DiagnosisClinical DiagnosisThe diagnosis of Hermansky-Pudlak syndrome (HPS) is established by clinical findings of oculocutaneous albinism in combination with a bleeding diathesis of variable severity [Gahl et al 1998, Huizing et al 2008]. The diagnosis of oculocutaneous albinism is established by finding hypopigmentation of the skin and hair on physical examination associated with the following characteristic ocular findings:Nystagmus Reduced iris pigment with iris transillumination Reduced retinal pigment on fundoscopic examination Foveal hypoplasia associated with significant reduction in visual acuity Increased crossing of the optic nerve fibers [King et al 2001] TestingAbsence of platelet dense bodies. Currently, the sine qua non for diagnosis of HPS is absence of dense bodies on whole mount electron microscopy of platelets [Witkop et al 1987]. Upon stimulation of platelets, the dense bodies, which contain ADP, ATP, serotonin, calcium, and phosphate, release their contents to attract other platelets. This process constitutes the secondary aggregation response, which cannot occur in the absence of the dense bodies. There are normally four to eight dense bodies per platelet; there are none in the platelets of individuals with HPS. Coagulation studies The secondary aggregation response of platelets is impaired.Bleeding time is generally prolonged. Coagulation factor activity and platelet counts are normal. Ceroid lipofuscin. The demonstration of a yellow, autofluorescent, amorphous lipid-protein complex, called ceroid lipofuscin, in urinary sediment and parenchymal cells is characteristic of HPS; however, this laboratory finding is virtually never used in diagnosis. Molecular Genetic TestingGenes. The genes in which mutations are known to cause HPS are HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, and BLOC1S6. Evidence for locus heterogeneity. Most likely, mutations in other genes also result in HPS. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in HPSView in own windowGene Symbol
(HPS Subtype)Proportion of HPS Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityPuerto RicanNon-Puerto RicanHPS1(HPS-1)~75% ¹ 0%Targeted mutation analysisc.1470_1486dup CCAGCAGGGGAGGCCC (16-bp duplication) ^{2Clinical45% 3Sequence analysisSequence variants 4AP3B1(HPS-2)0 ~10% 5Sequence analysisSequence variants 4Clinical~1% Deletion / duplication analysis 6Exonic or whole-gene deletions 7HPS3(HPS-3)0~13% 8Sequence analysisSequence variants 4Clinical25% 0% Deletion / duplication analysis 6Exonic or whole-gene deletions 9 HPS4(HPS-4)0~12% 10Sequence analysisSequence variants 4ClinicalHPS5(HPS-5)0~9% 11Sequence analysisSequence variants 4ClinicalHPS6(HPS-6)0 ~7% 12Sequence analysisSequence variants 4ClinicalDeletion / duplication analysis 6Exonic or whole-gene deletions 13DTNBP1(HPS-7)0~1% 14Sequence analysisSequence variants 4ClinicalBLOC1S3(HPS-8)01% 15Sequence analysisSequence variants 4ClinicalBLOC1S6(HPS-9)0Only 2 patients reported 16Sequence analysisSequence variants 4Clinical Deletion / duplication analysis 6Unknown, none reported6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.1. Homozygosity for a 16-bp duplication is found in approximately 75% of all affected individuals of Puerto Rican ancestry [Santiago Borrero et al 2006] and in most affected individuals from northwestern Puerto Rico [Oh et al 1996, Huizing et al 2008]. Three Puerto Rican individuals with HPS-1 were compound heterozygotes for the 16-bp duplication and a second HPS1 mutation [Carmona-Rivera et al 2011b].2. To date, the 16-bp duplication has been found exclusively in affected individuals of Puerto Rican ancestry. 3. HPS1 is mutated in approximately 50% of affected non-Puerto Ricans, including Japanese, Indian, Swiss, and African Americans [Oh et al 1996, Oh et al 1998, Shotelersuk & Gahl 1998, Shotelersuk et al 1998, Oetting & King 1999, Hermos et al 2002, Huizing & Gahl 2002, Ito et al 2005, Merideth et al 2009, Vincent et al 2009]. Homozygotes as well as compound heterozygotes for HPS1 mutations have been identified. Several non-Puerto Rican Hispanic individuals have been reported with HPS1 mutations [Carmona-Rivera et al 2011a].4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.5. Mutations in AP3B1 have been identified in at least 12 individuals: two adult brothers [Dell'Angelica et al 1999], a boy age six years [Huizing et al 2002], another child [Clark et al 2003], two sibs with consanguineous Turkish parents [Jung et al 2006], two Italian sibs [Fontana et al 2006], a child originally diagnosed with Griscelli syndrome [Enders et al 2006], and three unrelated individuals with typical findings of HPS-2 [Chiang et al 2010, Wenham et al 2010].7. A deletion of 8 kb has been reported [Jung et al 2006].8. Sequence analysis of individuals known to have HPS is expected to identify mutations in HPS3 about 15% of the time. In addition to novel mutations, sequence analysis will identify individuals with HPS who are of Ashkenazi Jewish background with the c.1303+1G>A splice site mutation [Huizing et al 2001a]. Of six individuals with this mutation, four were homozygotes and two were compound heterozygotes.9. Homozygosity for g.339_4260del3904, (also referred to as the 3.9-kb deletion) has been identified in affected individuals of Puerto Rican ancestry only [Anikster et al 2001]. Newborn screening of 12% of the Puerto Rican population detected two homozygotes and 73 heterozygotes [Torres-Serrant et al 2010].10. Mutations in HPS4 have been reported in 16 affected individuals [Suzuki et al 2002, Anderson et al 2003], including a Sri Lankan [Bachli et al 2004] and a Uruguayan [Carmona-Rivera et al 2011a].11. Mutations in HPS5 have been found in eight individuals, including a Turkish boy age three years [Zhang et al 2003], sisters of Swiss extraction age 51 and 43 years [Huizing et al 2004], a woman of English and Irish background age 21 years [Huizing et al 2004], a boy of English, Irish, Dutch, and Swedish background age ten years [Huizing et al 2004], a Turkish woman age 38 years [Korswagen et al 2008], a Mexican boy age eight months [Carmona-Rivera et al 2011a], and a Cuban-Venezuelan boy age three years [Carmona-Rivera et al 2011a].12. Five individuals with eight different mutations in HPS6 have been reported [Zhang et al 2003, Huizing et al 2009], in addition to an Israeli Bedouin family with a homozygous founder frameshift mutation [Schreyer-Shafir et al 2006]. 13. One large ~20kb deletion has been identified in one patient with HPS-6 [Huizing et al 2009].14. About 1% of individuals with HPS have mutations in DTNBP1. A homozygous nonsense mutation in DTNBP1 has been reported in a single person, a Portuguese woman age 48 years with HPS-7 [Li et al 2003].15. A family in Britain was identified with a homozygous frameshift mutation in BLOC1S3 [Morgan et al 2006], and an Iranian boy age six years with a homozygous nonsense mutation has been described [Cullinane et al 2012]. 16. A homozygous nonsense mutation in BLOC1S6 was identified in a male of Indian descent age nine months [Cullinane et al 2011] and in an Italian female age 17 years [Badolato et al 2012].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband presumably manifesting signs of oculocutaneous albinism and bleeding:Electron microscopy (preferably “whole mount” as opposed to transmission) of platelets to show absent dense bodies should be performed to confirm the diagnosis of HPS. In a person of northwest Puerto Rican ancestry, the HPS1 founder mutation should be pursued next. In a person of central Puerto Rican or Ashkenazi Jewish ancestry, the HPS3 founder mutations should be investigated. For other individuals, the order of testing can depend on the severity of clinical findings; visual acuity provides a rough measure of severity: Severely affected individuals can be tested for HPS1 and HPS4 mutations initially.Mildly affected individuals can be tested for HPS3, HPS5, or HPS6 mutations. If an affected individual had neutropenia or infections as a child, testing of AP3B1 (HPS-2) should be considered. If the above HPS-associated gene testing does not identify two disease causing mutations in trans in the same gene, testing for mutations in DTNBP1 (HPS-7), BLOC1S3 (HPS-8), and BLOC1S6 (PLDN) (HPS-9) should be considered.
