Hermansky-Pudlak syndrome

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Classification according to ICD-10
E70.3 Albinism
Hermansky-Pudlak syndrome
ICD-10 online (WHO version 2019)

The Hermansky-Pudlak syndrome (HPS) is a rare genetic disease , which is the deposition of ceroid in the lysosomes , the melanocytes and the Serotoningranula (δ granules) of platelets is. The disease is characterized by albinism of the skin and conjunctiva, an increased tendency to bleed due to a disturbance in platelet aggregation and the occurrence of pulmonary fibrosis ( interstitial lung disease ).

The disease was first described by the Czech internists F. Hermansky and P. Pudlak in 1959 and named after these first authors.

Epidemiology

Hermansky-Pudlak syndrome is a very rare disease. Therefore, there is an overall lack of epidemiological data. The disease occurs sporadically worldwide. There is a geographical cluster of unexplained causes in northwest Puerto Rico . About 400 patients (prevalence 1: 1800) were reported here. Exact figures for the German-speaking area are not known.

Etiology and pathogenesis

There are some membrane-coated vesicles related to lysosomes that share the initial stages of their development. They include the following organelles :

Both the core symptoms and the rarer symptoms that can occur in connection with Hermansky-Pudlak syndrome are due to malfunctions in these vesicles, which are related to the lysosomes. Albinism is based on a malfunctioning synthesis of melanin in the melanosomes . The bleeding tendency arises from the fact that the platelets do not clump together during bleeding ( platelet aggregation ), a process in which the serotonous granules play a role. Pulmonary fibrosis is due to abnormal "lamellar bodies" in the alveolar cells. Some mouse models of Hermansky-Pudlak syndrome are excreted through the lysosomes. Defective cytotoxic granules cause impaired activity of the cytotoxic T lymphocytes . Mild neuronal ceroid lipofuscinosis is presumably due to impaired breakdown in the lysosomes.

BLOC

BLOC is an abbreviation for " b iogenesis of l ysosome-related o rganelles c omplex". This expression literally means "complex to build up organelles that are related to lysosomes".

BLOC1 consists of the HPS7 protein dysbindin, the HPS8 protein, pallidin , Muted, Cappuchino, Snapin, BLOS1 and BLOS2. There may be other previously unknown subunits. Mutations in the dysbindin and HPS8 genes are known to cause Hermansky-Pudlak syndrome in humans and mice. Mutations in the genes for pallidin, muted and cappuccino have only been shown to be the cause of the syndrome in mice. BLOC1 is used to build specialized organelles that belong to the endosomal-lysosomal system.

BLOC2 is made up of HPS3, HPS5 and HPS6. It assigns some of the proteins intended for the melanosomes in the early endosomes to the correct transport vesicles or plays a role in the fusion of these transport vesicles with the maturing melanosomes. When BLOC2 is not working, these proteins are not transported to the melanosomes. Instead, they move back and forth between the endosomes and the cell membrane and are eventually broken down.

To BLOC3 include HPS1 and HPS4. Only HPS1 of BLOC4 and BLOC5 is known as a component. BLOC3, BLOC4 and BLOC5 are found in the cell plasma and contribute to the formation of organelles such as melanosomes, lysosomes and the serotonous granules (δ-granules).

Adapter protein 3 (AP3)

The adapter protein-3 (AP3) is distributed in the cell plasma and transports proteins from the trans-Golgi network and the endosomal network to organelles that are related to lysosomes.

Overview of the different forms of Hermansky-Pudlak syndrome

syndrome Chromosome (gene location) Gene or protein name (alternative names) Protein complex to which it belongs
Hermansky-Pudlak syndrome type 1 Chromosome 10 (10q23.1-q23.3) HPS1 BLOC-3, BLOC4 and BLOC5.
Hermansky-Pudlak syndrome type 2 Chromosome 5 (5q14.1) HPS2 or AP3B1 AP3
Hermansky-Pudlak syndrome type 3 Chromosome 3 (3q24) HPS3 BLOC2
Hermansky-Pudlak syndrome type 4 Chromosome 22 (22q11.2-q12.2) HPS4 BLOC3
Hermansky-Pudlak syndrome type 5 Chromosome 11 (11p15-p13) HPS5 (homologue to Ruby-Eye-Gene 2 of the mouse (Ru2), KIAA1017, ALPHA-INTEGRIN-BINDING PROTEIN 63) BLOC2
Hermansky-Pudlak syndrome type 6 Chromosome 10 (10q24.32) HPS6 (homologue to the Ruby Eye gene of the mouse (Ru)) BLOC2
Hermansky-Pudlak syndrome type 7 Chromosome 6 (6p22.3) Dystrobrevin-binding protein 1 (DTNBP1, dysbindin, homologue to the Sandy gene of the mouse (Sdy)) BLOC1
Hermansky-Pudlak syndrome type 8 Chromosome 19 (19q13) HPS8, BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 3 (BLOC1S3, BLOC1, SUBUNIT 3; BLOS3, homologue to the mouse's reduced pigmentation gene (Rp)) BLOC1

