Inherited macrothrombocytopenia (IMTP) is a highly heterogeneous group of inherited disorders characterized by a low platelet count and abnormally platelet size. Even though IMTP-causing mutations have been reported in several genes, only 50% of patients have to date a molecular diagnosis. In March 2013 Kunishima and colleagues identified alpha-actinin 1 (ACTN1) as a new gene responsible for IMTP which accounted for 5,5% of cases in Japanese population. To evaluate the frequency of ACTN1 mutations in the Italian population, we performed a screening in 160 probands in which all the known forms of IMTP were previously excluded. Ten, including 8 novel, different missense have been identified in 11 patients. All except one (p.D666V) segregated with the macrotrombocytopenia within the families. In vivo transfection experiments in Hela cells were performed to demonstrate the pathogenicity of the variants identified. Except for p.D666V, preliminary data indicate that the missense mutations are associated with disorganization of cytoskeleton, as determined different co-localization of mutant and wild type actinin-a with actin. Further studies will be needed to determine how these mutations may lead to the onset of disease.

ACTN1 : identification of novel mutations in a cohort of Italian IMTP patients

A. Savoia
2014

Abstract

Inherited macrothrombocytopenia (IMTP) is a highly heterogeneous group of inherited disorders characterized by a low platelet count and abnormally platelet size. Even though IMTP-causing mutations have been reported in several genes, only 50% of patients have to date a molecular diagnosis. In March 2013 Kunishima and colleagues identified alpha-actinin 1 (ACTN1) as a new gene responsible for IMTP which accounted for 5,5% of cases in Japanese population. To evaluate the frequency of ACTN1 mutations in the Italian population, we performed a screening in 160 probands in which all the known forms of IMTP were previously excluded. Ten, including 8 novel, different missense have been identified in 11 patients. All except one (p.D666V) segregated with the macrotrombocytopenia within the families. In vivo transfection experiments in Hela cells were performed to demonstrate the pathogenicity of the variants identified. Except for p.D666V, preliminary data indicate that the missense mutations are associated with disorganization of cytoskeleton, as determined different co-localization of mutant and wild type actinin-a with actin. Further studies will be needed to determine how these mutations may lead to the onset of disease.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/1064368
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