473; DOI=10.1002/ana.10035;
RA Danek A., Rubio J.P., Rampoldi L., Ho M., Dobson-Stone C., Tison F.,
RA Symmans W.A., Oechsner M., Kalckreuth W., Watt J.M., Corbett A.J.,
RA Hamdalla H.H., Marshall A.G., Sutton I., Dotti M.T., Malandrini A.,
RA Walker R.H., Daniels G., Monaco A.P.;
RT "McLeod neuroacanthocytosis: genotype and phenotype.";
RL Ann. Neurol. 50:755-764(2001).
RN [9]
RP VARIANT MLS GLY-222.
RX PubMed=11961232; DOI=10.1046/j.1537-2995.2002.00049.x;
RA Russo D.C., Lee S., Reid M.E., Redman C.M.;
RT "Point mutations causing the McLeod phenotype.";
RL Transfusion 42:287-293(2002).
RN [10]
RP VARIANT MLS LYS-327.
RX PubMed=12823753; DOI=10.1046/j.1537-2995.2003.t01-1-00434.x;
RA Jung H.H., Hergersberg M., Vogt M., Pahnke J., Treyer V.,
RA Rothlisberger B., Kollias S.S., Russo D., Frey B.M.;
RT "McLeod phenotype associated with a XK missense mutation without
RT hematologic, neuromuscular, or cerebral involvement.";
RL Transfusion 43:928-938(2003).
CC -!- FUNCTION: May be involved in sodium-dependent transport of neutral
CC amino acids or oligopeptides.
CC -!- SUBUNIT: Heterodimer with Kell; disulfide-linked.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein
CC (Potential).
CC -!- TISSUE SPECIFICITY: High levels in skeletal muscle, heart, brain,
CC and pancreas; low levels in placenta, lung, liver, and kidney.
CC -!- PTM: Not glycosylated.
CC -!- POLYMORPHISM: XK is responsible for the Kx blood group system.
CC -!- DISEASE: McLeod syndrome (MLS) [MIM:300842]: A multisystem
CC disorder characterized by the absence of red blood cell Kx
CC antigen, weak expression of Kell red blood cell antigens,
CC acanthocytosis, and compensated hemolysis. Most carriers of this
CC McLeod blood group phenotype have acanthocytosis and elevated
CC serum creatine kinase levels and are prone to develop a severe
CC neurologic disorder resembling Huntington disease. Additional
CC symptoms include generalized seizures, neuromuscular symptoms
CC leading to weakness and atrophy, and cardiomyopathy mainly
CC manifesting with atrial fibrillation, malignant arrhythmias, and
CC dilated cardiomyopathy. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the XK family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/XK";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/xk/";
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DR EMBL; Z32684; CAA83632.2; -; mRNA.
DR EMBL; AY534238; AAT07087.1; -; mRNA.
DR EMBL; DQ062746; AAY43132.1; -; Genomic_DNA.
DR EMBL; BC036019; AAH36019.1; -; mRNA.
DR PIR; I39294; I39294.
DR RefSeq; NP_066569.1; NM_021083.2.
DR UniGene; Hs.78919; -.
DR ProteinModelPortal; P51811; -.
DR IntAct; P51811; 1.
DR STRING; 9606.ENSP00000367879; -.
DR TCDB; 2.A.112.1.1; 2.a.112. the kx blood-group antigen (kxa) family.
DR PhosphoSite; P51811; -.
DR DMDM; 85700269; -.
DR PaxDb; P51811; -.
DR PRIDE; P51811; -.
DR Ensembl; ENST00000378616; ENSP00000367879; ENSG00000047597.
DR Ensembl; ENST00000601300; ENSP00000469825; ENSG00000269380.
DR GeneID; 7504; -.
DR KEGG; hsa:7504; -.
