Alternative titles; symbols
ORPHA: 231500, 79430; DO: 0060539;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q24.2 | Hermansky-Pudlak syndrome 1 | 203300 | Autosomal recessive | 3 | HPS1 | 604982 |
A number sign (#) is used with this entry because Hermansky-Pudlak syndrome-1 (HPS1) is caused by homozygous or compound heterozygous mutation in the HPS1 gene (604982) on chromosome 10q24.
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles: melanosomes, platelet-dense granules, and lysosomes (Oh et al., 1998).
Genetic Heterogeneity of Hermansky-Pudlak Syndrome
HPS2 (608233) is caused by mutation in the AP3B1 gene (603401) on chromosome 5q14. HPS3 (614072) is caused by mutation in the HPS3 gene (606118) on chromosome 3q24. HPS4 (614073) is caused by mutation in the HPS4 gene (606682) on chromosome 22q12. HPS5 (614074) is caused by mutation in the HPS5 gene (607521) on chromosome 11p14. HPS6 (614075) is caused by mutation in the HPS6 gene (607522) on chromosome 10q24. HPS7 (614076) is caused by mutation in the DTNBP1 gene (607145) on chromosome 6p22. HPS8 (614077) is caused by mutation in the BLOC1S3 gene (609762) on chromosome 19q13. HPS9 (614171) is caused by mutation in the PLDN gene (604310) on chromosome 15q21. HPS10 (617050) is caused by mutation in the AP3D1 gene (607246) on chromosome 19p13. HPS11 (619172) is caused by mutation in the BLOC1S5 gene (607289) on chromosome 6p24.
Hermansky and Pudlak (1959) described 2 unrelated patients with albinism, a lifelong bleeding tendency, and peculiar pigmented reticular cells in the bone marrow as well as in lymph node and liver biopsies. One patient was male and the other female; both were 33 years old. After the woman's death, she was found to have large amounts of the pigment in reticuloendothelial cells everywhere and in the walls of small blood vessels (Hermansky, 1963). Two families, each with 2 sibs affected with this syndrome, had come to the attention of Hermansky (1963). This syndrome is clearly different from the Chediak-Higashi syndrome (214500) because no qualitative changes of leukocytes are found in Hermansky syndrome and no pigmented macrophages are found in Chediak-Higashi syndrome. Report of a family by Verloop et al. (1964) supports this conclusion.
Logan et al. (1971) described a patient with albinism and bleeding diathesis in whom a defect in platelet ADP release was demonstrated. Prolonged bleeding time and defective platelet aggregation were found. Two other patients with albinism and a defect in ADP release had been reported, as well as 12 others with prolonged bleeding. In 6 of 7 in whom the bone marrow was studied, histiocytes were found to contain abnormal granules. Weiss et al. (1979) studied the platelet defect, which they called delta storage pool disease, in 7 patients; 6, including 3 sisters, were of Puerto Rican ancestry. Four other unrelated patients had the same platelet defect but did not have albinism. Depinho and Kaplan (1985) reported 3 affected sibs from a consanguineous Puerto Rican kindred. The proband, a 31-year-old woman with 2 children, had fatal restrictive lung disease, a complication pointed out by others (Davies and Tuddenham, 1976; Garay et al., 1979). Indeed, the first patient (Hermansky and Pudlak, 1959) was a 33-year-old farmer who developed chronic interstitial pulmonary fibrosis. Davies and Tuddenham (1976) described 4 sibs with HPS-associated pulmonary fibrosis. The onset of pulmonary fibrosis is most often in the third or fourth decade.
Inflammatory bowel disease, with onset of symptoms between 12 and 30 years of age, in HPS patients has been reported by several authors (e.g., Schinella et al., 1980). Most of the patients with HPS-related bowel disease have been Puerto Rican. Response to medical therapy was said to be poor. Mahadeo et al. (1991) reported 2 children, aged 7 years and 3 years, with granulomatous colitis in association with HPS. One of the children was Puerto Rican. Epistaxis is the most frequent hemorrhagic manifestation. All 3 sibs studied by Depinho and Kaplan (1985) had recurrent infections and were anergic.
