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
1  Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy
2  PhD Programme in Experimental Medicine, University of Pavia, Pavia, Italy
,
Daniela De Rocco
3  Institute for Maternal and Child Health, “IRCCS Burlo Garofolo,” Trieste, Italy
,
Tania Giangregorio
4  Department of Medical Sciences, University of Trieste, Trieste, Italy
,
Valeria Bozzi
1  Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy
,
Judit Demeter
5  Division of Hematology, First Department of Internal Medicine, Semmelweis University, Budapest, Hungary
,
Pietro Leoni
6  Hematology Clinic, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy
,
Patrizia Noris
1  Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy
,
Samppa Ryhänen
7  Division of Hematology, Oncology, and Stem Cell Transplantation, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
,
Serena Barozzi
1  Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy
,
Alessandro Pecci
1  Department of Internal Medicine, IRCCS Policlicnico San Matteo Foundation, University of Pavia, Pavia, Italy
,
Anna Savoia
3  Institute for Maternal and Child Health, “IRCCS Burlo Garofolo,” Trieste, Italy
4  Department of Medical Sciences, University of Trieste, Trieste, Italy
› Author Affiliations
Further Information

Publication History

24 January 2018

26 February 2018

Publication Date:
11 July 2018 (eFirst)

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.

Authors' Contributions

C.Z., A.P. and A.S. conceived and designed the study, analysed and interpreted data and wrote the manuscript. D.D.R., T.G., V.B., S.B., J.D., P.L., P.N. and S.R. performed research, collected, analysed and interpreted the data. All the authors critically revised the manuscript and accepted the final version.