MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder

Carlo Zaninetti; Daniela De Rocco; Tania Giangregorio; Valeria Bozzi; Judit Demeter; Pietro Leoni; Patrizia Noris; Samppa Ryhänen; Serena Barozzi; Alessandro Pecci; Anna Savoia

doi:10.1055/s-0038-1645840

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 2019; 39(01): 087-094
DOI: 10.1055/s-0038-1645840

Original Article

Georg Thieme Verlag KG Stuttgart · New York

MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder

Carlo Zaninetti

¹Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy

²PhD Programme in Experimental Medicine, University of Pavia, Pavia, Italy

,

Daniela De Rocco

³Institute for Maternal and Child Health, “IRCCS Burlo Garofolo,” Trieste, Italy

,

Tania Giangregorio

⁴Department of Medical Sciences, University of Trieste, Trieste, Italy

,

Valeria Bozzi

¹Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy

,

Judit Demeter

⁵Division of Hematology, First Department of Internal Medicine, Semmelweis University, Budapest, Hungary

,

Pietro Leoni

⁶Hematology Clinic, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy

,

Patrizia Noris

¹Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy

,

Samppa Ryhänen

⁷Division of Hematology, Oncology, and Stem Cell Transplantation, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

,

Serena Barozzi

¹Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy

,

Alessandro Pecci

¹Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy

,

Anna Savoia

³Institute for Maternal and Child Health, “IRCCS Burlo Garofolo,” Trieste, Italy

⁴Department of Medical Sciences, University of Trieste, Trieste, Italy

› Institutsangaben

Abstract

MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). Patients present congenital macrothrombocytopenia and inclusions of NMMHC-IIA in leukocytes, and have a variable risk of developing kidney damage, sensorineural deafness, presenile cataracts and/or liver enzymes abnormalities. The spectrum of mutations found in MYH9-RD patients is limited and the incidence and severity of the non-congenital features are predicted by the causative MYH9 variant. In particular, different alterations of the C-terminal tail domain of NMMHC-IIA associate with remarkably different disease evolution. We report four novel MYH9 mutations affecting the tail domain of NMMHC-IIA and responsible for MYH9-RD in four families. Two variants cause amino acid substitutions in the coiled-coil region of NMMHC-IIA, while the other two are a splicing variant and a single nucleotide deletion both resulting in frameshift alterations of the short non-helical tailpiece. Characterization of phenotypes of affected individuals shows that all of these novel variants are associated with a mild clinical evolution of the disease.

Zusammenfassung

MYH9-assoziierte Erkrankung (MYH9-RD) ist eine autosomal-dominante Thrombozytopenie, die durch Mutationen im Gen für die Nicht-Muskel-Myosin schwere Kette IIA (NMMHC-IIA) verursacht wird. Die Patienten weisen eine kongenitale Makrothrombozytopenie und Einschlüsse von NMMHC-IIA in Leukozyten auf und haben ein variables Risiko, Nierenschäden, sensorineurale Taubheit, präsenile Katarakte und / oder Leberenzyme zu entwickeln. Das Spektrum der bei MYH9-RD-Patienten gefundenen Mutationen ist begrenzt und die Inzidenz und der Schweregrad der nicht-kongenitalen Merkmale werden durch die verursachende MYH9-Variante prognostiziert. Insbesondere assoziieren verschiedene Veränderungen der C-terminalen Schwanzdomäne von NMMHC-IIA mit einer bemerkenswert unterschiedlichen Krankheitsentwicklung. Wir berichten über vier neue MYH9-Mutationen, die die Schwanzdomäne von NMMHC-IIA betreffen und in vier Familien für MYH9-RD verantwortlich sind. Zwei Varianten verursachen Aminosäuresubstitutionen in der Coiled-Coil-Region von NMMHC-IIA, während die anderen beiden eine Splicing-Variante und eine Einzelnucleotid-Deletion sind, die beide zu Frameshift-Veränderungen des kurzen nicht-helikalen Schwanzstückes führen. Die Charakterisierung der Phänotypen betroffener Individuen zeigt, dass alle diese neuen Varianten mit einer milden klinischen Entwicklung der Erkrankung einhergehen.

Keywords

inherited platelet disorders - inherited thrombocytopenia - MYH9-related disease - non-muscle myosin IIA

Schlüsselwörter

erbliche Thrombozytopathien - erbliche Thrombozytopenie - MYH9-assoziierte Erkrankung - Nicht-Muskel Myosin IIA

Volltext

Referenzen

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