Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history ofMYH9-related disease

Abstract

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA). All patients present from birth with macrothrombocytopenia, but in infancy or adult life, some of them develop sensorineural deafness, presenile cataracts, and/or progressive nephritis leading to end-stage renal failure. No consistent correlations have been identified between the 27 different MYH9 mutations identified so far and the variable clinical evolution of the disease. We have evaluated 108 consecutive MYH9-RD patients belonging to 50 unrelated pedigrees. The risk of noncongenital manifestations associated with different genotypes was estimated over time by event-free survival analysis. We demonstrated that all subjects with mutations in the motor domain of NMMHC-IIA present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. We also evaluated the clinical course of patients with mutations in the four most frequently affected residues of NMMHC-IIA (responsible for 70% of MYH9-RD cases). We concluded that mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures. These findings are relevant not only to patients' clinical management but also to the elucidation of the pathogenesis of the disease.

A comprehensive targeted next‐generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia

“…Following analysis of the IT‐specific panel sequencing, a missense variant was identified in MYH9 ; c.2152C>T, p.Arg718Trp. This variant has been noted once previously in a patient initially diagnosed with MYH9‐RD 3. The variant occurs within the motor domain of MYH9 and is associated with an increased risk of deafness and nephritis, however, no secondary symptoms have previously been reported in patient 64 or any of the affected family members also recruited to the UK‐GAPP study.…”

“…Four pathogenic or likely pathogenic variants were identified that are previously known to cause IT. These were found in patients; 54 ( GATA1 ; c.1240T>C, p.*414Arg+41), 59 ( RUNX1 ; c.386C>A, p.Ala129Glu), 70 ( GFI1B ; c.503G>T, p.Cys168Phe), and 64 ( MYH9 ; c.2152C>T, p.Arg718Trp) 3 , 15 , 16 , 17 …”

“…Since the discovery of disease inheritance patterns in disorders such as Bernard Soulier Syndrome (BSS), genetic studies of thrombocytopenia have been a vital tool in determining megakaryocyte and platelet physiology 1. As a result of parallel whole exome and whole genome sequencing over the past 5‐10 years, we are discovering increasing numbers of novel genes and variants with a critical role in platelet production, physiology, and function 2, 3, 4, 5…”

MYH9-related disease: Report on five German families and description of a novel mutation

“…As an adult he developed cataract in the remaining eye. The study of Pecci et al [4] revealed that the occurrence of cataracts in MYH9RD represents an exception to the observation of better prognosis of mutations affecting the tail domain of myosin-9 -the prevalence was similar for mutations affecting the motor head domain or the tail domain, respectively. However, we cannot rule out factors independent from the MYH9 mutation as the cause of juvenile glaucoma and cataract in patient F5-II-2.…”

Association between MYH9 gene polymorphisms and membranous glomerulonephritis patients in Taiwan

“…MYH9-related disorders (MYH9-RD) are inherited in an autosomal dominant manner and are characterized by congenital thrombocytopenia and large platelets. These disorders are associated with the development of progressive nephropathy during infancy or adult life, sensorineural deafness, and presenile cataract 10,11 . The MYH9 gene encodes the nonmuscle myosin IIA and is expressed in glomerular podocytes and mesangial cells 12,13 .…”