Protein analysis. If fibroblasts are available, immunoblotting of cell extracts with antibodies against one of the subunits of each of the four HPS protein complexes can identify which complex is deficient [Nazarian et al 2008] (see Molecular Genetic Pathogenesis).Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be caused by mutations in HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, or BLOC1S6 (PLDN).}

Natural HistoryThe clinical characteristics of Hermansky-Pudlak syndrome (HPS) consist of oculocutaneous albinism, a bleeding diathesis, a platelet storage pool deficiency, and other organ involvement [Huizing et al 2001b, Huizing & Gahl 2002, Huizing et al 2008]. Signs and symptoms of oculocutaneous albinism in HPS are variable but visual acuity generally remains stable. Eyes. Nearly all children with the albinism of HPS have nystagmus at birth, often noticed by the parents in the delivery room and by the examining physician. Children with HPS may also have periodic alternating nystagmus [Gradstein et al 2005], wandering eye movements, and lack of visual attention. The initial diagnosis of albinism is sometimes made by the ophthalmologist. The nystagmus can be very fast early in life, and generally slows with time, but nearly all individuals with albinism have nystagmus throughout their lives. The development of pigment in the iris or retina does not affect the nystagmus. Nystagmus is most noticeable when an individual is tired or anxious, and less marked when s/he is well rested and relaxed.Photophobia may accompany severe foveal hypoplasia. Iris color may remain blue or change to a green/hazel or brown/tan color. Globe transillumination can be complete or can show peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina. Visual acuity, usually between 20/50 and 20/400, is typically 20/200 and usually remains constant after early childhood [Iwata et al 2000]. Alternating strabismus is found in many individuals with albinism and is generally not associated with the development of amblyopia. Skin/hair. The hair color ranges from white to brown, and can occasionally darken with age. Skin color can be white to olive, but is generally at least a shade lighter than that of other family members. Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare.Affected Puerto Ricans typically have solar damage manifesting as actinic keratoses and nevi. Ephelids, lentigines, and basal cell carcinoma also occur with increased frequency among Puerto Ricans with HPS [Toro et al 1999]. Bleeding diathesis. The bleeding diathesis of HPS results from absent or severely deficient dense granules in platelets; the alpha granule contingent is normal [Huizing et al 2007]. Affected individuals experience variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding during menstruation or after tooth extraction, circumcision, or other surgeries. Typically, cuts bleed longer than usual but heal normally. Bruising generally first appears at the time of ambulation. Epistaxis occurs in childhood and diminishes after adolescence. Menstrual cycles may be heavy and irregular. Prolonged bleeding after tooth extraction can lead to the diagnosis of HPS. Affected individuals with colitis may bleed excessively per rectum. Exsanguination as a complication of childbirth, trauma, or surgery is extremely rare. Pulmonary fibrosis. The pulmonary fibrosis of HPS typically causes symptoms in the thirties and is usually fatal within a decade. The pulmonary fibrosis has been described largely in individuals with HPS-1 from northwestern Puerto Rico [Brantly et al 2000, Avila et al 2002], but also occurs in other individuals with HPS-1 [Brantly et al 2000, Hermos et al 2002] or HPS-4 [Anderson et al 2003, Bachli et al 2004] or HPS-2 [Gochuico et al 2012]. To date, convincing evidence of pulmonary fibrosis has not been reported for HPS-3, HPS-5, or HPS-6. The fibrosis consists of progressive, restrictive lung disease with an extremely variable time course [Gahl et al 1998, Brantly et al 2000, Gahl et al 2002]. Colitis. A bleeding granulomatous colitis resembling Crohn's disease presents, on average, at age 15 years, with wide variability [Gahl et al 1998]. The colitis is severe in 15% of cases and occasionally requires colectomy; affected individuals may have the inflammatory bowel disease of HPS without the explicit diagnosis of colitis. Objective signs of colitis have been found primarily in persons with HPS-1 or HPS-4 [Hussain et al 2006]. Although the colon is primarily involved in HPS, any part of the alimentary tract, including the gingiva, can be affected. Other. Cardiomyopathy and renal failure have also been reported in HPS [Witkop et al 1989]. Neutropenia and/or immune defects have been associated with HPS-2 [Shotelersuk et al 2000, Huizing & Gahl 2002, Clark et al 2003, Fontana et al 2006].Pathogenesis. The mechanism of pulmonary fibrosis, granulomatous colitis, cardiomyopathy, and renal failure remains unknown.

