Hermansky-Pudlak syndrome type 2

Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils

M. de Boer, K. van Leeuwen, J. Geissler, F. van Alphen, E. de Vries, M. van der Kuip, S.W.J. Terheggen, H. Janssen, T.K. van den Berg, A.B. Meijer, D. Roos, T.W. Kuijpers

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
Pages (from-to)1402-1411
JournalHuman Mutation
Volume38
Issue number10
DOIs
Publication statusPublished - 2017

Fingerprint

Neutrophils
Mutation
Immunoelectron Microscopy
Nonsense Codon
Gene Deletion
Neutropenia
Point Mutation
Peroxidase
Siblings

Cite this

de Boer, M., van Leeuwen, K., Geissler, J., van Alphen, F., de Vries, E., van der Kuip, M., ... Kuijpers, T. W. (2017). Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils. Human Mutation, 38(10), 1402-1411. https://doi.org/10.1002/humu.23271
de Boer, M. ; van Leeuwen, K. ; Geissler, J. ; van Alphen, F. ; de Vries, E. ; van der Kuip, M. ; Terheggen, S.W.J. ; Janssen, H. ; van den Berg, T.K. ; Meijer, A.B. ; Roos, D. ; Kuijpers, T.W. / Hermansky-Pudlak syndrome type 2 : Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils. In: Human Mutation. 2017 ; Vol. 38, No. 10. pp. 1402-1411.
@article{176862a92ac04f38ab74776c225fb74a,
title = "Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils",
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.",
author = "{de Boer}, M. and {van Leeuwen}, K. and J. Geissler and {van Alphen}, F. and {de Vries}, E. and {van der Kuip}, M. and S.W.J. Terheggen and H. Janssen and {van den Berg}, T.K. and A.B. Meijer and D. Roos and T.W. Kuijpers",
year = "2017",
doi = "10.1002/humu.23271",
language = "English",
volume = "38",
pages = "1402--1411",
journal = "Human Mutation",
issn = "1098-1004",
publisher = "Wiley-Liss Inc.",
number = "10",

}

de Boer, M, van Leeuwen, K, Geissler, J, van Alphen, F, de Vries, E, van der Kuip, M, Terheggen, SWJ, Janssen, H, van den Berg, TK, Meijer, AB, Roos, D & Kuijpers, TW 2017, 'Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils', Human Mutation, vol. 38, no. 10, pp. 1402-1411. https://doi.org/10.1002/humu.23271

Hermansky-Pudlak syndrome type 2 : Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils. / de Boer, M.; van Leeuwen, K.; Geissler, J.; van Alphen, F.; de Vries, E.; van der Kuip, M.; Terheggen, S.W.J.; Janssen, H.; van den Berg, T.K.; Meijer, A.B.; Roos, D.; Kuijpers, T.W.

In: Human Mutation, Vol. 38, No. 10, 2017, p. 1402-1411.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Hermansky-Pudlak syndrome type 2

T2 - Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils

AU - de Boer, M.

AU - van Leeuwen, K.

AU - Geissler, J.

AU - van Alphen, F.

AU - de Vries, E.

AU - van der Kuip, M.

AU - Terheggen, S.W.J.

AU - Janssen, H.

AU - van den Berg, T.K.

AU - Meijer, A.B.

AU - Roos, D.

AU - Kuijpers, T.W.

PY - 2017

Y1 - 2017

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.

U2 - 10.1002/humu.23271

DO - 10.1002/humu.23271

M3 - Article

VL - 38

SP - 1402

EP - 1411

JO - Human Mutation

JF - Human Mutation

SN - 1098-1004

IS - 10

ER -