LAUSR

MYH9 is a large gene localized on chromosome 22q12.3-13.1 constituted of one 5ˊ-untranslated (exon 1) and 40 coding exons (Figure 1). It encodes for the heavy chain of the nonmuscle myosin IIA (NMMHC-IIA), a cytoplasmic myosin expressed in most cells and tissues, where it participates in several processes requiring generation of chemomechanical forces by the cytoskeleton. Like the other conventional myosins, NMMHC-IIA dimerizes and associates with two pairs of regulatory and essential light chains. The coding region of exons 2 to 19 translates for the N-terminal globular head, exon 20 for the neck, and exons 21 to 41 for the coiled-coil domain of NMMHC-IIA (Figure 1). The last 34 amino acid residues form a C-terminal nonhelical tail encoded by exon 41 [1]. Different variants of MYH9 cause the MYH9-related disease (MYH9-RD), the most frequent form of inherited thrombocytopenia worldwide. Thrombocytopenia is a completely penetrant feature and is characterized by marked platelet macrocytosis with giant platelets and no platelet functional defects. The degree of thrombocytopenia is highly variable among patients and remains stable during life; the majority of patients have moderately reduced platelet count [2]. The presence of bleeding and its severity strongly correlate with the platelet count. Around 25-30% of patients have spontaneous mucocutaneous hemorrhages, whereas most individuals have no spontaneous bleeding or only easy bruising [2]. MYH9-RD is a syndromic form of thrombocytopenia. NMMHC-IIA inclusions in the cytoplasm of granulocytes represent the other feature present in all the patients. Moreover, most of theMYH9-RD patients develop noncongenital extra-hematological manifestations, such as sensorineural hearing loss, presenile cataract, proteinuric nephropathy often evolving to end-stage renal disease, and/or chronic or intermittent elevation of liver enzymes [3]. To our knowledge, almost 80 different mutations have been identified in the MYH9-RD pedigrees (Table I). They are mainly amino acid substitutions that hit specific residues, with mutational hot spots (exons 2, 11, and 17) in the globular head, whereasmutations aremore uniformly distributed in coiled-coil domain of NMMHC-IIA (Figure 1). There are residues, such as Ala95, Arg702, Thr1155, Asp1424, or Asp1447, which can be substituted by more than one amino acid. A few in-frame deletions or duplications also affect the coding region primarily in exons 25 and 26, where repetitive sequences lead to copy number variations through nonallelic homologous recombination mechanisms [4]. Of note, all the frameshift and nonsense mutations are localized in the nonhelical tail (exon 41). Moreover, mutations affecting residues Ser96, Arg702, Arg1165, Asp1424, and Glu1841 account for the disease in approximately 80% of the cases [2]. MYH9-RD should always be suspected in individuals with thrombocytopenia and giant platelets, not only in familiar but also in sporadic cases. Indeed, the latter is relatively frequent (35%) and associated with de novo mutations, as demonstrated by molecular genetic testing of parents, who in a few cases resulted to have somatic or germline mosaicism [1]. In asymptomatic patients, MYH9-RD is often recognized only in the adulthood after thrombocytopenia is discovered incidentally. A significant proportion of MYH9-RD patients are initially misdiagnosed as having immune thrombocytopenia [1]. The finding of the NMMHC-IIA aggregates in granulocytes allows a definite diagnosis of the disease [5]. These inclusions are detected after conventional staining of blood smears as basophilic “Döhle-like” bodies in 42–84% of patients [1]. However, immunofluorescence analysis of NMMHC-IIA provides a much easier recognition of the aggregates in all the patients; this assay has high sensitivity and specificity for the diagnosis of MYH9-RD [6]. Both the severity of thrombocytopenia and the onset of the noncongenital features strongly correlate with the MYH9 genotype (Figure 1). The first investigations showed that patients with mutations in the head domain have significantly lower platelet count and higher incidence of extra-hematological features than affected individuals with mutations in the coiled-coil domain or nonhelical tail [7]. Subsequent studies in large case series not only confirmed the previous findings but also supported a correlation with the single variants that are more frequently found in patients (Figure 1). In particular, mutations affecting residue R702 (exon 17) lead to the most severe phenotype, characterized by severe thrombocytopenia and early onset of end-stage renal disease and deafness. Mutations in exon 2, those affecting residue R1165, and the p.D1424H substitution are associated with intermediate risks of developing the noncongenital features. Finally, patients with p.D1424N, p.E1841K, or the mutations in the nonhelical tail have very low risk of kidney damage, hearing loss, and cataract [2]. Concerning the thrombocytopenia, the analysis of a large case series showed that the median platelet count was Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/iplt. Correspondence: Dr. Anna Savoia, Department of Medical Sciences, University of Trieste, IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste 34137, Italy. E-mail: [email protected] http://www.tandfonline.com/iplt ISSN: 0953-7104 (print), 1369-1635 (electronic)