Genotype-Phenotype CorrelationsCorrelations between specific HPS-causing mutations in any one gene and particular clinical presentations are not convincing. However, individuals with mutations in the same HPS protein complex exhibit similar clinical characteristics [Huizing et al 2008]. Those complexes are described in Molecular Genetic Pathogenesis. Molecular subtyping in HPS is important for prognosis with respect to the occurrence of pulmonary fibrosis [Huizing et al 2008, Thielen et al 2010]. The lethal pulmonary fibrosis of HPS is associated with defects in BLOC-3 (HPS-1 and HPS-4), as demonstrated in Puerto Ricans homozygous for the c.1470_1486dup16 mutation in HPS1 [Gahl et al 1998], in an Irish individual with HPS1 mutations [Brantly et al 2000] and in Sri Lankan [Bachli et al 2004] and eastern European [Anderson et al 2003] individuals with HPS4 mutations. Pulmonary fibrosis has also been associated with AP-3 defects. At least three of the dozen known individuals with HPS-2 have documented interstitial lung disease [Gochuico et al 2012]. Pulmonary fibrosis has not been reported in studies of individuals with HPS-3 [Huizing et al 2001a], HPS-5 [Huizing et al 2007], HPS-6 [Huizing et al 2009], HPS-7, HPS-8 [Morgan et al 2006, Cullinane et al 2012], or HPS-9 [Cullinane et al 2011, Badolato et al 2012].Two brothers and a six-year-old boy with compound heterozygosity for AP3B1 mutations had typical HPS but also persistent neutropenia and an increased frequency of infections in childhood [Shotelersuk et al 2000, Huizing & Gahl 2002]. No clinical information is available on a fourth individual with AP3B1 mutations [Clark et al 2003]. A boy age two years diagnosed with HPS-2 had fatal hemophagocytic lymphohistiocytosis [Enders et al 2006], and two Italian sibs had an immune defect involving abnormal natural killer cell function [Fontana et al 2006]. Two Turkish sibs with HPS-2 manifested developmental delay and dysmorphic features, but consanguinity was also involved [Jung et al 2006]. A Hispanic boy with HPS-2 has also been described [Chiang et al 2010]. Individuals with HPS3 mutations have milder symptoms than those with HPS1 mutations [Huizing et al 2001a]. The albinism in HPS-3 is characterized by such minimal hypopigmentation that some individuals have carried the diagnosis of ocular albinism rather than oculocutaneous albinism. Visual acuity often approximates 20/100 or better. Bleeding is also mild and pulmonary involvement has not been observed. Significant granulomatous colitis occurs primarily in HPS-1 and HPS-4 [Hussain et al 2006]. The severity of clinical symptoms does not appear to correlate with the severity of the molecular defect.The variability and severity of oculocutaneous albinism and bleeding diathesis found in HPS-4 are similar to those of HPS-1 [Suzuki et al 2002, Anderson et al 2003]. No correlation has been found between the severity of symptoms and specific mutations. HPS-5 and HPS-6 resemble HPS-3 in their mildness and lack of pulmonary disease. It is difficult to discern the severity of HPS-7, HPS-8, or HPS-9 based on the single cases reported for each.There is insufficient information to know if the HPS-7, HPS-8 and HPS-9 subtypes are prone to complications besides albinism and a bleeding diathesis.

Differential DiagnosisAlbinism. The diagnosis of Hermansky-Pudlak syndrome (HPS) should be considered in anyone with oculocutaneous albinism or ocular albinism, as the bleeding diathesis can be mild, unrecognized, or previously disregarded. Some would advocate screening all individuals with albinism for HPS by examining their platelets for absent dense bodies. Disorders with albinism included in the differential diagnosis: Oculocutaneous albinism type 1 (OCA1) is caused by mutations in TYR. Ocular findings include nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity usually in the range of 20/100 to 20/400, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irises that do not darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens with age, white skin that over time develops some generalized pigment and may tan with sun exposure, and blue irises that change to green/hazel or brown/tan with age. Visual acuity may be 20/60 or better in some individuals. Oculocutaneous albinism type 2 (OCA2) is caused by mutations in OCA2. Affected individuals usually have pigmented hair at birth and usually do not tan later in life, but some have been identified who have white hair at birth. They may develop pigmented nevi and freckles, but the skin does not develop generalized pigment. The irises usually develop some pigment that can be seen by the hazel/green to tan/brown color or by globe transillumination. Oculocutaneous albinism type 4 (OCA4) is caused by mutation in SLC45A2 (also known as MAPT, membrane-associated transporter protein). OCA4 was initially identified in one male of Turkish origin. Studies now suggest that this is the second most common type of OCA in Japanese individuals. The phenotype is similar to that of OCA2 in individuals of northern European origin. X-linked ocular albinism (XLOA) is caused by mutations in GPR143. Affected males have congenital and persistent visual impairment. XLOA is characterized by congenital nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. Skin and hair pigment are normal. Disorders of platelet dense bodies. Reviewed in Gunay-Aygun et al [2004], these disorders include the following: Chediak-Higashi syndrome (CHS). Affected individuals have a significantly increased frequency of infection in childhood, mild oculocutaneous albinism, and a bleeding diathesis [Introne et al 1999]. This entity is characterized by huge, fused, dysfunctional lysosomes and macromelanosomes. Individuals with CHS always have giant intracellular granules in their neutrophils on a peripheral blood smear; individuals with HPS never exhibit this finding. Persons with CHS also frequently develop fatal lymphohistiocytosis or the accelerated phase of CHS, a finding that has been reported in a single person with HPS (HPS-2) [Enders et al 2006]. Without bone marrow transplantation, individuals with classic Chediak-Higashi syndrome die in childhood. Griscelli syndrome. Affected individuals have mild hypopigmentation and immunodeficiency and can have the accelerated phase of lymphohistiocytosis. A distinguishing finding is silvery-gray hair.
