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©Ferrata Storti Foundation Disorders of Erythropoiesis • Brief Report Two new mutations of the P5’N-1 gene found in Italian patients with hereditary hemolytic anemia: the molecular basis of the red cell enzyme disorder Laurent R. Chiarelli Inherited pyrimidine 5'-nucleotidase type-1 (P5’N-1) deficiency is the most frequent Elisa Fermo abnormality of red cell nucleotide metabolism causing non-spherocytic hemolytic ane- Patrizia Abrusci mia. We describe two novel mutations in two Italian patients affected by P5’N-1 defi- Paola Bianchi ciency. One mutation is a two base deletion that occurs at the splice site junction Chiara M. Dellacasa between intron 7 and exon 8 (c.396-397del AG); the second is an in-frame deletion of Alessandro Galizzi three adjacent bases (c.427-429del CAA), leading to deletion of glutamine 143. The Alberto Zanella kinetic properties of Q143del variant were not grossly altered, but the variant was very Giovanna Valentini heat unstable even at physiological temperatures. Key words: P5'N-1 deficiency, hemolytic anemia, mutations, recombinant mutant. Haematologica 2006; 91:1244-1247 ©2006 Ferrata Storti Foundation From the Dipartimento di ereditary pyrimidine 5'-nucleotidase 7p15-p14.8 It consists of 11 exons leading to Biochimica “A. Castellani”, Università degli Studi di Pavia, type-1 (P5’N-1) deficiency is the the production of three alternatively spliced Via Taramelli 3/b, 27100 Pavia, most frequent disorder of nucleotide mRNA.9 Presently, only the 286 amino acid H 1,2 Italy (LRC, PA, GV); Dipartimento metabolism causing hereditary non-sphero- protein has been isolated from RBC. di Genetica e Microbiologia cytic hemolytic anemia.1,2 It is an autosomal Eighteen different mutations of P5’N-1 “A. Buzzati-Traverso”, Università recessive disease and is characterized by gene have been so far described in 30 unre- degli Studi di Pavia, Via Ferrata 1, 6,8-13 27100 Pavia, Italy (LRC, PA, AG); mild-to moderate hemolytic anemia, reticu- lated families. Recently, four pathological Dipartimento di Ematologia, locytosis and hyperbilirubinemia. The hall- variants of the P5’N-1 were expressed in an Fondazione IRCCS Ospedale mark of this red cell enzyme disorder is the E. coli system and characterized. The correla- Maggiore, Mangiagalli e Regina presence of pronounced basophilic stippling tion between the molecular defects and the Elena, Via Francesco Sforza 35, in red blood cells (RBC) on a peripheral residual enzyme activity of the patients’ 20122 Milano, Italy (EF, PB, AZ); Reparto di Ematologia Universitaria, blood smear, associated with accumulation blood samples suggested that in vivo defi- Ospedale Molinette, Via Genova 3, of pyrimidine nucleotides within the ery- ciency of P5’N-1 is at least in part compen- Torino, Italy (CMD). throcytes.3,4 sated by other nucleotidases.7 P5’N-1 (EC 3.1.3.5) also known as uridine In this study we investigated two unrelat- Correspondence: monophosphate hydrolase type-1 (UMPH-1) ed Italian patients affected by hereditary Giovanna Valentini, Dipartimento di Biochimica "A. Castellani", catalyzes the dephosphorylation of pyrimi- hemolytic anemia associated with P5’N-1 Università degli Studi di Pavia, dine 5'-ribose monophosphates, especially deficiency. We found two novel mutations, a via Taramelli 3/b 27100 Pavia, Italy. UMP and CMP, allowing them to diffuse out two bp deletion at the splice site junction E-mail: [email protected] of the cell as nucleosides. The enzyme has between intron 7 and exon 8 (c.396-397del no activity on purine nucleotides.3,5 Its major AG) and an in-frame deletion of one codon role is in the catabolism of the pyrimidine (c.427-429del CAA) corresponding to gluta- nucleotides, mainly resulting from ribosomal mine 143. The pathological variant resulting RNA degradation during final erythroid mat- from the deletion of glutamine 143 uration.6 The enzyme also transfers phos- (Q143del) was produced in a recombinant phate groups from pyrimidine nucleotides to form, purified, and characterized. pyrimidine nucleosides, suggesting that it has an additional role in nucleotide metabo- lism.5 The P5’N-1 activity is dependent on Design and Methods magnesium ions (Mg2+) and is readily inhib- ited by heavy metal ions, and metal chelat- Patients ing and thiol reactive reagents. P5’N-1 is a Case 1. The propositus was a 37-year old 286 amino acid-long monomer with an woman originating from southern Italy who apparent molecular mass of approximately had been affected by moderate chronic 34 kDa.7 The gene encoding P5’N-1 (NT5C3, hemolytic anemia since childhood. She also UMPH-1) has been mapped to chromosome had jaundice, hepatomegaly and gallstones, | 1244 | haematologica/the hematology journal | 2006; 91(9) New mutations of the P5’N-1 gene in HHA but no splenomegaly. The patient needed one blood Table 1. Hematologic data of the two P5’N deficient patients at transfusion during a pregnancy. the time of the