Hermansky–Pudlak syndrome type 2: Aberrant pre‐mRNA splicing and mislocalization of granule proteins in neutrophils. Issue 10 (15th June 2017)

• Record Type: Journal Article
• Authors: de Boer, Martin; van Leeuwen, Karin; Geissler, Judy; van Alphen, Floris; de Vries, Esther; van der Kuip, Martijn; Terheggen, Suzanne W.J.; Janssen, Hans; van den Berg, Timo K.; Meijer, Alexander B.; Roos, Dirk; Kuijpers, Taco W.
• Is Part Of: Human mutation. Volume 38:Issue 10(2017)
• Page Start: 1402
• Page End: 1411
• Publication Date: 2017-06-15
• Subjects: AP3B1 -- cryptic splice site -- Hermansky–Pudlak syndrome -- neutrophil granule formation -- pre‐mRNA splicing; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23271
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Mutations in AP3B1 results in the absence of all AP‐3 complex subunits with aberrant granule formation at the ultrastructural and proteomics level (while granular protein expression seems to be spared). The major consequence is defective neutrophil development, as demonstrated in a series of five unreported HPS2 cases. Abstract: Hermansky–Pudlak syndrome type 2 (HPS2) is a syndrome caused by mutations in the beta‐3A subunit of the adaptor protein (AP)‐3 complex ( AP3B1 gene). We describe five unreported cases with four novel mutations, one of which caused aberrant pre‐mRNA splicing. A point mutation c.2702C>G in exon 23 of the AP3B1 gene caused deletion of 112 bp in the mRNA in two siblings. This mutation activates a cryptic donor splice site that overrules the wild‐type donor splice site of this exon. Three other novel mutations in AP3B1 were identified, that is, a nonsense mutation c.716G>A (p.Trp239Ter), a 1‐bp and a 4‐bp deletion c.177delA and c.1839_1842delTAGA, respectively, both causing frameshift and premature termination of translation. Mass spectrometry in four of these HPS2 patients demonstrated the (near) absence of all AP‐3 complex subunits. Immunoelectron microscopy on the neutrophils of two of these patients showed abnormal granule formation. We found clear mislocalization of myeloperoxidase in the neutrophils even though the content of this protein but not the activity seemed to be present at normal levels. In sum, HPS2 is the result of the absence of the entire AP‐3 complex, which results in severe neutropenia with a defect in granule formation as the major hematological finding.