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Hermansky–Pudlak syndrome type 2: Aberrant pre‐mRNA splicing and mislocalization of granule proteins in neutrophils
Author(s) -
Boer Martin,
Leeuwen Karin,
Geissler Judy,
Alphen Floris,
Vries Esther,
der Kuip Martijn,
Terheggen Suzanne W.J.,
Janssen Hans,
den Berg Timo K.,
Meijer Alexander B.,
Roos Dirk,
Kuijpers Taco W.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23271
Subject(s) - exon , frameshift mutation , biology , immunoelectron microscopy , rna splicing , nonsense mediated decay , microbiology and biotechnology , nonsense mutation , splice site mutation , point mutation , exon skipping , genetics , hermansky–pudlak syndrome , gene , alternative splicing , messenger rna , mutation , rna , pathology , missense mutation , medicine , pulmonary fibrosis , antibody , fibrosis
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.