Genetic and phenotypic analysis of Hermansky-Pudlak syndrome type 6 family with a special platelet phenotype_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhou Zhongqiang , Shi Pingling ,  Peng Haiying , Li Qian , Tang He , Wei Yuanmeng

Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan Eye Hospital, Zhengzhou 450003, China;

Corresponding author：

Peng Haiying, Email: angelphy@163.com

Keywords：

Hermansky-Pudlak syndrome; Clinical manifestation; Genetic characteristics; Platelet dense granules

DOI：

10.3760/cma.j.cn511434-20241028-00397

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To identify and observe the pathogenic genes and clinical phenotypes of a family with a special platelet phenotype, Hermansky-Pudlak syndrome type 6 (HSP6). Methods A retrospective clinical study. In November 2019, one proband and three family members from six HSP families who visited Henan Eye Hospital were included in the study. The child's medical history and family history were inquired in detail. The proband and all family members underwent best corrected visual acuity (BCVA), fundus color photography, frequency-domain optical coherence tomography, and general physical examination. The proband underwent platelet transmission electron microscopy (PTEM) and colonoscopy. Peripheral venous blood was collected from the proband, her parents and younger brother, and genomic DNA was extracted. Whole exome sequencing (WES) is used to screen pathogenic genes and their loci. Bioinformatics analysis determines the pathogenicity of gene variation sites. Fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to verify the related variations. Results The proband (II-1) was a 7-year-old female. The BCVA in both eyes was 0.1, who exhibited mild horizontal nystagmus and iris depigmentation. Fundus examination revealed obvious depigmentation and an underdeveloped fovea centralis. At the age of 7, the patient underwent colonoscopy due to acute gastrointestinal bleeding. A polyp approximately 5 mm in size was found on the floor of the sigmoid colon, with erosion and mucosal leukoplakia on its surface. PTEM showed that the number of platelet dense granules was normal, but the nuclei were small or exhibited low compactness. The skin on both lower legs showed pigmentation. The clinical phenotypes of the proband’s parents (I-1, I-2) and younger brother (II-2) showed no obvious abnormalities. WES revealed that the proband carried compound heterozygous variants in exon 1 of the HPS6 gene: c.60_64dup (p.L22fs) (M1) and c.1147_1148del (p.L383fs) (M2). The mother carried the M1 variant, while the father and younger brother carried the M2 variant. Bioinformatics analysis predicted that both variants were pathogenic. RT-qPCR results showed that, compared with the relative expression level of HPS6^wt mRNA, the relative expression levels of HPS6^L22fs and HPS6^L383fs mRNA were significantly decreased (t = 3.549, 4.560; P＜0.05). Western blot analysis demonstrated that the HPS6^L383fs protein was truncated, whereas the HPS6^L22fs protein was not detected. Conclusions This family is a special HPS6 with a normal number of dense platelet granules. The compound heterozygous variations of M1 and M2 in the HPS6 gene are pathogenic genes in this family.

