Perturbations in specific steps during the formation, maturation and trafficking of melanosomes, may produce clinically recognizable phenotypes such as Hermansky-Pudlak Syndrome (HPS), CHS and GS (Table 3) (29).
Hermansky-Pudlak syndrome (MIM 203300) is a genetically heterogeneous group of related autosomal recessive conditions described in humans and mice. There are eight known human HPS genes causing different subtypes of HPS (HPS 1–8) and at least 14 murine HPS genes, eight of which are orthologous to the human genes (29). Defects in proteins encoded by these genes can affect the biogenesis and/or function of intracellular organelles found in specialized secretory cells such as pigment cells (melanocytes and retinal pigment epithelial cells), platelets, T cells, neutrophils and lung type II epithelial cells. The organelles affected by HPS genes belong to the family of organelles known as lysosome-related organelles (29).
HPS is a form of albinism with extrapigmentary disorders. The pigment phenotype of HPS patients is extremely variable and can range from a minimal to a severe reduction in skin, hair and ocular pigmentation. In general, there is no tanning response after sunlight exposure in these patients (6). While all HPS patients suffer from OCA and prolonged bleeding, different subtypes with distinguishing features have been recognized (Table 3) (29).
Mutations in two HPS genes namely HPS1 and HPS4 [murine orthologs are pale ear (ep) and light ear (le) respectively] cause the most common and most severe clinical subtypes, in which affected individuals have oculocutaneous albinism, prolonged bleeding (due to platelet storage pool deficiency) and can suffer morbidity from granulomatous colitis and premature mortality from pulmonary fibrosis (29).
The human HPS1 gene has been mapped on chromosome 10q23.1–q23.3. The most common HPS-1 mutation is found in Puerto Rican patients and is caused by a 16-bp frameshift duplication in exon 15 (29). HPS-1 protein is ubiquitous and primarily localized to the cytosol, with a small proportion being membrane-associated. It appears to play a role in regulating protein traffic targeted to the melanosome. In melanocytes derived from HPS-1 patients, immunostaining for tyrosinase, TYRP1 and TRP2/DCT produced a pattern with large vesicular structures in the cell body and dendrites, instead of a small granular pattern seen throughout the control cells (melanocytes from unaffected individuals) (47).
The HPS4 gene is located on chromosome 22q11.2-q12.2. As in other subtypes of HPS, HPS-4 patients have great variability in the degree of hypopigmentation, and may present with a severe phenotype, similar to that of HPS-1 patients (29).
The similarity in phenotypes between HPS-1 and HPS-4 subtypes and between ep and le mice is explained by the finding that intracellular HPS-1 and HPS-4 proteins associate together in a protein complex termed biogenesis of lysosome-related organelle complex (BLOC-3), as do the ep and le proteins (48). BLOC-3 complex regulates the biogenesis and/or function of the lung lamellar body as well as the platelet dense body and the melanosome (29).
A study in the ep mouse strain suggested that regulation of melanocytes differs in follicles versus interfollicular skin. Alternatively, melanocytes in different anatomic units (e.g. back versus tail) are differentially regulated. These findings underscore the role of HPS1 gene in influencing the developmental fate of melanocytes. They may also offer a possible explanation for the disassociation of pigment phenotype which is observed in people with dark hair but fair skin (49).
HPS-2 is caused by mutations in the AP3B1 gene encoding the β3A subunit of the heterotetrameric adaptor protein complex AP-3. AP-3 plays a role in mediating cargo protein selection into transport vesicles and in trafficking those membrane proteins to the lysosome (28,29). Τhe HPS-2 subtype may be clinically distinguished from the other forms of HPS, as it is unique in causing immunodeficiency and manifesting with neutropenia and susceptibility to recurrent respiratory illnesses. It may be differentiated from CHS, as large intracellular granules which are seen in CHS, are not present in HPS-2 (29).
The HPS-3, HPS-5 and HPS-6 subtypes are clinically similar. They may present with ocular albinism and bruising, but without pulmonary fibrosis or colitis.