DR UCSC; uc004ddq.3; human.
DR CTD; 7504; -.
DR GeneCards; GC0XP037545; -.
DR HGNC; HGNC:12811; XK.
DR HPA; HPA019036; -.
DR MIM; 300842; phenotype.
DR MIM; 314850; gene.
DR neXtProt; NX_P51811; -.
DR Orphanet; 59306; McLeod neuroacanthocytosis syndrome.
DR PharmGKB; PA37410; -.
DR eggNOG; NOG149424; -.
DR HOGENOM; HOG000118070; -.
DR HOVERGEN; HBG055838; -.
DR InParanoid; P51811; -.
DR OMA; TYRSAGD; -.
DR OrthoDB; EOG7034H1; -.
DR PhylomeDB; P51811; -.
DR GenomeRNAi; 7504; -.
DR NextBio; 29381; -.
DR PRO; PR:P51811; -.
DR ArrayExpress; P51811; -.
DR Bgee; P51811; -.
DR CleanEx; HS_XK; -.
DR Genevestigator; P51811; -.
DR GO; GO:0016021; C:integral to membrane; TAS:HGNC.
DR GO; GO:0005215; F:transporter activity; TAS:ProtInc.
DR GO; GO:0006865; P:amino acid transport; IEA:UniProtKB-KW.
DR InterPro; IPR018629; Transport_prot_XK.
DR Pfam; PF09815; XK-related; 1.
PE 1: Evidence at protein level;
KW Amino-acid transport; Blood group antigen; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond; Membrane;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 444 Membrane transport protein XK.
FT /FTId=PRO_0000190767.
FT TOPO_DOM 1 2 Cytoplasmic (Potential).
FT TRANSMEM 3 23 Helical; (Potential).
FT TOPO_DOM 24 37 Extracellular (Potential).
FT TRANSMEM 38 58 Helical; (Potential).
FT TOPO_DOM 59 68 Cytoplasmic (Potential).
FT TRANSMEM 69 89 Helical; (Potential).
FT TOPO_DOM 90 140 Extracellular (Potential).
FT TRANSMEM 141 161 Helical; (Potential).
FT TOPO_DOM 162 171 Cytoplasmic (Potential).
FT TRANSMEM 172 192 Helical; (Potential).
FT TOPO_DOM 193 208 Extracellular (Potential).
FT TRANSMEM 209 229 Helical; (Potential).
FT TOPO_DOM 230 235 Cytoplasmic (Potential).
FT TRANSMEM 236 256 Helical; (Potential).
FT TOPO_DOM 257 277 Extracellular (Potential).
FT TRANSMEM 278 298 Helical; (Potential).
FT TOPO_DOM 299 317 Cytoplasmic (Potential).
FT TRANSMEM 318 338 Helical; (Potential).
FT TOPO_DOM 339 349 Extracellular (Potential).
FT TRANSMEM 350 370 Helical; (Potential).
FT TOPO_DOM 371 444 Cytoplasmic (Potential).
FT DISULFID 347 347 Interchain (with C-72 in Kell).
FT VARIANT 222 222 R -> G (in MLS).
FT /FTId=VAR_013817.
FT VARIANT 294 294 C -> R (in MLS; dbSNP:rs28933690).
FT /FTId=VAR_013818.
FT VARIANT 327 327 E -> K (in MLS; atypical without
FT hematologic, neuromuscular, or cerebral
FT involvement; protein seems functional).
FT /FTId=VAR_023581.
FT MUTAGEN 347 347 C->S: Loss of Kell-XK complex.
FT CONFLICT 248 248 F -> L (in Ref. 3 and 5).
SQ SEQUENCE 444 AA; 50902 MW; 6F90B0B45659A1DA CRC64;
MKFPASVLAS VFLFVAETTA ALSLSSTYRS GGDRMWQALT LLFSLLPCAL VQLTLLFVHR
DLSRDRPLVL LLHLLQLGPL FRCFEVFCIY FQSGNNEEPY VSITKKRQMP KNGLSEEIEK
EVGQAEGKLI THRSAFSRAS VIQAFLGSAP QLTLQLYISV MQQDVTVGRS LLMTISLLSI
VYGALRCNIL AIKIKYDEYE VKVKPLAYVC IFLWRSFEIA TRVVVLVLFT SVLKTWVVVI
ILINFFSFFL YPWILFWCSG SPFPENIEKA LSRVGTTIVL CFLTLLYTGI NMFCWSAVQL
KIDSPDLISK SHNWYQLLVY YMIRFIENAI LLLLWYLFKT DIYMYVCAPL LVLQLLIGYC
TAILFMLVFY QFFHPCKKLF SSSVSEGFQR WLRCFCWACR QQKPCEPIGK EDLQSSRDRD
ETPSSSKTSP EPGQFLNAED LCSA
//