1.	Wei AH, Li W. Hermansky-Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis[J]. Pigment Cell Melanoma Res, 2013, 26(2): 176-192. DOI: 10.1111/pcmr.12051.
2.	McElvaney OJ, Huizing M, Gahl WA, et al. Hermansky-Pudlak syndrome with a novel genetic variant in HPS1 and subsequent accelerated pulmonary fibrosis: significance for phenocopy diseases[J]. Thorax, 2018, 73(11): 1085-1088. DOI: 10.1136/thoraxjnl-2018-211920.
3.	de Boer M, van Leeuwen K, Geissler J, et al. Hermansky-Pudlak syndrome type 2: aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils[J]. Hum Mutat, 2017, 38(10): 1402-1411. DOI: 10.1002/humu.23271.
4.	Bowman SL, Bi-Karchin J, Le L, et al. The road to lysosome-related organelles: insights from Hermansky-Pudlak syndrome and other rare diseases[J]. Traffic, 2019, 20(6): 404-435. DOI: 10.1111/tra.12646.
5.	De Jesus Rojas W, Young LR. Hermansky-Pudlak syndrome[J]. Semin Respir Crit Care Med, 2020, 41(2): 238-246. DOI: 10.1055/s-0040-1708088.
6.	Boeckelmann D, Wolter M, Käsmann-Kellner B, et al. A novel likely pathogenic variant in the BLOC1S5 gene associated with Hermansky-Pudlak syndrome type 11 and an overview of human BLOC-1 deficiencies[J/OL]. Cells, 2021, 10(10): 2630[2021-10-01]. https://pubmed.ncbi.nlm.nih.gov/34685610/. DOI: 10.3390/cells10102630.
7.	Gochuico BR, Huizing M, Golas GA, et al. Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease[J]. Mol Med, 2012, 18(1): 56-64. DOI: 10.2119/molmed.2011.00198.
8.	Hengst M, Naehrlich L, Mahavadi P, et al. Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood[J/OL]. Orphanet J Rare Dis, 2018, 13(1): 42[2018-03-27]. https://pubmed.ncbi.nlm.nih.gov/29580292/. DOI: 10.1186/s13023-018-0780-z.
9.	Ammann S, Schulz A, Krägeloh-Mann I, et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome[J]. Blood, 2016, 127(8): 997-1006. DOI: 10.1182/blood-2015-09-671636.
10.	Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type Ⅱ[J]. Blood, 2006, 108(1): 81-87. DOI: 10.1182/blood-2005-11-4413.
11.	Jessen B, Bode SF, Ammann S, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2[J]. Blood, 2013, 121(15): 2943-2951. DOI: 10.1182/blood-2012-10-463166.
12.	Mohammed M, Al-Hashmi N, Al-Rashdi S, et al. Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder[J/OL]. Eur J Med Genet, 2019, 62(11): 103583[2018-11-22]. https://pubmed.ncbi.nlm.nih.gov/30472485/. DOI: 10.1016/j.ejmg.2018.11.017.
13.	Anderson PD, Huizing M, Claassen DA, et al. Hermansky-Pudlak syndrome type 4(HPS-4): clinical and molecular characteristics[J]. Hum Genet, 2003, 113(1): 10-17. DOI: 10.1007/s00439-003-0933-5.
14.	Huizing M, Helip-Wooley A, Westbroek W, et al. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics[J]. Annu Rev Genomics Hum Genet, 2008, 9: 359-386. DOI: 10.1146/annurev.genom.9.081307.164303.
15.	Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks[J]. Nature, 2014, 506(7487): 179-184. DOI: 10.1038/nature12929.
16.	Ringeisen AL, Schimmenti LA, White JG, et al. Hermansky-Pudlak syndrome (HPS5) in a nonagenarian[J]. J AAPOS, 2013, 17(3): 334-336. DOI: 10.1016/j.jaapos.2013.02.002.
17.	Botero JP, Chen D, Majerus JA, et al. Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: the importance of recognizing a subtle phenotype[J]. Platelets, 2018, 29(1): 91-94. DOI: 10.1080/09537104.2017.1361019.
18.	Zhang Q, Zhao B, Li W, et al. Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6[J]. Nat Genet, 2003, 33(2): 145-153. DOI: 10.1038/ng1087.