Kinnear and Tuddenham (1985) reported 4 cases of Hermansky-Pudlak syndrome. Cutaneous malignant melanoma developed in 1. The ocular features were similar to those of tyrosinase-positive oculocutaneous albinism (203200). The triad of the syndrome is albinism, platelets lacking dense bodies, and storage of ceroid-like material in tissues. The manifestations of the storage disease include ulcerative colitis, restrictive lung disease, kidney failure, and cardiomyopathy. The autofluorescent material stored in HPS is histochemically similar to that stored in neuronal ceroid lipofuscinosis (204200).
Sandberg-Gertzen et al. (1999) described HPS in a mentally retarded patient with albinism and mild bleeding diathesis; the course was complicated by granulomatous colitis refractory to medical treatment and progressive, fatal pulmonary fibrosis.
Hearing (1993) reviewed the complexities of melanogenesis, including the parallels between mouse and the human. The complex nature of the process was anticipated since, in the mouse, more than 150 distinct mutations affect visible pigmentation, and those occur at more than 50 genetic loci.
The Hermansky-Pudlak syndrome observed in the isolated Swiss Alps village (Lattion et al., 1983 and Schallreuter et al., 1993) usually shows a relatively mild clinical course with normal life expectancy, and the patients lack manifestations of ceroid storage. The 2 most common complications associated with ceroid deposition in the usual form of HPS are pulmonary fibrosis and granulomatous colitis; the major cause of death in HPS after 1 year of age is pulmonary fibrosis. There is striking variability in pigmentation, which can vary from an almost total absence of pigment to an amount that is nearly normal. Obligate heterozygotes are normally pigmented. The third feature of HPS is the absence of dense bodies in the platelets.
Using immunofluorescence with antibodies against CD63 (155740), Nishibori et al. (1993) demonstrated deficiency of CD63 (155740) in HPS.
Vitamin E was thought to be of some benefit for the hemorrhagic problem in patients with HPS (Depinho and Kaplan, 1985). Wijermans and van Dorp (1989) reported that 1-desamino-8D-arginine vasopressin (dDAVP) is useful in the treatment of some cases of HPS. The authors suggested that it be combined with drugs that inhibit fibrinolysis because dDAVP also increases plasminogen activator activity.
HPS may be the most frequent single-gene disorder in Puerto Rico and is frequent in an isolated mountain village high in the Swiss Alps (Schallreuter et al., 1993). Witkop (1986) estimated a frequency of about 1 in 2,000 among Puerto Ricans. Wildenberg et al. (1995) stated that in Puerto Rico, HPS has a frequency of about 1 in 1,800, giving a carrier frequency estimated to be 1 in 21. The origin of HPS in Puerto Rico has been traced to a region of southern Spain, and a connection to cases in Holland was considered likely (King, 1987).
Evidence of locus heterogeneity for HPS was provided by findings of homozygosity analysis of 4 inbred non-Puerto Rican HPS patients in whom Oh et al. (1998) detected no mutations in the HPS1 gene. If these patients were homozygous (by descent) for occult HPS1 mutations, they should also have been homozygous for the polymorphic markers that Oh et al. (1998) had found immediately flanking the gene. However, 3 of these patients were heterozygous for these markers, thus apparently excluding the HPS1 locus in these cases. Furthermore, genetic linkage analysis of the extended family of 1 of these 4 patients, as well as in another non-inbred family, showed no evidence for linkage.
Fukai et al. (1995) found that HPS maps to chromosome 10. They used the linkage disequilibrium mapping approach to localize the HPS1 gene (604982) in 2 groups in whom the disorder is particularly frequent: a group in Puerto Rico and a group in an isolated village in the Swiss Alps. They localized the HPS1 gene in both groups to a 0.6-cM interval in chromosome segment 10q23.1-q23.2. Wildenberg et al. (1995) likewise mapped the HPS1 gene to 10q. They collected blood samples from a relatively homogeneous population in Puerto Rico. Analysis of pooled DNA samples allowed them to screen the genome rapidly for candidate loci, and identify linkage with a marker on 10q. The result was verified with additional markers, and a maximum lod score of 5.07 at theta = 0.001 was calculated for marker D10S198. Haplotype analysis placed the HPS1 gene in a region of approximately 14 cM that contains the markers D10S198 and D10S1239.
The transmission pattern of HPS1 in the families reported by Oh et al. (1996) was consistent with autosomal recessive inheritance.