MIM 300842
*RECORD*
*FIELD* NO
300842
*FIELD* TI
#300842 MCLEOD SYNDROME; MCLDS
;;MCLEOD PHENOTYPE;;
NEUROACANTHOCYTOSIS, MCLEOD TYPE
read moreMCLEOD SYNDROME WITH CHRONIC GRANULOMATOUS DISEASE, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because the McLeod phenotype
is caused by mutation in the XK gene (314850), encoding an antigen of
the Kell blood group system (see 110900).

DESCRIPTION

Hematologically, McLeod syndrome is characterized by the absence of red
blood cell Kx antigen, weak expression of Kell red blood cell antigens,
acanthocytosis, and compensated hemolysis. Most carriers of this McLeod
blood group phenotype have acanthocytosis and elevated serum creatine
kinase levels and are prone to develop a severe neurologic disorder
resembling Huntington disease (143100). Onset of neurologic symptoms
ranges between 25 and 60 years (mean onset 30-40 years), and penetrance
appears to be high. Additional symptoms include generalized seizures,
neuromuscular symptoms leading to weakness and atrophy, and
cardiomyopathy mainly manifesting with atrial fibrillation, malignant
arrhythmias, and dilated cardiomyopathy (summary by Jung et al., 2007).

The cooccurrence of McLeod syndrome and chronic granulomatous disease
(CGD; 306400) results from a contiguous gene deletion (Francke et al.,
1985).

CLINICAL FEATURES

The McLeod phenotype was described by Allen et al. (1961) in a man of
that surname. His red cells showed unaccountably weak reactivity to Kell
antisera. In 1970, his red cells were noted to be acanthocytic in the
absence of abetalipoproteinemia. The precursor missing in McLeod's red
cells is called Kx. The X-linked locus determining this substance is
called Xk. McLeod had a compensated hemolytic state (Wimer et al.,
1976). He did not have CGD. Evidence for X-linkage of Xk was provided by
mosaicism in females for both acanthocytosis and red cell Kx. The
observations showed that some blood group antigenic substances are
important to both structure and function of cell membranes.

Jung et al. (2007) stated that Hugh McLeod, the original propositus,
died at the age of 69 after developing all major McLeod syndrome
manifestations.

Symmans et al. (1979) described the second example of the McLeod
phenotype in the absence of CGD and the first example of a rare blood
group being recognized because of a morphologic abnormality of red
cells. Heterozygous females showed mosaicism with a normal and an
acanthocytic red cell population. Thus, lyonization of this locus occurs
even though nonlyonization holds for the Xg (314700) and ichthyosis
(steroid sulfatase) loci (308100) which are in the same small segment of
Xp. All cases of X-linked CGD that had been studied had Kx-negative
leukocytes (Marsh, 1979). At least two Xg:XK recombinants are known
(Tippett, 1981).

Danek et al. (2001) remarked that, like other erythrocyte phenotypes,
the peculiar pattern of weakly expressed Kell antigens received its name
from the propositus. Acanthocytosis was noted much later (Wimer et al.,
1977). The diagnosis of the McLeod phenotype in a boy with chronic
anemia from a large New Zealand family led to the recognition of
features such as hemolysis, hepatomegaly, and splenomegaly (Symmans et
al., 1979) and proved the previous assumption of X-linked inheritance.
It was Marsh et al. (1981) who recognized muscle involvement and
proposed the designation 'McLeod syndrome.' Schwartz et al. (1982)
reported areflexia and chorea in the New Zealand family. Faillace et al.
(1982) noted the presence of McLeod red cells in a patient with
amyotrophic chorea and acanthocytosis.

Densen et al. (1981) reported a highly informative family in which 4 of
8 brothers had CGD by clinical history and tests of neutrophil function.
All 4 had Kx-negative neutrophils. The remaining 4 were in good health
and had normal nitroblue tetrazolium reduction tests. However, 1 of
these latter 4 had Kx-negative neutrophils that functioned normally. The
findings were interpreted as indicating that closely linked but distinct
genes code for CGD and Kx. In addition, close linkage of the XK and Xg
loci was demonstrated; no recombinant was found in this sibship.

Swash et al. (1983) studied 2 healthy males with the McLeod syndrome.
Both had raised creatine kinase levels, with myopathic EMG changes and
'active myopathy' changes on muscle biopsy.