study. Case 2. The propositus, a 37-year old woman origi- nating from Northern Italy, had a history of chronic Case 1 Case 2 Reference range hemolytic anemia since childhood with jaundice, splenomegaly, and hepatomegaly. She was found to be Hb (g/dL) 8.4 9.3 11.8-14.7 a double heterozygote for HbD Punjab and Hb Zurich, MCV (fL) 106 124 82-99 Reticulocytes (109/L) 300 752 24-84 which did not, however, justify the degree of hemoly- Unconjugated bilirubin (UI/L) 54.4 226 <12.8 sis. Bone marrow morphology showed mild dysery- Lactate dehydrogenase (U/L) 1218 440 230 - 460 thropoiesis; ferrokinetic studies revealed a slightly Serum ferritin (µg/L) 36 1980 19-238 Transferrin saturation (%) 45 100 16-54 increased iron turnover associated with increased Osmotic fragility normal normal peripheral hemolysis. At the age of 14 years she had undergone cholecystectomy and splenectomy, without any significant increase in hemoglobin values. Before with 0.5 mM isopropyl-β-D-thiogalactopyranoside splenectomy she had had low serum iron levels (55 (21°C, 12 hours) and purified using the method previ- µg/dL). Thereafter, progressive rises in serum ferritin ously reported.7 Kinetic analyses, thermal stability and transferrin saturation were observed associated at assays and far-UV circular dichroism (far-UV CD) meas- the age of 22 with marked hepatic siderosis at liver urements were performed as described in the same biopsy and increased cardiac iron burden detected by report.7 magnetic resonance imaging. The patient was treated with desferrioxamine. At the age of 34 blood transfu- sions (4U) were required because of exacerbation of Results and Discussion anemia (Hb 4.7g/dL) during parvovirus B19 infection. P5’N-1 deficiency (OMIM 606224) has been suggest- Hematologic assays, enzyme detection and molecular ed to be the third most common hereditary red cell studies enzyme disorder causing hemolysis after glucose 6- Hematologic investigations were carried out as phosphate dehydrogenase and pyruvate kinase defi- reported elsewhere.12 The ratio of purine/pyrimidine ciencies.8 It can also be acquired as a result of lead poi- nucleotides was calculated as described by Beutler et al.4 soning or oxidative threat.6,10 In this study, we investi- P5’N-1 activity was determined by micellar electroki- gated two Italian patients affected by non-spherocytic netic chromatography.14 After obtaining informed con- hemolytic anemia who were found to have two new sent, genomic DNA was extracted from leukocytes. The mutations in the gene encoding P5’N-1. entire coding region and intronic flanking regions of the The hematologic data at the time of the study are P5’N-1 gene were analyzed as described previously.12 reported in Table 1. In case 1 the molecular analysis of The nucleotide numbering adopted is referred to cDNA the P5'N-1 gene showed the presence of a new two bp reported in EMBL (coding sequence) accession no. homozygous deletion (c.396-397del AG); given the AAF36153, whereas amino acid numbering is according DNA sequence (cttacagAGAAGGAT), it is not possible to Swiss-Prot accession no. Q9H0P0-2. to determine whether the deletion affects the last bases of intron 7 or the first bases of exon 8. In any case, the Construction of pEA9 coding for the Q143del mutant deletion may affect the splice site resulting in a splicing form. alteration and in the absence of a functional protein in The DNA sequence encoding the mutant enzyme RBC. Moreover, if splicing should occur, the two bp Q143del was obtained by a two-step total gene synthe- deletion would generate a frameshift and a premature sis method.15 pEA1, a derivative of pET23b(+) contain- stop codon at position 135. A functional protein is not ing the P5'N-1 cDNA, was used as the template.7 5'- expected in this situation either. In fact, P5’N-1 activity GAGAATTTCTTTGATAAGCTCCAACATAGCATC- could not be detected in the patient’s RBC, despite using CCCGTGTTC-3' and 5'-GAACACGGGGATGCTAT- a very sensitive detection method such as capillary elec- GTTGGAGCTTATCAAAGAAATTCT-3', as sense and trophoresis.14 Intriguingly, the degree of anemia was antisense mutagenic oligonucleotides, respectively, and moderate, suggesting that there is a mechanism of com- T7 Reverse and T7 Forward as outer primers, were pensation, as there is in other enzyme deficiencies.16-17 used. The construct, pEA9, was checked by sequencing. In case 2 complete sequencing of the P5’N-1 gene showed that the patient was a compound heterozygote. Expression, purification and characterization of the One allele had the frameshift mutation c.710-711insGG, Q143del enzyme already described in Italian and Turkish patients,11,12 The mutant protein was expressed in E. coli while the second allele showed a new in-frame deletion BL21(DE3)pLysS transformed with pEA9 by induction of three base pairs (c.427-429del CAA), leading to dele- haematologica/the hematology journal | 2006; 91(9) | 1245 | L.R.
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