Note: Elejalde syndrome is now considered to be a type of Griscelli syndrome in which neurologic involvement, rather than immunodeficiency and lymphohistiocytosis, occurs.Cross syndrome [Huizing et al 2000b]. Affected individuals have hypopigmentation, ocular anomalies, and severe central nervous system involvement with developmental delay; the latter findings are not part of Hermansky-Pudlak syndrome. Pulmonary fibrosis. Individuals with familial pulmonary fibrosis or with idiopathic pulmonary fibrosis do not have hypopigmentation, visual defects, or a bleeding diathesis; the only feature shared with HPS is a diathesis toward interstitial lung disease. Lymphohistiocytosis. See Familial Hemophagocytic Lymphohistiocytosis and X-Linked Lymphoproliferative Disease (XLP). Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Hermansky-Pudlak syndrome (HPS), the following are recommended:Complete ophthalmologic evaluation Skin examination for severity of hypopigmentation and, after infancy, for evidence of skin damage and skin cancer History of bleeding problems and symptoms suggesting pulmonary fibrosis and/or colitis. For evaluation for lung fibrosis, pulmonary function tests (PFTs) should be performed in individuals older than age 20 years. Medical genetics consultationTreatment of ManifestationsEyes The majority of individuals with albinism have significant hyperopia (far-sightedness) or myopia (near-sightedness), and astigmatism. Correction of these refractive errors can improve visual acuity. Strabismus surgery is usually not required but can be performed for cosmetic purposes, particularly if the strabismus is marked or fixed. The surgery is not always successful. Aids such as hand-held magnifying devices or bioptic lenses are helpful adjuncts in the care of visually impaired individuals with HPS. Preferential seating in school is beneficial, and a vision consultant may be useful. Skin. Treatment of skin cancer does not differ from that in the general population. BleedingHumidifiers may reduce the frequency of nosebleeds.Oral contraceptives can limit the duration of menstrual periods. Menorrhagia has been treated with a levonorgestrel-releasing intrauterine system [Kingman et al 2004] and with recombinant factor VIIa [Lohse et al 2011]. Treatment of minor cuts includes placing thrombin-soaked Gelfoam® over an open wound that fails to clot spontaneously. For more invasive trauma, such as wisdom tooth extraction, DDAVP (1-desamino-8-D-arginine vasopressin, 0.2 µg/kg in 50 mL of normal saline) can be given as a 30-minute intravenous infusion just prior to the procedure. The use of DDAVP may or may not improve the bleeding time [Cordova et al 2005]. For extensive surgeries or protracted bleeding, platelet or red blood cell transfusions may be required. Pulmonary fibrosis When the pulmonary disease becomes severe, oxygen therapy can be palliative. One individual with HPS-1 remains well after undergoing lung transplantation [Lederer et al 2005]. The authors know of several additional successful lung transplantations [Author, personal communication]. Colitis. The granulomatous colitis of HPS resembles Crohn's colitis and, as such, may respond to steroids and other anti-inflammatory agents [Mora & Wolfsohn 2011]. Remicade® has also been used with benefit [Erzin et al 2006, Felipez et al 2010]. Prevention of Secondary ComplicationsSkin. Skin care in HPS is dictated by the amount of pigment in the skin and the cutaneous response to sunlight. Protection from the sun should be provided to prevent burning, other skin damage, and skin cancer. In very sensitive individuals, sun exposure as short as five to ten minutes can be significant, while exposure of 30 minutes or more is usually significant in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, and socks). For extremely sun-sensitive individuals, sun screens with a high SPF value (total blocks with SPF 45-50+) are appropriate; for less sun-sensitive individuals, sun screens with SPF values of 15 or above can be used. Bleeding. Individuals with HPS should consider obtaining a medical alert bracelet that explicitly describes the functional platelet defect, as the standard tests for bleeding dysfunction (platelet count, prothrombin time, partial thromboplastin time) are normal in HPS. Pulmonary fibrosis. Prior to the development of pulmonary fibrosis, attention should be paid to maximizing pulmonary function. This entails avoidance of cigarette smoke, prompt treatment of pulmonary infections, immunization with influenza and pneumococcal vaccines, and regular moderate exercise. SurveillanceEyes. Annual ophthalmologic examination, including assessment of refractive error, is indicated. Skin. Over many years, exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Although skin melanocytes are present in individuals with HPS, melanoma is rare. Examination for these findings should be performed at least annually. Pulmonary fibrosis. Pulmonary function testing should be performed annually in adults. Colitis. Colitis is suspected in those with a history of cramping, increased mucus in the stool, and rectal bleeding; colonoscopy is used to confirm the diagnosis. Agents/Circumstances to AvoidBleeding. All aspirin-containing products as well as activities that could involve the risk of a bleeding episode should be avoided. Pulmonary fibrosis. Cigarette smoking decreases pulmonary function and may worsen progression of pulmonary fibrosis. Evaluation of Relatives at RiskIn individuals with HPS-1 and HPS-4, the diagnosis of HPS will be apparent because the hypopigmentation and nystagmus are clinically evident.In rare families with the milder types (HPS-3, HPS-5, or HPS-6), the evaluation of apparently unaffected sibs may yield a positive diagnosis. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Pregnancies should proceed normally for an affected mother or an affected fetus. Delivery, however, carries risk for bleeding in a woman with HPS; surveillance and a hematology consultation for anticipation of bleeding complications during delivery should be initiated once pregnancy is confirmed.Therapies Under InvestigationInitial studies suggest a salutary effect on pulmonary function of the investigational drug pirfenidone in affected individuals with pulmonary function greater than 50% of normal [Gahl et al 2002]. A follow-up clinical trial was unable to confirm this finding, but also did not refute it [O’Brien et al 2011].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherIn general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because they reduce vision.No successful therapy for or prophylaxis against the pulmonary fibrosis of HPS exists. Steroids are often tried but have no apparent beneficial effect.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hermansky-Pudlak Syndrome: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHPS1HPS110q24​.2Hermansky-Pudlak syndrome 1 proteinAlbinism Database Mutations of the Hermansky-Pudlak Syndrome-1 gene (HPS1)