Malandrini et al. (1994) described 2 brothers and their maternal uncle
with 'atypical' McLeod syndrome presenting with a late-onset choreic
syndrome mimicking Huntington disease. The proband also suffered from
severe dilated cardiomyopathy and showed slight neuromuscular
involvement. Acanthocytosis and weak antigenicity of the Kell blood
antigen system were present in combination with prominent neurologic
involvement.

Danek et al. (2001) analyzed the mutations and clinical findings of 22
men, aged 27 to 72 years, with McLeod neuroacanthocytosis. All of the
patients showed elevated levels of muscle creatine phosphokinase, but
clinical myopathy was less common. A peripheral neuropathy with
areflexia was found in all but 2 patients. The central nervous system
was affected in 15 patients, as indicated by the occurrence of seizures,
cognitive impairment, psychopathology, and choreatic movements.
Neuroimaging emphasized the particular involvement of the basal ganglia,
which was also detected in 1 asymptomatic young patient. Most features
developed with age, mainly after the fourth decade. The resemblance of
McLeod syndrome to Huntington disease and to autosomal recessive
chorea-acanthocytosis (200150) suggested that the corresponding
proteins--XK, huntingtin (613004), and chorein (605978)--may belong to a
common pathway, the dysfunction of which causes degeneration of the
basal ganglia.

Jung et al. (2007) remarked that patients with McLeod syndrome usually
show a slow progression of disease, with a mean onset between 30 and 40
years of age. A review of the literature found that disease duration
ranged from 7 to 51 years, and mean age at death was 53 years, ranging
from 31 to 69 years. Cardiovascular events, epileptic seizures, and
aspiration pneumonia might be the major causes of death in older McLeod
patients.

MAPPING

In a patient with CGD and McLeod syndrome, Frey et al. (1988)
demonstrated a deletion of the entire CGD gene. They concluded that the
CGD and XK loci are physically close in the Xp21 region and are proximal
to DMD (300377).

Bertelson et al. (1988) studied patients with the McLeod phenotype with
or without CGD or DMD. Comparison of the cloned segments absent from 2
cousins with only the McLeod phenotype with the cloned segments absent
from 2 DMD boys and a CGD/McLeod patient led to submapping of various
cloned DNA segments within the Xp21 region. The results placed the locus
for the McLeod phenotype within a 500-kb interval distal from the CGD
locus and toward the DMD locus.

MOLECULAR GENETICS

Using nucleotide sequence analysis of the XK gene in 2 unrelated
patients with McLeod syndrome, Ho et al. (1994) demonstrated point
mutations at invariant residues of 5-prime and 3-prime donor sites
(e.g., 314850.0001).

Danek et al. (2001) demonstrated that the original propositus carried a
13-bp deletion in the XK gene (314850.0006).

*FIELD* RF
1. Allen, F. H.; Krabbe, S. M. R.; Corcoran, P. A.: A new phenotype
(McLeod) in the Kell blood-group system. Vox Sang. 6: 555-560, 1961.

2. Bertelson, C. J.; Pogo, A. O.; Chaudhuri, A.; Marsh, W. L.; Redman,
C. M.; Banerjee, D.; Symmans, W. A.; Simon, T.; Frey, D.; Kunkel,
L. M.: Localization of the McLeod locus (XK) within Xp21 by deletion
analysis. Am. J. Hum. Genet. 42: 703-711, 1988.

3. Danek, A.; Rubio, J. P.; Rampoldi, L.; Ho, M.; Dobson-Stone, C.;
Tison, F.; Symmans, W. A.; Oechsner, M.; Kalckreuth, W.; Watt, J.
M.; Corbett, A. J.; Hamdalla, H. H. M.; Marshall, A. G.; Sutton, I.;
Dotti, M. T.; Malandrini, A.; Walker, R. H.; Daniels, G.; Monaco,
A. P.: McLeod neuroacanthocytosis: genotype and phenotype. Ann.
Neurol. 50: 755-764, 2001.

4. Densen, P.; Wilkinson-Kroovand, S.; Mandell, G. L.; Sullivan, G.;
Oyen, R.; Marsh, W. L.: Kx: its relationship to chronic granulomatous
disease and genetic linkage with Xg. Blood 58: 34-37, 1981.