19.	Miyamichi D, Asahina M, Nakajima J, et al. Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism[J]. J Hum Genet, 2016, 61(9): 839-482. DOI: 10.1038/jhg.2016.56.
20.	Badolato R, Prandini A, Caracciolo S, et al. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome[J]. Blood, 2012, 119(13): 3185-3187. DOI: 10.1182/blood-2012-01-404350.
21.	Okamura K, Abe Y, Araki Y, et al. Characterization of melanosomes and melanin in patients with Hermansky-Pudlak syndrome types 1, 4, 6 and 9[J]. Pigment Cell Melanoma Res, 2018, 31(2): 267-276. DOI: 10.1111/pcmr.12662.
22.	Chen D, Uhl CB, Bryant SC, et al. Diagnostic laboratory standardization and validation of platelet transmission electron microscopy[J]. Platelets, 2018, 29(6): 574-582. DOI: 10.1080/09537104.2018.1476682.
23.	Tsurusaki Y, Koshimizu E, Ohashi H, et al. De novo SOX11 mutations cause Coffin-Siris syndrome[J/OL]. Nat Commun, 2014, 5: 4011[2014-06-02]. https://pubmed.ncbi.nlm.nih.gov/24886874/. DOI: 10.1038/ncomms5011.
24.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
25.	Mohammadi M, Spotin A, Mahami-Oskouei M, et al. MicroRNA-365 promotes apoptosis in human melanoma cell A375 treated with hydatid cyst fluid of Echinococcus granulosus sensu stricto[J/OL]. Microb Pathog, 2021, 153: 104804[2021-02-17]. https://pubmed.ncbi.nlm.nih.gov/33609644/. DOI: 10.1016/j.micpath.2021.104804.
26.	Stephen J, Yokoyama T, Tolman NJ, et al. Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5[J/OL]. PLoS One, 2017, 12(3): e0173682[2017-03-15]. https://pubmed.ncbi.nlm.nih.gov/28296950/. DOI: 10.1371/journal.pone.0173682.
27.	Huizing M, Malicdan MCV, Wang JA, et al. Hermansky-Pudlak syndrome: mutation update[J]. Hum Mutat, 2020, 41(3): 543-580. DOI: 10.1002/humu.23968.
28.	Han CG, O'Brien KJ, Coon LM, et al. Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant[J]. Am J Med Genet A, 2018, 176(12): 2819-2823. DOI: 10.1002/ajmg.a.40514.
29.	Wang C, Shi P, Li Q, et al. Hermansky-Pudlak syndrome: five Chinese patients with novel variants in HPS1 and HPS6[J/OL]. Eur J Med Genet, 2021, 64(6): 104228[2021-03-18]. https://pubmed.ncbi.nlm.nih.gov/33878481/. DOI: 10.1016/j.ejmg.2021.104228.
30.	Witkop CJ, Krumwiede M, Sedano H, et al. Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome[J]. Am J Hematol, 1987, 26(4): 305-311. DOI: 10.1002/ajh.2830260403.
31.	Di Pietro SM, Falcón-Pérez JM, Dell'Angelica EC. Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6[J]. Traffic, 2004, 5(4): 276-283. DOI: 10.1111/j.1600-0854.2004.0171.x.
32.	Wei A, Yuan Y, Bai D, et al. NGS-based 100-gene panel of hypopigmentation identifies mutations in Chinese Hermansky-Pudlak syndrome patients[J]. Pigment Cell Melanoma Res, 2016, 29(6): 702-706. DOI: 10.1111/pcmr.12534.
33.	Bastida JM, Morais S, Palma-Barqueros V, et al. Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing[J]. Ann Med, 2019, 51(2): 141-148. DOI: 10.1080/07853890.2019.1587498.
34.	Chen C, Wang R, Yuan Y, et al. Clinical features and novel genetic variants associated with Hermansky-Pudlak syndrome[J/OL]. Genes(Basel), 2022, 13(7): 1283[2022-07-20]. https://pubmed.ncbi.nlm.nih.gov/35886065/. DOI: 10.3390/genes13071283.
35.	Huizing M, Pederson B, Hess RA, et al. Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6[J]. J Med Genet, 2009, 46(12): 803-810. DOI: 10.1136/jmg.2008.065961.

