Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency
Por:
Bottega, R, Pecci, A, De Candia, E, Pujol-Moix, N, Heller, PG, Noris, P, De Rocco, D, Podda, GM, Glembotsky, AC, Cattaneo, M, Balduini, CL, Savoia, A
Publicada:
1 jun 2013
Resumen:
The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (alpha)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and alpha-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the alpha-granule content by immunofluorescence analysis for alpha-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet alpha-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the alpha-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the alpha-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with alpha-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the alpha-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype.
Filiaciones:
Bottega, R:
Univ Trieste, Dept Med Sci, Trieste, Italy
Pecci, A:
Univ Pavia, Dept Internal Med, I-27100 Pavia, Italy
IRCCS Policlin San Matteo Fdn, Pavia, Italy
De Candia, E:
Univ Cattolica Sacro Cuore, Hemostasis & Thrombosis Unit, Policlin Agostino Gemelli, Rome, Italy
Pujol-Moix, N:
Univ Autonoma Barcelona, E-08193 Barcelona, Spain
Hosp Santa Creu & Sant Pau, Platelet Pathol Unit, Barcelona, Spain
Heller, PG:
Univ Buenos Aires, CONICET, Inst Invest Med Alfredo Lanari, Buenos Aires, DF, Argentina
Noris, P:
Univ Pavia, Dept Internal Med, I-27100 Pavia, Italy
IRCCS Policlin San Matteo Fdn, Pavia, Italy
De Rocco, D:
Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy
Podda, GM:
Univ Milan, Osped San Paolo, Dipartimento Sci Salute, Milan, Italy
Glembotsky, AC:
Univ Buenos Aires, CONICET, Inst Invest Med Alfredo Lanari, Buenos Aires, DF, Argentina
Cattaneo, M:
Univ Milan, Osped San Paolo, Dipartimento Sci Salute, Milan, Italy
Balduini, CL:
Univ Pavia, Dept Internal Med, I-27100 Pavia, Italy
IRCCS Policlin San Matteo Fdn, Pavia, Italy
Savoia, A:
Univ Trieste, Dept Med Sci, Trieste, Italy
Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy
Gold, Green Published
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