therapy

There is currently no causal therapy. According to current studies, glucocorticoids have no influence on the course of the disease. Hermansky-Pudlak syndrome can therefore only be treated symptomatically. The course of the disease, especially the progression of pulmonary fibrosis, can be influenced by pulmonary risk factors, e.g. B. by smoking, can be negatively influenced. Prophylactic vaccinations can reduce the likelihood of complications, such as developing pneumonia. These include above all the pneumococcal and influenza vaccination (flu vaccination). Because of the impaired platelet function, platelet aggregation inhibitors are a relative contraindication .

See also

literature

  • V. Poletti et al .: Rare infiltrative lung diseases: a challenge for clinicians. In: Respiration. 2004 Sep-Oct; 71 (5), pp. 431-443 PMID 15467318 .
  • H. Burkhardt et al.: Unusual cause of pulmonary fibrosis in a 71-year-old patient. In: Medical Clinic. 2002; 97, pp. 165-169 (No. 3). doi : 10.1007 / s00063-002-1141-0
  • Harrison's internal medicine. 15th edition. ABW Wissenschaftsverlag, Berlin 2003, ISBN 3-936072-10-8 .

Individual evidence

  1. ^ F. Hermansky, P. Pudlak: Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow. In: Blood . 1959, 14, pp. 162-169.
  2. ↑ V. Shotelersuk et al.: Hermansky-Pudlak syndrome: models for intracellular vesicle formation. In: Mol Genet Metab. 1998; 65, pp. 85-96.
  3. ↑ a b c M. Starcevic, EC Dell'Angelica: Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3 / reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). In: J Biol Chem . 2004 Jul 2; 279 (27), pp. 28393-28401. Epub 2004 Apr 21. PMID 15102850 .
  4. ↑ a b c HPS8 Hermansky-Pudlak syndrome 8.  In: Online Mendelian Inheritance in Man . (English).
  5. ↑ a b c d HPS7 Hermansky-Pudlak syndrome 7.  In: Online Mendelian Inheritance in Man . (English).
  6. ↑ Amanda Helip-Wooley, Wendy Westbroek, Heidi M. Dorward, Amy Koshoffer, Marjan Huizing, Raymond E. Boissy, William A. Gahl: Improper Trafficking of Melanocyte-Specific Proteins in Hermansky-Pudlak Syndrome Type-5. In: J Invest Dermatol. 2007 Jun; 127 (6), pp. 1471-1478. Epub 2007 Feb 15. PMID 17301833 .
  7. ^ A b S. M. Di-Pietro, JM Falcón-Pérez, EC Dell'Angelica: Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6. In: Traffic. 2004 Apr; 5 (4), pp. 276-283. PMID 15030569 .
  8. ↑ a b c NCBI Entrez Gene HPS1 Hermansky-Pudlak syndrome 1 (Homo sapiens) GeneID: 3257.
  9. ↑ a b c HPS4 Hermansky-Pudlak syndrome 4.  In: Online Mendelian Inheritance in Man . (English).
  10. ↑ a b c d HPS2 Hermansky-Pudlak syndrome 2.  In: Online Mendelian Inheritance in Man . (English).
  11. ↑ a b HPS3 Hermansky-Pudlak syndrome 3.  In: Online Mendelian Inheritance in Man . (English).
  12. ↑ a b c d HPS5 Hermansky-Pudlak syndrome 5.  In: Online Mendelian Inheritance in Man . (English).
  13. ↑ a b c d HPS6 Hermansky-Pudlak syndrome 6.  In: Online Mendelian Inheritance in Man . (English).