5. Faillace, R. T.; Kingston, W. J.; Nanda, N. C.; Griggs, R. C.:
Cardiomyopathy associated with the syndrome of amyotrophic chorea
and acanthocytosis. Ann. Intern. Med. 96: 616-617, 1982.

6. Francke, U.; Ochs, H. D.; de Martinville, B.; Giacalone, J.; Lindgren,
V.; Disteche, C.; Pagon, R. A.; Hofker, M. H.; van Ommen, G.-J. B.;
Pearson, P. L.; Wedgwood, R. J.: Minor Xp21 chromosome deletion in
a male associated with expression of Duchenne muscular dystrophy,
chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am.
J. Hum. Genet. 37: 250-267, 1985.

7. Frey, D.; Machler, M.; Seger, R.; Schmid, W.; Orkin, S. H.: Gene
deletion in a patient with chronic granulomatous disease and McLeod
syndrome: fine mapping of the Xk gene locus. Blood 71: 252-255,
1988.

8. Ho, M.; Chelly, J.; Carter, N.; Danek, A.; Crocker, P.; Monaco,
A. P.: Isolation of the gene for McLeod syndrome that encodes a novel
membrane transport protein. Cell 77: 869-880, 1994.

9. Jung, H. H.; Danek, A.; Frey, B. M.: McLeod syndrome: a neurohaematological
disorder. Vox Sang. 93: 112-121, 2007.

10. Malandrini, A.; Fabrizi, G. M.; Truschi, F.; Di Pietro, G.; Moschini,
F.; Bartalucci, P.; Berti, G.; Salvadori, C.; Bucalossi, A.; Guazzi,
G.: Atypical McLeod syndrome manifested as X-linked chorea-acanthocytosis,
neuromyopathy and dilated cardiomyopathy: report of a family. J.
Neurol. Sci. 124: 89-94, 1994.

11. Marsh, W. L.: Personal Communication. New York, N. Y. 11/13/1979.

12. Marsh, W. L.; Marsh, N. J.; Moore, A.; Symmans, W. A.; Johnson,
C. L.; Redman, C. M.: Elevated serum creatine phosphokinase in subjects
with McLeod syndrome. Vox Sang. 40: 403-411, 1981.

13. Schwartz, S. A.; Marsh, W. L.; Symmans, A.; Johnson, C. L.; Mueller,
K. A.: 'New' clinical features of McLeod syndrome. (Abstract) Transfusion 22:
404 only, 1982.

14. Swash, M.; Schwartz, M. S.; Carter, N. D.; Heath, R.; Leak, M.;
Rogers, K. L.: Benign X-linked myopathy with acanthocytes (McLeod
syndrome): its relationship to X-linked muscular dystrophy. Brain 106:
717-733, 1983.

15. Symmans, W. A.; Sheperd, C. S.; Marsh, W. L.; Oyen, R.; Shohet,
S. B.; Linehan, B. J.: Hereditary acanthocytosis associated with
the McLeod phenotype of the Kell blood group system. Brit. J. Haemat. 42:
575-583, 1979.

16. Tippett, P.: Personal Communication. London, England 7/1981.

17. Wimer, B. M.; Marsh, W. L.; Taswell, H. F.: Clinical characteristics
of the McLeod blood group phenotype. (Abstract) Am. Soc. Hemat.,
Boston , 12/1976.

18. Wimer, B. M.; Marsh, W. L.; Taswell, H. F.; Galey, W. R.: Haematological
changes associated with the McLeod phenotype of the Kell blood group
system. Brit. J. Haemat. 36: 219-224, 1977.

*FIELD* CN
Anne M. Stumpf - reorganized: 5/2/2011

*FIELD* CD
Anne M. Stumpf: 4/20/2011

*FIELD* ED
carol: 08/09/2012
carol: 4/24/2012
terry: 6/15/2011
alopez: 5/3/2011
terry: 5/3/2011
alopez: 5/2/2011
alopez: 4/20/2011

MIM 314850
*RECORD*
*FIELD* NO
314850
*FIELD* TI
*314850 KELL BLOOD GROUP PROTEIN, MCLEOD SYNDROME-ASSOCIATED; XK
;;KELL BLOOD GROUP PRECURSOR;;
read moreXK LOCUS;;
PRECURSOR SUBSTANCE, KELL BLOOD GROUP; KX;;
KELL COMPLEX, 37-KD COMPONENT
*FIELD* TX

DESCRIPTION

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).

