Open Access Case report

Disruption of AP3B1 by a chromosome 5 inversion: a new disease mechanism in Hermansky-Pudlak syndrome type 2

Matthew L Jones1, Sherina L Murden1, Claire Brooks2, Viv Maloney3, Richard A Manning4, Kimberly C Gilmour5, Vandana Bharadwaj6, Josu de la Fuente6, Subarna Chakravorty67* and Andrew D Mumford1

Author Affiliations

1 Bristol Heart Institute & School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK

2 North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK

3 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK

4 Department of Haematology, Imperial College Academic Health Care Trust, Hammersmith Hospital, London, UK

5 Department of Immunology, Great Ormond Street Hospital for Children NHS Trust, London, UK

6 Department of Medicine, Imperial College, London, UK

7 Department of Paediatric Haematology, St Marys Hospital, Imperial College Healthcare NHS Trust, London, UK

For all author emails, please log on.

BMC Medical Genetics 2013, 14:42  doi:10.1186/1471-2350-14-42

Published: 4 April 2013



Hermansky-Pudlak syndrome 2 (HPS2; OMIM #608233) is a rare, autosomal recessive disorder caused by loss-of-function genetic variations affecting AP3B1, which encodes the β3A subunit of the adaptor-related protein complex 3 (AP3). Phenotypic characteristics include reduced pigmentation, absent platelet dense granule secretion, neutropenia and reduced cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function. To date HPS2 has been associated with non-synonymous, stop-gain or deletion-insertion nucleotide variations within the coding region of AP3B1.

Case presentation

We describe a consanguineous female infant with reduced pigmentation, neutropenia and recurrent infections. Platelets displayed reduced aggregation and absent ATP secretion in response to collagen and ADP, indicating a platelet dense granule defect. There was increased basal surface expression of CD107a (lysosome-associated membrane protein 1(LAMP-1)) on NK cells and CTLs from the study subject and a smaller increase in the percentage of CD107a positive cells after stimulation compared to most healthy controls. Immunoblotting of protein extracts from EBV-transformed lymphoblasts from the index case showed absent expression of full-length AP-3 β3A subunit protein, confirming a phenotypic diagnosis of HPS2.

The index case displayed a homozygous pericentric inv(5)(p15.1q14.1), which was also detected as a heterozygous defect in both parents of the index case. No loss of genetic material was demonstrated by microarray comparative genome hybridisation at 60kb resolution. Fluorescence in-situ hybridisation using the 189.6kb probe RP11-422I12, which maps to 5q14.1, demonstrated dual hybridisation to both 5q14.1 and 5p15.1 regions of the inverted Chr5. The RP11-422I12 probe maps from intron 1 to intron 16 of AP3B1, thus localising the 5q inversion breakpoint to within AP3B1. The probe RP11-211K15, which corresponds to an intergenic region on 5p also showed dual hybridisation, enabling localisation of the 5p inversion breakpoint.


This case report extends the phenotypic description of the very rare disorder HPS2. Our demonstration of a homozygous Chr5 inversion predicted to disrupt AP3B1 gene provides a novel pathogenic mechanism for this disorder.

Chromosome 5 inversion; Hermansky-Pudlak syndrome type 2; Adaptor-related protein complex 3 β3A subunit; Fluorescence in situ hybridisation