Clin Genet 2015: 87: 299 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12424
Correspondence
Platelets are not all gray in GFI1B disease We read with interest the commentary by F. Aminkeng (1) regarding the recent description of an autosomal dominant GFI1B mutation (c.859 C→T) described by Monteferrario and colleagues (2) as a type of Gray Platelet Syndrome (GPS). We have recently identified a similar family with a dominantly inherited frame shift mutation in GFI1B, c.880-881insC, in the same DNA-binding zinc finger domain (3). The kindred we described has a heterogeneous alpha-granule deficiency in platelets and a subtle red cell phenotype of anisopoikilocytosis on blood film examination and increased red cell distribution width on automated cell counter analysis. Classic descriptions of the GPS describe a bleeding disorder characterized by gray platelets on blood film examination due to alpha-granule deficiency that is confirmed by electron microscopy. Both autosomal dominant and recessive patterns of inheritance of GPS have been observed (2, 4). Morphological investigations suggest the alpha-granule deficiency is severe in GPS with less than 15% of normal levels in quantitative electron microscopy studies (4–6). No red cell defect is typically described. The Australian kindred we describe has 84% of platelets from affected individuals (n = 6) above this alpha-granule deficiency level with 18% of platelets containing more than the average alpha-granule content. The subtle red cell phenotype associated with the platelet changes observed are consistent with animal studies that suggest GFI1B is a transcriptional regulator of both platelet and red cell development (7). As a key transcriptional repressor of haematopoiesis, GFI1B may be considered a novel target for therapies aimed at correcting red cell and platelet abnormalities. We propose that GFI1B mutation encompasses a syndrome of variable platelet alpha-granule deficiency and red cell shape change that may be better described as ‘GFI1B
disease’ or perhaps the more prosaic designation of ‘bleeding disorder, platelet type, 17; BDPLT17’ as listed in the OMIM (http://www.omim.org/entry/187900). W.S. Stevenson M.-C. Morel-Kopp C.M. Ward Royal North Shore Hospital, Kolling Institute of Medical Research, Sydney, Australia References 1. Aminkeng F. GFI1B mutation causes autosomal dominant gray platelet syndrome. Clin Genet 2014: 85: 534–535. 2. Monteferrario D, Bolar NA, Marneth AE et al. A dominant-negative GFI1B mutation in the gray platelet syndrome. N Engl J Med 2014: 370: 245–253. 3. Stevenson WS, Morel-Kopp MC, Chen Q et al. GFI1B mutation causes a bleeding disorder with abnormal platelet function. J Thromb Haemost 2013: 11: 2039–2047. 4. Gunay-Aygun M, Zivony-Elboum Y, Gumruk F et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood 2010: 116: 4990–5001. 5. White JG. Ultrastructural studies of the gray platelet syndrome. Am J Pathol 1979: 95: 445–462. 6. Gerrard JM, Phillips DR, Rao GH et al. Biochemical studies of two patients with the gray platelet syndrome. Selective deficiency of platelet alpha granules. J Clin Invest 1980: 66: 102–109. 7. Saleque S, Cameron S, Orkin SH. The zinc-finger proto-oncogene Gf1-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev 2002: 16: 301–306.
Correspondence: William S. Stevenson, MBBS, PhD, Royal North Shore Hospital, Kolling Institute of Medical Research, Sydney, Australia. Tel.: +612 99264385; fax: +612 99264070; e-mail: [email protected]
299
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12424
Correspondence
Platelets are not all gray in GFI1B disease We read with interest the commentary by F. Aminkeng (1) regarding the recent description of an autosomal dominant GFI1B mutation (c.859 C→T) described by Monteferrario and colleagues (2) as a type of Gray Platelet Syndrome (GPS). We have recently identified a similar family with a dominantly inherited frame shift mutation in GFI1B, c.880-881insC, in the same DNA-binding zinc finger domain (3). The kindred we described has a heterogeneous alpha-granule deficiency in platelets and a subtle red cell phenotype of anisopoikilocytosis on blood film examination and increased red cell distribution width on automated cell counter analysis. Classic descriptions of the GPS describe a bleeding disorder characterized by gray platelets on blood film examination due to alpha-granule deficiency that is confirmed by electron microscopy. Both autosomal dominant and recessive patterns of inheritance of GPS have been observed (2, 4). Morphological investigations suggest the alpha-granule deficiency is severe in GPS with less than 15% of normal levels in quantitative electron microscopy studies (4–6). No red cell defect is typically described. The Australian kindred we describe has 84% of platelets from affected individuals (n = 6) above this alpha-granule deficiency level with 18% of platelets containing more than the average alpha-granule content. The subtle red cell phenotype associated with the platelet changes observed are consistent with animal studies that suggest GFI1B is a transcriptional regulator of both platelet and red cell development (7). As a key transcriptional repressor of haematopoiesis, GFI1B may be considered a novel target for therapies aimed at correcting red cell and platelet abnormalities. We propose that GFI1B mutation encompasses a syndrome of variable platelet alpha-granule deficiency and red cell shape change that may be better described as ‘GFI1B
disease’ or perhaps the more prosaic designation of ‘bleeding disorder, platelet type, 17; BDPLT17’ as listed in the OMIM (http://www.omim.org/entry/187900). W.S. Stevenson M.-C. Morel-Kopp C.M. Ward Royal North Shore Hospital, Kolling Institute of Medical Research, Sydney, Australia References 1. Aminkeng F. GFI1B mutation causes autosomal dominant gray platelet syndrome. Clin Genet 2014: 85: 534–535. 2. Monteferrario D, Bolar NA, Marneth AE et al. A dominant-negative GFI1B mutation in the gray platelet syndrome. N Engl J Med 2014: 370: 245–253. 3. Stevenson WS, Morel-Kopp MC, Chen Q et al. GFI1B mutation causes a bleeding disorder with abnormal platelet function. J Thromb Haemost 2013: 11: 2039–2047. 4. Gunay-Aygun M, Zivony-Elboum Y, Gumruk F et al. Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p. Blood 2010: 116: 4990–5001. 5. White JG. Ultrastructural studies of the gray platelet syndrome. Am J Pathol 1979: 95: 445–462. 6. Gerrard JM, Phillips DR, Rao GH et al. Biochemical studies of two patients with the gray platelet syndrome. Selective deficiency of platelet alpha granules. J Clin Invest 1980: 66: 102–109. 7. Saleque S, Cameron S, Orkin SH. The zinc-finger proto-oncogene Gf1-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev 2002: 16: 301–306.
Correspondence: William S. Stevenson, MBBS, PhD, Royal North Shore Hospital, Kolling Institute of Medical Research, Sydney, Australia. Tel.: +612 99264385; fax: +612 99264070; e-mail: [email protected]
299
