title: ACTN1-related thrombocytopenia: identification of novel families for phenotypic characterization.
abstract: Inherited thrombocytopenias (ITs) are a heterogeneous group of syndromic and nonsyndromic diseases caused by mutations affecting different genes. Alterations of ACTN1, the gene encoding for α-actinin 1, have recently been identified in a few families as being responsible for a mild form of IT (ACTN1-related thrombocytopenia; ACTN1-RT). To better characterize this disease, we screened ACTN1 in 128 probands and found 10 (8 novel) missense heterozygous variants in 11 families. Combining bioinformatics, segregation, and functional studies, we demonstrated that all but 1 amino acid substitution had deleterious effects. The clinical and laboratory findings of 31 affected individuals confirmed that ACTN1-RT is a mild macrothrombocytopenia with low risk for bleeding. Low reticulated platelet counts and only slightly increased serum thrombopoietin levels indicated that the latest phases of megakaryopoiesis were affected. Given its relatively high frequency in our cohort (4.2%), ACTN1-RT has to be taken into consideration in the differential diagnosis of ITs.
authors.affiliation: Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico Burlo Garofolo, Trieste, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Bottega
authors.affiliation: Genetica Medica, Dipartimento di Scienze Mediche Chirurgiche, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy;
authors.forename: Caterina
authors.initials: C
authors.lastname: Marconi
authors.affiliation: Department of Medical Sciences and.
authors.forename: Michela
authors.initials: M
authors.lastname: Faleschini
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Baj
authors.affiliation: Department of Internal Medicine, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy;
authors.forename: Claudia
authors.initials: C
authors.lastname: Cagioni
authors.affiliation: Department of Internal Medicine, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pecci
authors.affiliation: Genetica Medica, Dipartimento di Scienze Mediche Chirurgiche, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy;
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.affiliation: Hematology Unit, Pediatric Department, University of Torino, Torino, Italy;
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.affiliation: Istituto di Ematologia, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy;
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pardini
authors.affiliation: Royal Devon & Exeter Hospital, Devon, United Kingdom;
authors.forename: Loretta
authors.initials: L
authors.lastname: Ngu
authors.affiliation: Department of Pediatric Hematology and Oncology, Pediatric Hospital "Bambino Gesù", Rome, Italy; and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Baronci
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.affiliation: Department of Internal Medicine, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy;
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.affiliation: Genetica Medica, Dipartimento di Scienze Mediche Chirurgiche, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico Burlo Garofolo, Trieste, Italy; Genetica Medica, Dipartimento di Scienze Mediche Chirurgiche, Policlinico Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy; Department of Medical Sciences and.
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
authors.affiliation: Department of Internal Medicine, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Foundation, Pavia, Italy;
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010976:Platelet Count; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D034061:Thrombopoiesis / Q000235:genetics; D013926:Thrombopoietin / Q000097:blood
chemical_list: C526905:ACTN1 protein, human; D000185:Actinin; D013926:Thrombopoietin