Retina International Mutations of the ep-Gene (HPS1)
Hermansky-Pudlak Syndrome DatabaseHPS1HPS2AP3B15q14​.1AP-3 complex subunit beta-1Albinism Database Mutations of the b3A subunit of the AP-3 complex gene
Resource of Asian Primary Immunodeficiency Diseases (RAPID)
Retina International Mutations of the Adaptin b3a Gene (ADTB3A)
Hermansky-Pudlak Syndrome Database
AP3B1 homepage - Mendelian genesAP3B1HPS3HPS33q24Hermansky-Pudlak syndrome 3 proteinAlbinism Database Mutations of the Hermansky-Pudlak Syndrome-3 gene (HPS3)
Retina International Mutations of the HPS3 Gene
Hermansky-Pudlak Syndrome Database
HPS3 homepage - Mendelian genesHPS3HPS4HPS422q12​.1Hermansky-Pudlak syndrome 4 proteinRetina International Mutations of the Human light ear Gene (le, HPS4)
Hermansky-Pudlak Syndrome Database
HPS4 homepage - Mendelian genesHPS4HPS5HPS511p15​.1Hermansky-Pudlak syndrome 5 proteinHermansky-Pudlak Syndrome Database
HPS5 homepage - Mendelian genesHPS5HPS6HPS610q24​.32Hermansky-Pudlak syndrome 6 proteinHermansky-Pudlak Syndrome Database
HPS6 homepage - Mendelian genesHPS6HPS7DTNBP16p22​.3DysbindinHermansky-Pudlak Syndrome Database
DTNBP1 homepage - Mendelian genesDTNBP1HPS8BLOC1S319q13​.32Biogenesis of lysosome-related organelles complex 1 subunit 3Hermansky-Pudlak Syndrome Database
BLOC1S3 homepage - Mendelian genesBLOC1S3HPS9BLOC1S615q21​.1PallidinHermansky-Pudlak Syndrome Database
BLOC1S6 homepage - Mendelian genesBLOC1S6Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hermansky-Pudlak Syndrome (View All in OMIM) View in own window 203300HERMANSKY-PUDLAK SYNDROME 1; HPS1 603401ADAPTOR-RELATED PROTEIN COMPLEX 3, BETA-1 SUBUNIT; AP3B1 604310BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 6; BLOC1S6 604982HPS1 GENE; HPS1 606118HPS3 GENE; HPS3 606682HPS4 GENE; HPS4 607145DYSTROBREVIN-BINDING PROTEIN 1; DTNBP1 607521HPS5 GENE; HPS5 607522HPS6 GENE; HPS6 608233HERMANSKY-PUDLAK SYNDROME 2; HPS2 609762BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 3; BLOC1S3 614072HERMANSKY-PUDLAK SYNDROME 3; HPS3 614073HERMANSKY-PUDLAK SYNDROME 4; HPS4 614074HERMANSKY-PUDLAK SYNDROME 5; HPS5 614075HERMANSKY-PUDLAK SYNDROME 6; HPS6 614076HERMANSKY-PUDLAK SYNDROME 7; HPS7 614077HERMANSKY-PUDLAK SYNDROME 8; HPS8 614171HERMANSKY-PUDLAK SYNDROME 9; HPS9Molecular Genetic PathogenesisThe proteins encoded by the nine genes in which mutations are known to cause HPS associate into four HPS protein complexes, which are involved in intracellular vesicle formation and trafficking. The four complexes include:AP-3, with a subunit encoded by AP3B1 that is defective in HPS-2 [Dell’Angelica et al 1999, Huizing et al 2002];Biogenesis of lysosome-related organelles complex-1 (BLOC-1) that includes protein products of DTNBP1 [Li et al 2003], BLOC1S3 [Morgan et al 2006, Cullinane et al 2012], and BLOC1S6 (PLDN) [Cullinane et al 2011], which are defective in HPS-7, HPS-8, and HPS-9, respectively; BLOC-2 that includes subunits encoded by HPS3, HPS5, and HPS6; andBLOC-3 that includes subunits encoded by HPS1 and HPS4. HPS1 Normal allelic variants. Normal HPS1 (formerly known as HPS) is 30.5 kb in length and has 20 exons coding for a cDNA of 2100 bp [Oh et al 1996, Bailin et al 1997]. Four alternative splicing events have been described, including a common splice removing 99 bp of exon 9 [Wildenberg et al 1998]; this protein product lacks amino acids 257-289. A rare splicing event adds 43 nucleotides of the donor site of intron 6 and results in a frameshift. Two other splicing events can occur in untranslated regions of the HPS1 transcript. On northern blot analysis, the main transcript is 3.0 kb, but minor 3.9-kb and 4.4-kb species appear as well. A 1.5-kb transcript with the same 5' sequence as the published cDNA but with a different 3' sequence has been reported in bone marrow and melanoma cells. Eighteen non-pathologic benign variants have been reported, including four that change amino acids (p.Gly283Trp, p.Pro491Arg, p.Arg603Gln, p.Val630Ile). See Table 2. [Shotelersuk & Gahl 1998]. A partial pseudogene of HPS1 exists [Huizing et al 2000a]. Pathologic allelic variants. At least 24 distinct mutations in HPS1 have been reported [Oh et al 1996, Oh et al 1998, Shotelersuk & Gahl 1998, Shotelersuk et al 1998, Oetting & King 1999, Hermos et al 2002, González-Conejero et al 2003, Griffin et al 2005, Ito et al 2005, Iwakawa et al 2005]. All except four – p.Ile56del, p.Leu239Pro, p.Leu668Pro, and c.398+5G>A – result in a truncated protein. Among the pathologic mutations, founder effects have been reported for the c.1470_1486dup16 duplication in exon 15 (in northwestern Puerto Rico), for the p.Met325Hisfs*128 mutation (in a Swiss Alpine village), and for c.398+5G>A, a splicing mutation in affected Japanese and Indian [Vincent et al 2009] individuals. Otherwise, the most common reported mutations among non-Puerto Ricans involve the insertion or deletion of a C nucleotide in a repeat tract of eight Cs. Following the convention that the most 3' change in a nucleotide repeat is arbitrarily assigned to be the one that is changed, these mutations are p.Met325Hisfs*128 and p.Met325Trpfs*6. Both mutations are frameshifts that predict a new translational stop codon at amino acids 453 and 331, respectively. The tract of eight C nucleotides in this region is an apparent hot spot for mutation. Multiple other intragenic specific deletions and insertions have been reported. Other pathologic mutations are listed in Table 2.Table 2.Selected HPS1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change
