BMSEHA15
Published online 13 August 2009
Haematologica, Vol 95, Issue 2, 333-337 doi:10.3324/haematol.2009.012286
Copyright © 2010 by Ferrata Storti Foundation
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Platelet Disorders

Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

Matt Wenham1,2, Samantha Grieve1, Michelle Cummins3, Matthew L. Jones4, Sarah Booth2,5, Rachel Kilner2, Philip J. Ancliff6, Gillian M. Griffiths1,2, Andrew D. Mumford7

1 Cambridge Institute for Medical Research, University of Cambridge, Cambridge
2 Sir William Dunn School of Pathology, University of Oxford, Oxford
3 Bristol Royal Hospital for Children, Bristol
4 Department of Physiology and Pharmacology, University of Bristol, Bristol
6 Great Ormond St Hospital for Children NHS Trust, London
7 Bristol Heart Institute, University of Bristol, Bristol, UK

Correspondence: Gillian Griffiths, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 0XY, UK. E-mail: gg305{at}cam.ac.uk Andrew Mumford, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail: a.mumford{at}bristol.ac.uk

Hermansky Pudlak syndrome type 2 (HPS2) is a rare disorder associated with mutations in the Adaptor Protein 3 (AP-3) complex, which is involved in sorting transmembrane proteins to lysosomes and related organelles. We now report 2 unrelated subjects with HPS2 who show a characteristic clinical phenotype of oculocutaneous albinism, platelet and T-lymphocyte dysfunction and neutropenia. The subjects were homozygous for different deletions within AP3B1 (g.del180242-180866, c.del153-156), which encodes the AP-3β3A subunit, resulting in frame shifts and introduction of nonsense substitutions (p.E693fsX13, p.E52fsX11). In the subject with p.E693fsX13, this resulted in expression of a truncated variant β3A protein. Cytotoxic T-lymphocyte (CTL) clones from both study subjects showed increased cell-surface expression of CD63 and reduced cytotoxicity. Platelets showed impaired aggregation and reduced uptake of 3H-serotonin. These findings are consistent with CTL granule and platelet dense granule defects, respectively. This report extends the clinical and laboratory description of HPS2.

Key words: Hermansky Pudlak syndrome, mutations, AP3B1.