Molecular Basis for the p Phenotype

Abstract

p phenotype individuals lack both P k (Gb3) and P (Gb4) glycolipid antigens of the P blood group system. To explore the molecular basis for this phenotype, DNA sequences of Gb3 synthase (␣1,4-galactosyltransferase; ␣1,4Gal-T) in six p phenotype individuals from Japan and Sweden were analyzed. A missense mutation P251L and a nonsense mutation W261stop in three and one Japanese indivuiduals, respectively, and missense mutations M183K and G187D in one each of two Swedish p individuals were found, indicating that p individuals from Japan and Sweden have distinct and multiple homozygous point mutations in the coding region. In the function analysis of the mutated ␣1,4Gal-Ts by the transfection of the expression vectors, P251L and M183K mutations showed complete loss of enzyme function, and W261stop and G187D mutations resulted in the marginal activity. BLAST analysis of homologous sequences of ␣1,4Gal-T revealed that three residues, Met 183 , Gly 187 , and Pro 251 , at which missense mutations were found, were highly conserved among all species examined, suggesting their importance for the function of ␣1,4Gal-T.

The Blood Group P1 Synthase Gene Is Identical to the Gb3/CD77 Synthase Gene

“…P2 Erythrocytes Contain P1 Antigen at Lower Levels Than P1 Erythrocytes-To examine the presence/absence of P1 antigen in p and P2 individuals, glycolipids of erythrocytes from two p donors, in whom function-losing mutations were found in the Gb3/CD77 synthase gene (13), and five P2 samples, as well as three P1 samples, were analyzed. In TLC, Gb3 and Gb4 were not found in the two p samples, whereas bands of lactosylceramide were increased in intensity as detected with orcinol (Fig.…”

“…Lack of Gb3 synthase results in p phenotype expressing neither Gb3 nor P (Gb4), because P is generated from Gb3 with Gb4 synthase (12). In fact, multiple mutations in the Gb3/CD77 synthase gene leading to functional loss of the enzyme activity were identified in the individuals with p phenotype (9,13). On the other hand, P1/P2 (P1 negative) is the last glycolipid antigen system for which the genetic mechanisms has not yet been clarified, because the P1 synthase gene has not been isolated to date.…”

Glycosphingolipids—Nature, Function, and Pharmacological Modulation

“…[71] Exeptions are GM3 synthase deficiency, [93] hereditary sensory neuropathy I (deficiency in a subunit of serine palmitoyltransferase), [94] and deficiency in the a-1,4-galactosyltransferase Gb 3 synthase (resulting in the rare P blood group phenotype). [95] Systemic deletion of the GCS gene in a mouse model resulted in death during the early stages of embryogenesis. [96] …”

Fabry Disease

“…Red blood cells in the C57BL/6 × 129/Svj hybrid strain of mice used for knocking out α-galactosidase A do not contain a detectable quantity of either Gb4 (globoside) or Gb3. They therefore have some resemblance to human blood group p that do not contain Gb3 or Gb4 in their red blood cells due to absence of Gb3 synthase that catalyzes the addition of galactose from UDP-galactose to ceramidelactoside [14]. If the findings in the α-galactosidase A -/-mouse models of Fabry disease can be extrapolated to humans, it would seem unlikely that a reduction or lack of α-galactosidase A activity in blood group p humans would cause the array of pathological manifestations conventionally associated with Fabry disease.…”