(Alias ¹)Reference SequencesNormalc.847G>Tp.Gly283TrpNM_000195​.2
NP_000186​.2c.1472C>Gp.Pro491Argc.1808G>Ap.Arg603Glnc.1888G>Ap.Val630IlePathologicc.166_168delATC
(369-371delATC)p.Ile56del
(p.Ile55del)c.288delT
(494delT)p.Asp97Thrfs*27c.355delC
(561delC)p.His119Thrfs*5c.391C>Tp.Arg131Xc.397G>Tp.Glu133Xc.398+5G>A
(c.644+5G>A)
(IVS5+5G>A)--c.418delG
(624delG)p.Ala140Argfs*35c.532dupC
(178insC)p.Gln178Profs*4c.716T>Cp.Leu239Proc.962delG
(1168delG)p.Gly321Alafs*10c.972delC
(T322delC)p.Met325Trpfs*6
(p.324Profs*330)c.972dupC
(T322insC)p.Met325Hisfs*128
(p.His325Profs*452)c.1189delC
(1395delC)p.Gln397Serfs*2c.1323dupA
(1528-1529insA)p.Gln442Thrfs*11c.1375delA
(1581delA)p.Ser459Valfs*16c.1470_1486dup16 or
c.1470_1486dupCCAGCAGGGGAGGCCC
(16-bp duplication)p.His497Profs*24c.1691delAp.Lys564Argfs*22c.1744-2A>C
(c.1990-2A>C)
(IVS17-2A>C)--c.1749G>Ap.Trp583Xc.1996G>Tp.Glu666Xc.2003T>Cp.Leu668Proc.932delG
(1178delG)p.Ser311Thrfs*20c.532dupC
(532insC)p.Gln178Profs*4c.974_975insC
(insC974)p.Met325Ilefs*128See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. The protein product of HPS1 is a 700-amino acid peptide with a predicted molecular weight of 79.3 kd and without homology to other proteins. It has two potential N-linked glycosylation sites (residues 528 and 560) and a possible melanosomal localization signal, PLL, at the carboxy terminus. Although two transmembrane domains (at residues 79-95 and 369-396) have been proposed to exist, the protein is largely cytosolic in location, with a slight portion associating with membranes [Dell'Angelica et al 2000, Oh et al 2000]. The function of the protein remains unknown; it is likely involved in vesicle formation or trafficking [Huizing et al 2001c, Sarangarajan et al 2001]. Cellular and biochemical evidence indicates that HPS1 gene product interacts with the HPS4 protein in biogenesis of lysosome-related organelles complex-3 (BLOC-3) [Suzuki et al 2002, Chiang et al 2003, Martina et al 2003, Nazarian et al 2003]. Abnormal gene product. The mutant alleles of HPS1 are generally predicted to produce truncated, dysfunctional proteins. Further understanding of the abnormal gene products awaits determination of the function of the normal HPS1 gene product. AP3B1 Normal allelic variants. The organization of AP3B1 has been described for the mouse [Gorin et al 1999], and the human cDNA is expressed as a 4.2-kb transcript in a variety of tissues [Dell'Angelica et al 1997, Simpson et al 1997]. The human coding sequence is 3282 bp. There are 27 exons. Pathologic allelic variants. AP3B1 mutations have been identified in several individuals with HPS-2; including two adult brothers [Dell’Angelica et al 1999], a six-year-old boy [Huizing et al 2002], another child [Clark et al 2003], two siblings with consanguineous Turkish parents [Jung et al 2006], two Italian siblings [Fontana et al 2006], a child originally diagnosed with Griscelli syndrome [Enders et al 2006] and three more unrelated individuals with typical findings of HPS-2 [Wenham et al 2010, Chiang et al 2010]. See Table 3.Table 3. Selected AP3B1 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change ^{1(Alias) 2Protein Amino Acid Change 1(Alias) 2Reference Sequencesc.155_158delAGAGp.Glu52Alafs*11 3NM_003664​.3
NP_003655​.3c.904A>Tp.Arg302X 4c.1063_1064delinsTATCAATATCp.Gln355Tyrfs*6 5(IVS10+5G; /i>A)Unconfirmed splicing defect 6c.1166_1228del
(exon 12 skip)
(IVS11-1G>C)p.Leu390_Gln410del 7(147279..155450del)(Thr491_Gln550del)
(deletion of exon 15) 8c.1473+6T>C
(exon 15 skip)
(IVS14+6T>C)p.Thr491_Gln550del 9c.1525C>Tp.Arg509X 10c.1619dupGp.Ala541Serfs*25 9c.1739T>Gp.Leu580Arg 7(1789dupA) (Ile597Asnfs*12) 5c.1975G>Tp.Glu659X 10c.2078_2165delp.Glu693Valfs*13 3See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designations are updated to current naming conventions; therefore, not all directly correlate to the nomenclature in their original publications.2. Variant designation that does not conform to current naming conventions3. Wenham et al [2010]4. Enders et al [2006]5. Fontana et al [2006]. Nomenclature updated to current naming conventions.6. Chiang et al [2010]7. Dell’Angelica et al [1999]. Compound heterozygous for a missense variant, and a deletion, which was later found to result from splice site mutation. Nomenclature updated to current naming conventions.8. Jung et al [2006]9. Clark et al [2003]10. Huizing et al [2002]Normal gene product. The product of AP3B1 is a 1094-amino acid peptide with a predicted mass of 121.35 kd. The protein has an amino-terminal region (residues 1-642), a hydrophilic span (residues 643-809), and a carboxy-terminal region (810-1094). The gene product is the beta-3A subunit of adaptor complex-3 (AP-3, also known as beta-3A adaptin), a heterotetrameric coat protein complex that forms intracellular vesicles (presumably lysosomes, melanosomes, and dense bodies) from the trans-Golgi network and endosomes in a clathrin-mediated fashion. Beta-3A adaptin interacts with the other AP-3 subunits to effect this function. Abnormal gene product. Compound heterozygosity for the two in-frame mutations of AP3B1 results in a very small amount of beta-3A adaptin on western blot, reduced amounts of another AP-3 subunit (mu), and decreased internalization of certain integral lysosomal membrane proteins into fibroblasts [Dell'Angelica et al 1999]. Compound heterozygosity for the two nonsense mutations of AP3B1 produces no beta-3A adaptin on western blot and a more severe cellular phenotype, i.e., significant default trafficking of selected lysosomal membrane proteins through the plasma membrane [Huizing et al 2002]. Compound heterozygosity for the missense and splice site mutations result in cytotoxic T-lymphocytes with enlarged lytic granules that cannot