CLONING

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
(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.

GENE STRUCTURE

The XK gene contains 3 exons (Ho et al., 1994).

MAPPING

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).

OTHER FEATURES

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).

MOLECULAR GENETICS

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).

De Saint-Basile et al. (1988) described an instructive patient with CGD,
retinitis pigmentosa, and McLeod phenotype, who had no microscopically
detectable deletion, but had evidence of deletion with DNA markers.
Findings in the mother were consistent with carrier status for all 3
disorders.

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.

HISTORY

The McLeod syndrome is a multisystem disorder which includes elevation
of serum levels of the muscle isoform of creatine kinase due to a
usually subclinical, nonspecific myopathy (Marsh et al., 1981). In such
a patient with histopathologic evidence of a mild subclinical myopathy,
Danek et al. (1990) detected no abnormality by immunologic studies of
dystrophin (300377) in 2 separate biopsy specimens and analysis of the
dystrophin gene in blood samples detected no abnormality. They concluded
that the dystrophin is probably normal and that the mechanism of the
myopathy does not involve the dystrophin gene, which is located near at
hand on Xp21.

- Chronic Granulomatous Disease

For a time it was thought that in addition to acanthocytosis and
compensated hemolytic anemia, chronic granulomatous disease (CGD;
306400) might result from mutation at the XK locus. Mr. McLeod did not
have CGD, but there were some patients with CGD whose red cells showed
the McLeod phenotype. It was thought that because of the structural
abnormality in the Kx substance of the white cell membrane, activation
of NADH dehydrogenase was defective. Some patients with CGD lacked Kx in
both white cells and red cells so that acanthocytosis and hemolysis were
present in addition to granulomatous disease. This was called CGD II; in
CGD I, the red cells are spared. Marsh (1979) thought that Kx 'makes a
functional structure on leukocytes and red cells' and that XK (or the
variant form thereof) is the CGD gene. It turned out, however, that CGD
with the McLeod phenotype is a contiguous gene syndrome, as defined by
Schmickel (1986), due to the deletion of 2 very closely linked genes, XK
and CGD, on Xp21. Indeed, Branch et al. (1986) showed that granulocytes
lack Kx antigen. The previous finding of Kx on white cells was
presumably due to contamination of the testing serum by anti-WBC
antibodies of non-Kx specificity.

*FIELD* AV
.0001
MCLEOD SYNDROME
XK, IVS2DS, G-A, +1

In a patient with McLeod syndrome (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.

.0002
MCLEOD SYNDROME
XK, IVS2AS, G-A, -1

In a patient with McLeod syndrome (300842), Ho et al. (1994) observed a
change in the invariant dinucleotide at the 3-prime splice acceptor site
from AG to AA.

.0003
MCLEOD SYNDROME
XK, 1-BP DEL

In a female with McLeod syndrome (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).

.0004
MCLEOD SYNDROME
XK, 1-BP DEL, 1095T

In a 50-year-old Japanese man with McLeod syndrome (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.

.0005
MCLEOD SYNDROME
XK, CYS294ARG

Of 15 different mutations identified in the XK gene by Danek et al.
(2001) in 22 men with McLeod neuroacanthocytosis (300842), only one was
a missense mutation: a 962T-C transition in exon 3 resulting in a
cys294-to-arg (C294R) substitution.

.0006
MCLEOD SYNDROME
XK, 13-BP DEL

In Hugh McLeod, the original propositus (Allen et al., 1961) for whom
the 'McLeod phenotype' (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.

.0007
MCLEOD SYNDROME
XK, TRP314TER

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 (300842) was suggested on the basis of prominent
acanthocytosis, mild compensated hemolysis, persistent elevation of
creatine kinase, and excessive sweating without neuromuscular symptoms.

.0008
MCLEOD SYNDROME
XK, GLN299TER

In a family with McLeod syndrome (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.

*FIELD* SA
Giblett et al. (1971); Marsh (1978); Marsh et al. (1976); Marsh et
al. (1975)
*FIELD* RF
1. Allen, F. H.; Krabbe, S. M. R.; Corcoran, P. A.: A new phenotype
(McLeod) in the Kell blood-group system. Vox Sang. 6: 555-560, 1961.