The HPS3 gene is found on chromosome 3q24. HPS-3 protein associates with HPS-5 and HPS-6 proteins in a multimeric protein complex, BLOC-2. Immunofluorescent imaging of melanocytes derived from HPS-3 patients demonstrated that molecules normally targeted to later stage melanosomes (e.g. the melanogenic enzymes tyrosinase and Tyrp1) are mislocalized. By contrast, the steady-state distribution of molecules targeted to stage I melanosomes (e.g. silver/Pmel17/gp100 and melan-a/MART1) were found to be normal. DOPA staining detected melanogenic enzymatic activity in melanosomes, suggesting that melanogenic enzymes can accesss melanosomes via an HPS-3-independent pathway. In addition, it has been suggested that the lack of detected melanin in later stage melanosomes in HPS-3 cells is due to the limiting quantity of another (presumably mis-trafficked) molecule (29,50).
HPS-5, a rare type of HPS, results from mutations in HPS5 gene which is located on chromosome 11p14 (29). It encodes a cytoplasmic protein of unknown function that interacts with the HPS-6 protein (gene locus on chromosome 10q24.32) (28). All HPS-5 patients have been reported to have elevated cholesterol levels, with several having mildly elevated triglycerides as well. The significance of these elevated lipid levels and whether they are a result of an underlying membrane trafficking defect, is not known (29).
The DTNBP1 gene which is defective in HPS-7 is located on chromosome 6p22.3 and encodes the dysbindin protein. A single patient reported with HPS-7, presented with oculocutaneous albinism, easy bruisability, bleeding tendency and a decreased lung compliance (29). Finally, in patients with HPS-8, the defective gene is BLOC1S3. Patients present with OCA and mild platelet dysfunction with easy bruising, epistaxis and a bleeding tendency (29).
Chediak-Higashi syndrome (MIM 214500) is a rare autosomal recessive disorder characterized by OCA (extensive depigmentation of skin, hair and eyes) and a silvery sheen to the hair. It is also characterized by a bleeding tendency, progressive primary neurological impairment and severe immune deficiency due to lack of natural killer cell function, resulting in recurrent pyogenic infection. Additionally, it causes a severe haemophagocytic lymphoproliferative syndrome caused by uncontrolled T-cell and macrophage activation. CHS is characterized by massive cytoplasmic lysosomal and non-lysosomal inclusions in granule containing cells, which are probably responsible for most of the impaired functions in CHS cells. Melanocytes containing giant melanosomes seem to account for the hypopigmentation (6). Most cases are fatal unless treated by bone marrow transplantation (28).
Chediak-Higashi syndrome has been linked to the human gene CHS1/LYST, which is homologous to the beige locus in mouse and is located on chromosome 1q43 (6,51). The CHS1 protein is predicted to be a cytosolic protein with a role in vesicular transport. It is similar to HSP proteins, since the presence of giant granules within various vesicles such as lysosomes, melanosomes, cytosolic granules and platelet dense bodies is also observed in various cells of CHS patients (4).
Griscelli syndrome is a rare autosomal recessive disorder characterized by pigmentary dilution of the skin, a silver-grey sheen of the hair, large clumps of pigment within hair shafts and the accumulation of large and abnormal end-stage melanosomes in the centre of melanocytes (52). The disease has been linked with defects of the Rab27a-Mlph-MyoVA protein complex formation in melanocytes, which is important to keep melanosomes connected to the actin network (52).
Patients with GS can be categorized in 3 types. Type 1 (GS1-MIM214450) is manifested with albinism, and severe primary neurological impairment, with developmental delay and mental retardation. It has been attributed to mutations of the myosin 5A gene (MYO5A) which encodes an organelle motor protein, myosin VA (53).
Griscelli syndrome-Type 2 (GS2-MIM 607624) presents with albinism and is associated with potentially lethal immune defects and a haemophagocytic syndrome. Bone marrow transplantation is the only curative treatment. GS2 is caused by mutations in RAB27A which encodes a small GTPase protein (Rab27a), involved in the function of the intracellular-regulated secretory pathway (53).
Griscelli syndrome 3 results from mutation in the gene that encodes melanophilin (MLPH). Unlike GS1 and GS2, GS3 has only dermatological manifestations (4). Deletion of MYO5AF exon may result in an identical phenotype without neurological manifestations.