move along microtubules and dock in secretory domains of the immunologic synapse [Clark et al 2003]. The Italian patients with an insertion-deletion and an insertion have natural killer cell dysfunction [Fontana et al 2006], and the person homozygous for a nonsense mutation in exon 8 had lymphohistiocytosis [Enders et al 2006]. HPS3 Normal allelic variants. The genomic organization of HPS3 has been described [Anikster et al 2001]. It has 17 exons coding for a cDNA of 3921 bp. The transcript is 4.4 kb in size. Pathologic allelic variants. A founder mutation in central Puerto Rico, consisting of a g.339_4260del3904 deletion that removes all of exon 1 and 673 bp of intron 1, accounts for the bulk of the molecular pathology in HPS-3. This mutant allele produces no HPS3 mRNA. A second founder mutation, c.1303+1G>A, occurs among Ashkenazi Jews, causes skipping of exon 5, and produces negligible amounts of mRNA [Huizing et al 2001a]. Other reported mutations include: three splice site mutations, c.1831+2T>G, c.2433-2A>G, and c.2729+1G>C; and a missense mutation, g.44101G>A, which creates a new splice site resulting in the insertion of an 89-bp alternative exon 16A and a missense mutation (p.Arg397Trp) [Huizing & Gahl 2002]. See Table 4. Table 4. Selected HPS3 Pathologic VariantsView in own windowDNA Nucleotide Change
(Alias 1) Protein Amino Acid Change Reference Sequencesc.1189C>Tp.Arg397TrpNM_032383​.3
NP_115759​.2c.1303+1G>A
(1163+1G>A)
(IVS5+1G>A)--c.1831+2T>G
(c.1691+2T>G or
IVS9+2T>G)--c.2433-2A>G
(c.2481-2A>G or
IVS13-2A>G)--c.2729+1G>C
(c.2589+1G>C)--g.339_4260del3904
(3.9-kb del)--AF375663g.44101G>A--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. The protein encoded by HPS3 has 1004 amino acids with a predicted molecular weight of 113.7 kd [Anikster et al 2001]. It is predicted to have no glycosylation sites or transmembrane regions, but to be 43% alpha-helix, 19% extended strand, 30% random coil, and 7% beta-turn. A clathrin binding motif exists at residues 172-176, and binding of the HPS3 protein to clathrin has been demonstrated [Helip-Wooley et al 2005]. The function of the gene product is not known, but it has been shown to interact within a complex including the products of HPS5 and HPS6 [Di Pietro et al 2004, Gautam et al 2004]. Abnormal gene product. The central Puerto Rican 3904-bp deletion produces no transcript and no protein. The c.1303+1G>A mutation eliminates exon 5, resulting in a premature translational stop at codon 350, which is predicted to produce a truncated protein if mRNA escapes the nonsense-mediated decay pathway. Similarly, truncated protein may be produced from the c.1831+2T>G splice mutant. The p.Arg397Trp allele is expected to produce a normal-sized HPS3 product. HPS4 Normal allelic variants. The genomic organization of HPS4 has been described [Anderson et al 2003]. HPS4 has 14 exons covering 32 kb of genomic DNA. Two transcripts of HPS4 differ at their 5' ends, with the major transcript providing a 708-amino acid peptide and the minor transcript producing a 703-amino acid protein. Eight non-pathogenic DNA polymorphisms have been reported, including four that change an amino acid [Anderson et al 2003]. Pathologic allelic variants. Reported mutations are listed in Table 5. Table 5. Selected HPS4 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias 1) Protein Amino Acid Change
(Alias 1)Reference Sequencesc.57dupT
(F19delT)p.Leu20Serfs*3NM_022081​.4
NP_071364​.4c.412G>Tp.Glu138Xc.461A>Gp.His154Argc.541C>Tp.Gln181Xc.649C>Tp.Arg217Xc.664G>Tp.Glu222Xc.949_972dup
(c.947_961dup24)p.Ala317_Glu324dup
(p.Glu316_Asn325dupACPDGRKE)c.1866delC
(c.1865delC)p.Thr623Profs*13
(p.Pro685Leufs*30)c.1891C>Tp.Gln631Xc.2089_2093dup
(c.2093_2094ins or Q698insAAGCA)p.Lys699Serfs*5See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. The protein encoded by HPS4 has 708 amino acids with a predicted molecular weight of 76.9 kd [Suzuki et al 2002]. The function of the gene product is not known, but it has been shown to interact with the HPS1 gene product in BLOC-3 and is considered to be involved in intracellular vesicle biogenesis [Suzuki et al 2002]. Abnormal gene product. No information is available on the abnormal gene products of HPS4. HPS5 Normal allelic variants. The genomic organization of HPS5 has been described [Huizing et al 2004]. HPS5 has 23 exons, spans 43.5 kb of genomic DNA, and has three splice variants, the longest of which is 4.8 kb and contains 23 exons encoding an 1129-amino acid protein. A second splice variant differs in the 5' UTR and lacks the first 114 amino acids coded for by exon 2. The third variant resembles variant 2 in lacking the first 114 amino acids, but also lacks a portion of exon 1 [Huizing et al 2004]. Pathologic allelic variants. Reported mutations are listed in Table 6. Table 6. Selected HPS5 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias 1) Protein Amino Acid Change
(Alias 1)Reference Sequencesc.879dupC
(c.879insC)p.Lys294Glnfs*6
(p.293Glnfs* or p293insC)NM_181507​.1
NP_852608​.1c.1871T>Gp.Leu624Argc.2025_2028delAGTTp.Val676Valfs*8c.2593C>Tp.Arg865Xc.2624delT
(1875delT)p.Leu875Cysfs*20
(p.Leu875Cysfs*)c.2929_2930dupGA
(T977insGA)p.Asp978Glnfs*14c.3293C>Tp.Thr1098IleSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. The HPS5 protein has 1129 amino acids (127.4 kd) and contains two WD40 domains at low statistical likelihood [Zhang et al 2003]. It interacts with the products of HPS3 and HPS6 in BLOC-2 [DiPietro et al 2004, Gautam et al 2004]. HPS5 function is not known, but in its absence, LAMP-3-containing fibroblast vesicles cluster around the nucleus and fail to normally populate the cell periphery [Huizing et al 2004]. Abnormal gene product. No information is available on the abnormal gene products of HPS5. HPS6 Normal allelic variants. HPS6 contains a 2418-bp open reading frame along with 93 bp of 5' untranslated sequence and 110 bp of 3' untranslated sequence all within a single exon [Zhang et al 2003]. A multiple-tissue northern blot demonstrated that HPS6 was expressed in all tissues tested, displaying a transcript size of approximately 2.6 kb, and no alternatively spliced transcripts were present [Huizing et al 2009]. Pathologic allelic variants. Reported mutations are listed in Table 7. Five HPS6 mutations have been reported, occurring in patients of European descent [Zhang et al 2003, Huizing et al 2009]. One mutation, p.Leu356Argfs*11, was found in a highly consanguineous Israeli Bedouin family [Schreyer-Shafir et al 2006]. Table 7. Selected HPS6 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.223C>Tp.Gln75XNM_024747​.4