2. Bertelson, C. J.; Pogo, A. O.; Chaudhuri, A.; Marsh, W. L.; Redman,
C. M.; Banerjee, D.; Symmans, W. A.; Simon, T.; Frey, D.; Kunkel,
L. M.: Localization of the McLeod locus (XK) within Xp21 by deletion
analysis. Am. J. Hum. Genet. 42: 703-711, 1988.

3. Branch, D. R.; Gaidulis, L.; Lazar, G. S.: Human granulocytes
lack red cell Kx antigen. Brit. J. Haemat. 62: 747-755, 1986.

4. Danek, A.; Rubio, J. P.; Rampoldi, L.; Ho, M.; Dobson-Stone, C.;
Tison, F.; Symmans, W. A.; Oechsner, M.; Kalckreuth, W.; Watt, J.
M.; Corbett, A. J.; Hamdalla, H. H. M.; Marshall, A. G.; Sutton, I.;
Dotti, M. T.; Malandrini, A.; Walker, R. H.; Daniels, G.; Monaco,
A. P.: McLeod neuroacanthocytosis: genotype and phenotype. Ann.
Neurol. 50: 755-764, 2001.

5. Danek, A.; Witt, T. N.; Stockmann, H. B. A. C.; Weiss, B. J.; Schotland,
D. L.; Fischbeck, K. H.: Normal dystrophin in McLeod myopathy. Ann.
Neurol. 28: 720-722, 1990.

6. Densen, P.; Wilkinson-Kroovand, S.; Mandell, G. L.; Sullivan, G.;
Oyen, R.; Marsh, W. L.: Kx: its relationship to chronic granulomatous
disease and genetic linkage with Xg. Blood 58: 34-37, 1981.

7. de Saint-Basile, G.; Bohler, M. C.; Fischer, A.; Cartron, J.; Dufier,
J. L.; Griscelli, C.; Orkin, S. H.: Xp21 DNA microdeletion in a patient
with chronic granulomatous disease, retinitis pigmentosa, and McLeod
phenotype. Hum. Genet. 80: 85-89, 1988.

8. Dubielecka, P. M.; Hwynn, N.; Sengun, C.; Lee, S.; Lomas-Francis,
C.; Singer, C.; Fernandez, H. H.; Walker, R. H.: Two McLeod patients
with novel mutations in XK. J. Neurol. Sci. 305: 160-164, 2011.

9. Giblett, E. R.; Klebanoff, S. J.; Pincus, S. H.; Swanson, J.; Park,
B. H.; McCullough, J.: Kell phenotypes in chronic granulomatous disease:
a potential transfusion hazard. Lancet 297: 1235-1236, 1971. Note:
Originally Volume I.

10. Hanaoka, N.; Yoshida, K.; Nakamura, A.; Furihata, K.; Seo, T.;
Tani, Y.; Takahashi, J.; Ikeda, S.; Hanyu, N.: A novel frameshift
mutation in the McLeod syndrome gene in a Japanese family. J. Neurol.
Sci. 165: 6-9, 1999.

11. Ho, M.; Chelly, J.; Carter, N.; Danek, A.; Crocker, P.; Monaco,
A. P.: Isolation of the gene for McLeod syndrome that encodes a novel
membrane transport protein. Cell 77: 869-880, 1994.

12. Ho, M. F.; Chalmers, R. M.; Davis, M. B.; Harding, A. E.; Monaco,
A. P.: A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis. Ann.
Neurol. 39: 672-675, 1996.

13. Ho, M. F.; Monaco, A. P.; Blonden, L. A. J.; van Ommen, G. J.
B.; Affara, N. A.; Ferguson-Smith, M. A.; Lehrach, H.: Fine mapping
of the McLeod locus (XK) to a 150-380-kb region in Xp21. Am. J. Hum.
Genet. 50: 317-330, 1992.

14. Jung, H. H.; Danek, A.; Frey, B. M.: McLeod syndrome: a neurohaematological
disorder. Vox Sang. 93: 112-121, 2007.

15. Jung, H. H.; Hergersberg, M.; Kneifel, S.; Alkadhi, H.; Schiess,
R.; Weigell-Weber, M.; Daniels, G.; Kollias, S.; Hess, K.: McLeod
syndrome: a novel mutation, predominant psychiatric manifestations,
and distinct striatal imaging findings. Ann. Neurol. 49: 384-392,
2001.