1. Wei AH, Li W. Hermansky-Pudlak syndrome: pigmentary and non-pigmentary defects and their pathogenesis[J]. Pigment Cell Melanoma Res, 2013, 26(2): 176-192. DOI: 10.1111/pcmr.12051.
2. McElvaney OJ, Huizing M, Gahl WA, et al. Hermansky-Pudlak syndrome with a novel genetic variant in HPS1 and subsequent accelerated pulmonary fibrosis: significance for phenocopy diseases[J]. Thorax, 2018, 73(11): 1085-1088. DOI: 10.1136/thoraxjnl-2018-211920.
3. de Boer M, van Leeuwen K, Geissler J, et al. Hermansky-Pudlak syndrome type 2: aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils[J]. Hum Mutat, 2017, 38(10): 1402-1411. DOI: 10.1002/humu.23271.
4. Bowman SL, Bi-Karchin J, Le L, et al. The road to lysosome-related organelles: insights from Hermansky-Pudlak syndrome and other rare diseases[J]. Traffic, 2019, 20(6): 404-435. DOI: 10.1111/tra.12646.
5. De Jesus Rojas W, Young LR. Hermansky-Pudlak syndrome[J]. Semin Respir Crit Care Med, 2020, 41(2): 238-246. DOI: 10.1055/s-0040-1708088.
6. Boeckelmann D, Wolter M, Käsmann-Kellner B, et al. A novel likely pathogenic variant in the BLOC1S5 gene associated with Hermansky-Pudlak syndrome type 11 and an overview of human BLOC-1 deficiencies[J/OL]. Cells, 2021, 10(10): 2630[2021-10-01]. https://pubmed.ncbi.nlm.nih.gov/34685610/. DOI: 10.3390/cells10102630.
7. Gochuico BR, Huizing M, Golas GA, et al. Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease[J]. Mol Med, 2012, 18(1): 56-64. DOI: 10.2119/molmed.2011.00198.
8. Hengst M, Naehrlich L, Mahavadi P, et al. Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood[J/OL]. Orphanet J Rare Dis, 2018, 13(1): 42[2018-03-27]. https://pubmed.ncbi.nlm.nih.gov/29580292/. DOI: 10.1186/s13023-018-0780-z.
9. Ammann S, Schulz A, Krägeloh-Mann I, et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome[J]. Blood, 2016, 127(8): 997-1006. DOI: 10.1182/blood-2015-09-671636.
10. Enders A, Zieger B, Schwarz K, et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type Ⅱ[J]. Blood, 2006, 108(1): 81-87. DOI: 10.1182/blood-2005-11-4413.
11. Jessen B, Bode SF, Ammann S, et al. The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2[J]. Blood, 2013, 121(15): 2943-2951. DOI: 10.1182/blood-2012-10-463166.
12. Mohammed M, Al-Hashmi N, Al-Rashdi S, et al. Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder[J/OL]. Eur J Med Genet, 2019, 62(11): 103583[2018-11-22]. https://pubmed.ncbi.nlm.nih.gov/30472485/. DOI: 10.1016/j.ejmg.2018.11.017.
13. Anderson PD, Huizing M, Claassen DA, et al. Hermansky-Pudlak syndrome type 4(HPS-4): clinical and molecular characteristics[J]. Hum Genet, 2003, 113(1): 10-17. DOI: 10.1007/s00439-003-0933-5.
14. Huizing M, Helip-Wooley A, Westbroek W, et al. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics[J]. Annu Rev Genomics Hum Genet, 2008, 9: 359-386. DOI: 10.1146/annurev.genom.9.081307.164303.
15. Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks[J]. Nature, 2014, 506(7487): 179-184. DOI: 10.1038/nature12929.
16. Ringeisen AL, Schimmenti LA, White JG, et al. Hermansky-Pudlak syndrome (HPS5) in a nonagenarian[J]. J AAPOS, 2013, 17(3): 334-336. DOI: 10.1016/j.jaapos.2013.02.002.
17. Botero JP, Chen D, Majerus JA, et al. Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: the importance of recognizing a subtle phenotype[J]. Platelets, 2018, 29(1): 91-94. DOI: 10.1080/09537104.2017.1361019.
18. Zhang Q, Zhao B, Li W, et al. Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6[J]. Nat Genet, 2003, 33(2): 145-153. DOI: 10.1038/ng1087.
19. Miyamichi D, Asahina M, Nakajima J, et al. Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism[J]. J Hum Genet, 2016, 61(9): 839-482. DOI: 10.1038/jhg.2016.56.