NP_079023​.2c.238dupGp.Asp80Glyfs*96c.815C>Tp.Thr272Ilec.913C>Tp.Gln305Xc.1066_1067insGp.Leu356Argfs*11c.1234C>Tp.Gln412Xc.1713_1716delTCTG p.Leu572Alafs*40c.1865_1866delTGp.Leu622Argfs*12del 19,972-bp-See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The human HPS6 open reading frame is predicted to code for a 775-amino acid, 83-kd protein of unknown function. The protein is highly homologous to its mammalian orthologs, but lacks homology to any other protein. No functional domains, leader sequence, or N-glycosylation sites are predicted [Zhang et al 2003, Huizing et al 2009]. HPS6 interacts with the HPS3 and HPS5 proteins to form BLOC-2 [Di Pietro et al 2004]. Abnormal gene product. Cellular studies performed on melanocytes of affected individuals with aberrant HPS6 protein expression indicated abnormal distribution patterns of the melanogenic proteins TYRP1 and TYR, as well as increased trafficking of TYRP1 through the plasma membrane [Huizing et al 2009], similar as those described for other BLOC-2 deficient (HPS3 and HPS5) melanocytes [Boissy et al 2005, Helip-Wooley et al 2007]. These findings confirmed that the BLOC-2 subunits HPS3, HPS5, and HPS6 act in the same pathway of LRO biogenesis. DTNBP1 Normal allelic variants. The genomic organization of human DTNBP1 has not been described, although the gene is known to contain ten exons. Six neutral polymorphisms have been reported [Li et al 2003]. Pathologic allelic variants. See Table 8. One nonsense mutation, p.Gln103X, has been described [Li et al 2003]. Table 8. Selected DTNBP1 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.307C>Tp.Gln103XNM_032122​.3
NP_115498​.2See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The protein encoded by DTNBP1 is dysbindin (also known as dystrobrevin binding protein 1), which binds to dystrobrevins in muscle and non-muscle cells and is also a component of biogenesis of lysosome-related organelles complex 1 (BLOC-1) [Falcon-Perez et al 2002, Moriyama & Bonifacino 2002, Ciciotte et al 2003]. Abnormal gene product. No information is available on the abnormal gene products of DTNBP1. BLOC1S3 Normal allelic variants. BLOC1S3 contains a single coding exon [Morgan et al 2006].Pathologic allelic variants. See Table 9. Two mutations in BLOC1S3 have been identified in the homozygous state. One mutation, p.Gly150Argfs*75, was identified in affected individuals of a single consanguineous Pakistani family [Morgan et al 2006], and the other mutation, p.Ser44X, was identified in an Iranian boy [Cullinane et al 2012]. Table 9. Selected BLOC1S3 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.131C>A p.Ser44XNM_212550​.3
NP_997715​.1c.448delCp.Gly150Argfs*75See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The protein encoded by BLOC1S3 has 203 amino acids and combines with seven other proteins to form BLOC-1. BLOC1S3 contains an unstructured amino terminal domain followed by an alpha-helical domain. The function of the BLOC1S3 subunit is unknown; BLOC-1 is hypothesized to regulate SNARE complex formation in the endocytic pathway [Falcon-Perez et al 2002]. Abnormal gene product. The homozygous p.Ser44X mutation resulted in aberrantly expressed BLOC1S3 protein in the patient’s melanocytes, which destabilized the BLOC1 complex and caused mis-trafficking of the melanogenic protein TYRP1, which abnormally accumulated in the Golgi region and cell membrane; this severely reduced pigment production [Cullinane et al 2012]. BLOC1S6Normal allelic variants. The genomic organization of BLOC1S6 has been described; the gene contains six exons. BLOC1S6 has two known human mRNA transcripts. Transcript 1 (AF080470) contains five coding exons, and transcript 2 (AK128626) has three coding exons; only exon 2 is shared by the two transcripts [Cullinane et al 2011]. Transcript 1 is ubiquitously expressed (with notable exception of brain) and transcript 2 is tissue-specific expressed only in adult brain, testis, and leukocytes as well as in fetal brain, lung, and thymus [Falcon-Perez et al 2002, Moriyama & Bonifacino 2002, Cullinane et al 2011]. Pathologic allelic variants. See Table 10. A homozygous nonsense mutation in BLOC1S6, c.232C>T; p.Gln78X, has been identified in a male of Indian ancestry [Cullinane et al 2011] and in a northern Italian female [Badolato et al 2012].Table 10. Selected BLOC1S6 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.232C>Tp.Gln78XNM_012388​.2
NP_036520​.1 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The protein encoded by BLOC1S6 (ubiquitously expressed variant 1, AF080470) comprises 172 amino acids and shares no homology to any known protein. The first 60 amino acids give rise to an unstructured protein, followed by two highly α-helical coiled-coil regions (amino acids 60-100 and 109-172). The two coiled-coil regions have been shown to be essential for pallidin to bind to itself and to syntaxin-13, an early endosomal t-SNARE [Moriyama & Bonifacino 2002, Cullinane et al 2011]. BLOC1S6 also combines with seven other proteins to form BLOC-1 [Falcon-Perez et al 2002, Moriyama & Bonifacino 2002]. Abnormal gene product. The homozygous p.Gln78X mutation affects only transcript 1 of BLOC1S6 resulting in a truncated protein product. The absence of functional BLOC1S6 in melanocytes of affected people destabilized other BLOC-1 subunits; decreased syntaxin-13-BLOC-1 binding; caused mistrafficking of the melanogenic protein TYRP1, which accumulated in the Golgi region, the early endosome compartment, and cell membrane; and severely reduced pigment production [Cullinane et al 2011].}