16. Marsh, W. L.: Chronic granulomatous disease, the McLeod syndrome,
and the Kell blood groups. Birth Defects Orig. Art. Ser. XIV(6A):
9-25, 1978.

17. Marsh, W. L.: Linkage relationship of the Xg and Xk loci. Cytogenet.
Cell Genet. 22: 531-533, 1978.

18. Marsh, W. L.: Personal Communication. New York, N. Y. 11/13/1979.

19. Marsh, W. L.: Chronic granulomatous disease, Kx antigen and the
Kell blood groups.In: Brewer, G. J.: Progress in Clinical and Biological
Research: The Red Cell. New York: Alan R. Liss (pub.) 1978. Pp.
493-507.

20. Marsh, W. L.: The Kell blood groups and their relationship to
chronic granulomatous disease.In: Antigens and Disease. Am. Assoc.
Blood Banks Symposium. 1977. Pp. 52-66.

21. Marsh, W. L.; Marsh, N. J.; Moore, A.; Symmans, W. A.; Johnson,
C. L.; Redman, C. M.: Elevated serum creatine phosphokinase in subjects
with McLeod syndrome. Vox Sang. 40: 403-411, 1981.

22. Marsh, W. L.; Oyen, R.; Nichols, M. E.: Kx antigen, the McLeod
phenotype, and chronic granulomatous disease: further studies. Vox
Sang. 31: 356-362, 1976.

23. Marsh, W. L.; Oyen, R.; Nichols, M. E.; Allen, F. H., Jr.: Chronic
granulomatous disease and the Kell blood groups. Brit. J. Haemat. 29:
247-262, 1975.

24. Schmickel, R. D.: Chromosomal deletions and enzyme deficiencies. J.
Pediat. 108: 244-246, 1986.

25. Stanfield, G. M.; Horvitz, H. R.: The ced-8 gene controls the
timing of programmed cell deaths in C. elegans. Molec. Cell 5: 423-433,
2000.

26. Supple, S. G.; Iland, H. J.; Barnett, M. H.; Pollard, J. D.:
A spontaneous novel XK gene mutation in a patient with McLeod syndrome. Brit.
J. Haemat. 115: 369-372, 2001.

27. Symmans, W. A.; Sheperd, C. S.; Marsh, W. L.; Oyen, R.; Shohet,
S. B.; Linehan, B. J.: Hereditary acanthocytosis associated with
the McLeod phenotype of the Kell blood group system. Brit. J. Haemat. 42:
575-583, 1979.

28. Wimer, B. M.; Marsh, W. L.; Taswell, H. F.: Clinical characteristics
of the McLeod blood group phenotype. (Abstract) Am. Soc. Hemat.,
Boston , 12/1976.

*FIELD* CN
Victor A. McKusick - updated: 2/22/2002
Victor A. McKusick - updated: 1/24/2002
Victor A. McKusick - updated: 1/15/2002
Victor A. McKusick - updated: 1/8/2002
Stylianos E. Antonarakis - updated: 6/9/2000
Victor A. McKusick - updated: 12/7/1999
Orest Hurko - updated: 4/6/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 10/24/2011
alopez: 5/2/2011
alopez: 4/20/2011
alopez: 4/18/2011
terry: 12/17/2009
terry: 3/31/2009
carol: 3/17/2004
carol: 3/2/2004
cwells: 11/5/2003
terry: 8/8/2003
terry: 3/12/2002
cwells: 3/11/2002
cwells: 3/7/2002
terry: 2/22/2002
carol: 2/6/2002
mcapotos: 2/1/2002
terry: 1/29/2002
terry: 1/24/2002
alopez: 1/15/2002
terry: 1/15/2002
carol: 1/9/2002
terry: 1/8/2002
mgross: 6/9/2000
carol: 12/10/1999
mcapotos: 12/10/1999
terry: 12/7/1999
alopez: 4/29/1999
terry: 6/1/1998
terry: 4/6/1998
terry: 8/24/1994
davew: 7/25/1994
jason: 7/12/1994
warfield: 4/20/1994
mimadm: 4/18/1994
carol: 12/14/1993