Oh et al. (1996) identified the HPS1 gene by positional cloning and found homozygous frameshifts in this gene in Puerto Rican, Swiss, Irish, and Japanese HPS patients. The HPS1 polypeptide is a novel transmembrane protein that is likely to be a component of multiple cytoplasmic organelles and is apparently crucial for their normal development and function. The different clinical phenotypes associated with different HPS1 frameshifts suggested that differentially truncated HPS1 polypeptides may have somewhat different consequences for subcellular function.
Oh et al. (1998) performed mutation analysis on 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication (604982.0001), the result of an apparent founder effect, was nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 (604982.0002) may be the most frequent HPS1 mutation in Europeans. Oh et al. (1998) also described 6 novel HPS1 mutations: a 5-prime splice-junction mutation of IVS5, 3 frameshifts, a nonsense mutation, and a 1-codon in-frame deletion. These mutations defined an apparent frameshift hotspot at codons 321-322. Overall, however, they detected mutations in the HPS1 gene in only about half of non-Puerto Rican patients, and presented evidence suggesting locus heterogeneity for HPS.
All identified patients with HPS in northwest Puerto Rico were found to be homozygous for the 16-bp duplication in exon 15 of the HPS1 gene (604982.0001). Gahl et al. (1998) compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. They studied 49 patients: 27 Puerto Ricans and 22 patients from mainland United States who were not of Puerto Rican descent. The diagnosis was based on the presence of albinism and the absence of platelet dense bodies. Homozygosity for the 16-bp duplication was found in 25 of the 27 Puerto Rican patients, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80% of the predicted value. High-resolution computed tomography in all 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in 8 patients without the duplication revealed minimal fibrosis in 3 and no fibrosis in the rest. Inflammatory bowel disease developed in 8 patients (4 in each group) between 3 and 25 years of age. Thus, the 16-bp duplication in exon 15 of the HPS1 gene, which has been found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.
Iwata et al. (2000) studied 2 groups of patients with Hermansky-Pudlak syndrome: those with the 16-bp duplication in the HPS1 gene on chromosome 10q23 (604982.0001), and those without the duplication. The visual acuity in the better eye was not statistically significantly different between the 2 groups. Although the authors attempted to compare visual acuity and iris transillumination versus visual acuity and macular translucency, they concluded that the variability in visual acuity was too great. The associations studied were not large enough for useful prediction of vision based on the amount of pigmentation.
Of 65 patients, aged 3 to 54 years, in whom the diagnosis of HPS had been made on the basis of absence of platelet dense bodies in individuals with albinism combined with a bleeding diathesis, Toro et al. (1999) found the 16-bp duplication in HPS1 by PCR amplification in 40 who were homozygous, whereas the other 25 lacked the duplication. All patients with the duplication were from northwest Puerto Rico; all patients without the duplication were non-Puerto Rican, except 4 from central Puerto Rico. Both groups displayed skin color ranging from white to light brown, hair color ranging from white to brown, and eye color ranging from blue to brown. New findings in both groups of patients with HPS were melanocytic nevi with dysplastic features, acanthosis nigricans-like lesions in the axilla and neck, and trichomegaly. In 80% of patients with the duplication, features of solar damage were found, including multiple freckles, stellate lentigines, actinic keratoses, and, occasionally, basal cell or squamous cell carcinomas. Only 8% of patients lacking the 16-bp duplication displayed these findings. As a group, the patients with the duplication lived closer to the equator than those without the duplication, but this was not thought to explain the difference entirely.
In a review of the trafficking of organellar-specific proteins to melanosomes, lysosomes, and cytoplasmic granules, Spritz (1999) proposed that the Hermansky-Pudlak syndrome due to mutations in the AP3B1 gene be named HPS2 and the original syndrome be called HPS1. Hermansky-Pudlak syndrome due to mutation in a gene on 3q24 (606118) is known as HPS3 (Anikster et al., 2001).
Two genetically distinct mouse loci, 'pale ear' (ep) and 'ruby-eye' (ru), both with mutant phenotypes similar to human HPS, map close together in the homologous region of murine chromosome 19, which suggested that one of these loci might be homologous to human HPS1. Feng et al. (1997) characterized the mouse Hps1 cDNA and genomic locus, and identified pathologic Hps1 gene mutations in ep but not in ru mice, establishing mouse 'pale ear' as an animal model for human HPS. (The human homolog of mouse ru is HPS6, 607522). The phenotype of homozygous ep mutant mice encompasses those of both HPS and Chediak-Higashi syndrome, suggesting that these disorders may be closely related.
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