20. Badolato R, Prandini A, Caracciolo S, et al. Exome sequencing reveals a pallidin mutation in a Hermansky-Pudlak-like primary immunodeficiency syndrome[J]. Blood, 2012, 119(13): 3185-3187. DOI: 10.1182/blood-2012-01-404350.
21. Okamura K, Abe Y, Araki Y, et al. Characterization of melanosomes and melanin in patients with Hermansky-Pudlak syndrome types 1, 4, 6 and 9[J]. Pigment Cell Melanoma Res, 2018, 31(2): 267-276. DOI: 10.1111/pcmr.12662.
22. Chen D, Uhl CB, Bryant SC, et al. Diagnostic laboratory standardization and validation of platelet transmission electron microscopy[J]. Platelets, 2018, 29(6): 574-582. DOI: 10.1080/09537104.2018.1476682.
23. Tsurusaki Y, Koshimizu E, Ohashi H, et al. De novo SOX11 mutations cause Coffin-Siris syndrome[J/OL]. Nat Commun, 2014, 5: 4011[2014-06-02]. https://pubmed.ncbi.nlm.nih.gov/24886874/. DOI: 10.1038/ncomms5011.
24. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
25. Mohammadi M, Spotin A, Mahami-Oskouei M, et al. MicroRNA-365 promotes apoptosis in human melanoma cell A375 treated with hydatid cyst fluid of Echinococcus granulosus sensu stricto[J/OL]. Microb Pathog, 2021, 153: 104804[2021-02-17]. https://pubmed.ncbi.nlm.nih.gov/33609644/. DOI: 10.1016/j.micpath.2021.104804.
26. Stephen J, Yokoyama T, Tolman NJ, et al. Cellular and molecular defects in a patient with Hermansky-Pudlak syndrome type 5[J/OL]. PLoS One, 2017, 12(3): e0173682[2017-03-15]. https://pubmed.ncbi.nlm.nih.gov/28296950/. DOI: 10.1371/journal.pone.0173682.
27. Huizing M, Malicdan MCV, Wang JA, et al. Hermansky-Pudlak syndrome: mutation update[J]. Hum Mutat, 2020, 41(3): 543-580. DOI: 10.1002/humu.23968.
28. Han CG, O'Brien KJ, Coon LM, et al. Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant[J]. Am J Med Genet A, 2018, 176(12): 2819-2823. DOI: 10.1002/ajmg.a.40514.
29. Wang C, Shi P, Li Q, et al. Hermansky-Pudlak syndrome: five Chinese patients with novel variants in HPS1 and HPS6[J/OL]. Eur J Med Genet, 2021, 64(6): 104228[2021-03-18]. https://pubmed.ncbi.nlm.nih.gov/33878481/. DOI: 10.1016/j.ejmg.2021.104228.
30. Witkop CJ, Krumwiede M, Sedano H, et al. Reliability of absent platelet dense bodies as a diagnostic criterion for Hermansky-Pudlak syndrome[J]. Am J Hematol, 1987, 26(4): 305-311. DOI: 10.1002/ajh.2830260403.
31. Di Pietro SM, Falcón-Pérez JM, Dell'Angelica EC. Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6[J]. Traffic, 2004, 5(4): 276-283. DOI: 10.1111/j.1600-0854.2004.0171.x.
32. Wei A, Yuan Y, Bai D, et al. NGS-based 100-gene panel of hypopigmentation identifies mutations in Chinese Hermansky-Pudlak syndrome patients[J]. Pigment Cell Melanoma Res, 2016, 29(6): 702-706. DOI: 10.1111/pcmr.12534.
33. Bastida JM, Morais S, Palma-Barqueros V, et al. Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing[J]. Ann Med, 2019, 51(2): 141-148. DOI: 10.1080/07853890.2019.1587498.
34. Chen C, Wang R, Yuan Y, et al. Clinical features and novel genetic variants associated with Hermansky-Pudlak syndrome[J/OL]. Genes(Basel), 2022, 13(7): 1283[2022-07-20]. https://pubmed.ncbi.nlm.nih.gov/35886065/. DOI: 10.3390/genes13071283.
35. Huizing M, Pederson B, Hess RA, et al. Clinical and cellular characterisation of Hermansky-Pudlak syndrome type 6[J]. J Med Genet, 2009, 46(12): 803-810. DOI: 10.1136/jmg.2008.065961.

Chinese Journal of Ocular Fundus Diseases

Latest ArticlesGenetic and phenotypic analysis of Hermansky-Pudlak syndrome type 6 family with a special platelet phenotype

Abstract Full text Figures/Tables Video References Cited by

Format

Content