{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T10:03:52Z","timestamp":1753869832506,"version":"3.41.2"},"reference-count":25,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,12,4]],"date-time":"2016-12-04T00:00:00Z","timestamp":1480809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pediatric Blood &amp; Cancer"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hermansky\u2013Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by oculocutaneous albinism and platelet dysfunction. We report on a novel <jats:italic>HPS6<\/jats:italic> homozygous frameshift variant (c.1919_1920delTC; p.Val640Glyfs*29) in a nonconsanguineous Caucasian family with two affected siblings (index patients) who presented with oculocutaneous albinism at birth and a mild bleeding phenotype during childhood and adolescence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Procedure<\/jats:title><jats:p>Genetic analysis was conducted by panel\u2010based next\u2010generation sequencing (NGS) and Sanger sequencing. Platelets of the index patients, their parents, and the unaffected sister were then comprehensively evaluated by luminoaggregometry, whole blood flow cytometry, immunoblotting, immunofluorescence, and transmission electron microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The homozygous frameshift variant in <jats:italic>HPS6<\/jats:italic> gene detected by panel\u2010based NGS and its segregation in the family was confirmed by Sanger sequencing. Flow cytometric analysis of the patients\u2019 platelets revealed a substantially decreased mepacrine uptake and release upon activation with a thrombin receptor agonist. Electron microscopy of resting platelets confirmed diminished dense granule content and enhanced vacuolization. Reduced release of adenosine triphosphate and CD63 neoexposition upon activation indicated not only a lack of dense granule content, but even an impairment of dense granule release.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate that the novel loss\u2010of\u2010function variant in the HPS6 subunit of biogenesis of lysosome\u2010related organelles complex 2 is pathologic and leads to a reduced platelet dense granules and their release. The findings are compatible with an impaired platelet function and hence an enhanced bleeding risk. In future, a valid genotype\u2013phenotype correlation may translate into best supportive care, especially regarding elective surgery or trauma management.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pbc.26320","type":"journal-article","created":{"date-parts":[[2016,12,5]],"date-time":"2016-12-05T03:18:54Z","timestamp":1480907934000},"source":"Crossref","is-referenced-by-count":11,"title":["A novel two\u2010nucleotide deletion in <i>HPS6<\/i> affects mepacrine uptake and platelet dense granule secretion in a family with Hermansky\u2013Pudlak syndrome"],"prefix":"10.1002","volume":"64","author":[{"given":"Oliver","family":"Andres","sequence":"first","affiliation":[{"name":"University Children's Hospital W\u00fcrzburg University of W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Wiegering","sequence":"additional","affiliation":[{"name":"University Children's Hospital W\u00fcrzburg University of W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva\u2010Maria","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Biocentre University of W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Lena","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University Hospital W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Semeniak","sequence":"additional","affiliation":[{"name":"Institute of Experimental Biomedicine I University Hospital W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Stritt","sequence":"additional","affiliation":[{"name":"Institute of Experimental Biomedicine I University Hospital W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Klopocki","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Biocentre University of W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Schulze","sequence":"additional","affiliation":[{"name":"Institute of Experimental Biomedicine I University Hospital W\u00fcrzburg  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,12,4]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"1","volume-title":"GeneReviews","author":"Gahl WA","year":"1993"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-09-671636"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2015-308067"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.12170"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a017046"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-835674"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.2830260403"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.5482\/HAMO-13-04-0024"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/09537109909169179"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2011.049619"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11097"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/09537100802132671"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2012-4003"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3109\/08820538.2013.825280"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2003.12.058"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2004.00208.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2008.065961"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1087"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2004.0171.x"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311311200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9463"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116388"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-08-597419"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-586727"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.3109\/09537104.2010.482163"}],"container-title":["Pediatric Blood &amp; 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