McLeod phenotype associated with a XK missense mutation without hematologic, neuromuscular, or cerebral involvement

Abstract

Known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations predicting absent or truncated XK protein devoid of the Kell-protein binding site. Although the E327K missense mutation was associated with the immunohematologic characteristics of McLeod syndrome, the mutated XK protein seemed to be largely functional. These findings contribute to the understanding of the physiology of XK and Kell proteins, and the pathogenetic mechanisms of acanthocytosis, myopathy, and striatal neurodegeneration in McLeod syndrome.

Cerebral Metabolic Alterations in McLeod Syndrome

“…Immunohematological testing revealed a normal XK/Kell blood group serotype [3]. RBC flow cytometry using several anti-Kell antibodies was performed as previously described [12]. Between 10 and 60% of RBCs in females carried the McLeod blood group phenotype, indicating a blood group mosaicism in all female heterozygotes (data not shown).…”

Neurodegeneration in the elderly – When the blood type matters: An overview of the McLeod syndrome with focus on hematological features

“…In many patients with MLS the blood group peculiarity goes along with acanthocytosis of variable degree and compensated hemolytic anemia. However, several individuals have been described with exclusive McLeod RBC phenotype without other hematological, neuropsychiatric and neuro-muscular symptoms 13,14 . Mostly, these cases are recognized when being blood group phenotyped for KEL antigens while serving as blood donors.…”

“…Normally, the patients suffer of unspecific neuropsychiatric symptoms for years without having assigned clear diagnosis. Sometimes, MLS is diagnosed in asymptomatic mutation carriers, most often when routinely phenotyped for KEL antigens while serving as blood donors [13][14][15] . These blood donors may develop clinical MLS later on and available data indicate a high penetrance of the disorder with a possible onset in the sixth and seventh decade 84 .…”

Kell and Kx Blood Group Systems

“…Single nucleotide mutations in the coding region causing premature stop codons: In these cases, a stop codon is created at the mutation site, resulting in a truncated XK protein that is probably not placed on the RBC membrane. 36,44,45 4. Single nucleotide mutations in an intron at a splice site or near a splice site: In these cases, normal RNA splicing is disrupted, creating a stop codon downstream of the mutation, resulting in an aberrant protein.…”

“…Table 2). 48 • 962T>C, C294R (8th TMR) 36 • 1061G>A, E327K (9th TMR) 44 * Numbering of nucleotides is based on the XK cDNA sequence in GenBank, Z32684. The first transcribed, not translated, nucleotide is numbered as #1.…”