TY - JOUR
T1 - Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils
T2 - Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils
AU - de Boer, Martin
AU - van Leeuwen, Karin
AU - Geissler, Judy
AU - van Alphen, Floris
AU - de Vries, Esther
AU - van der Kuip, Martijn
AU - Terheggen, Suzanne W. J.
AU - Janssen, Hans
AU - van den Berg, Timo K.
AU - Meijer, Alexander B.
AU - Roos, Dirk
AU - Kuijpers, Taco W.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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
AB - 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
KW - AP3B1
KW - Hermansky–Pudlak syndrome
KW - cryptic splice site
KW - neutrophil granule formation
KW - pre-mRNA splicing
UR - http://www.scopus.com/inward/record.url?scp=85020704202&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/humu.23271
DO - https://doi.org/10.1002/humu.23271
M3 - Article
C2 - 28585318
SN - 1059-7794
VL - 38
SP - 1402
EP - 1411
JO - Human mutation
JF - Human mutation
IS - 10
ER -