Hermansky-Pudlak Syndrome via the HPS3 Gene, Exon 1 Deletion

Hermansky-Pudlak Syndrome (HPS) is characterized by tyrosinase-positive oculocutaneous albinism, bleeding diathesis, and significant reduction in visual acuity often characterized by nystagmus, reduced retinal and iris pigmentation, and foveal hypoplasia (Hermansky and Pudlak 1959). Hair and skin color are typically shades lighter than is seen in unaffected relatives. HPS patients may experience frequent epistaxis, easy bruising, and prolonged bleeding with injury or surgery. HPS patients may also develop immunodeficiencies, granulomatous colitis, with onset usually in their teens, and/or pulmonary fibrosis, with onset typically in their thirties or forties (Huizing et al. 2008; Gahl et al. 1998). Similar characteristics are found with the related Chediak-Higashi Syndrome (CHS). HPS and CHS are disorders of storage granules, e.g. melanosomes, platelet-dense granules, lysosomes, and lytic granules. A hallmark of HPS is a lack of platelet dense granules, as seen on electron micrographs (Witkop et al. 1987). CHS is distinguished by giant azurophilic granules in neutrophils, eosinophils, and other granulocytes (Introne et al. 1999).

HPS is a genetically heterogeneous autosomal recessive disorder associated with the HPS1, AP3B1/(HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1/(HPS7), BLOC1S3/(HPS8), and BLOC1S6(HPS9) genes. HPS proteins belong to the BLOC (Biogenesis of Lysosome-related Organelle Complexes) groups of proteins that function during formation and/or trafficking of lysosme-related vesicles (Huizing et al. 2008). HPS is unusually common in Puerto Rico where regions of the country have an estimated carrier frequency as high as 1 in 21 (Wildenberg et al. 1995). Most affected Puerto Ricans harbor either a 16bp duplication in HPS1 or a 3.9kb deletion in HPS3 (Anikster et al. 2001; Santiago et al. 2006). In non-Puerto Ricans, HPS1 mutations account for ~50% of cases (Oh et al. 1998) with the remaining cases being distributed as follows: AP3B1/(HPS2) ~1%, HPS3 ~13%, HPS4 ~12%, HPS5 ~9%, HPS6 ~7%, DTNBP1/(HPS7) ~1%, BLOC1S3/(HPS8) ~1%, BLOC1S6 (HPS9) only two patients to date.

The severity of HPS varies among the subtypes and among family members having the same subtype, but some general genotype / phenotype correlations have emerged. Patients with HPS1 or HPS4 generally have more severe forms of HPS with more pronounced albinism, development of colitis (Hussain et al. 2006), a high occurrence of pulmonary fibrosis (Huizing et al. 2008), and accelerated ceroid lipfusin accumulation in lung, liver, bone marrow, kidney, and other cells (Huizing and Gahl 2002). The remaining subtypes are generally not associated with pulmonary fibrosis (Huizing et al. 2004), however, HPS2 and HPS9 have been associated with immunodeficiencies (Huizing et al. 2002; Badolato et al. 2012). Patients with HPS3 mutations tend to have milder symptoms than other HPS patients. Hypopigmentation and bleeding diathesis are mild and no significant granulomatous colitis or pulmonary fibrosis has been observed with HPS3. Most documented causative mutations in the HPS3 gene affect exon splicing; missense and nonsense mutations are rare.

This test is intended to detect the HPS3 exon 1 deletion found in Puerto Ricans; it will not detect any other sequence variant. In a cohort of 585 patients from 229 Puerto Rican families presenting with albinism, 39 patients were found  to be homozygous for the HPS3 exon 1 deletion (Santiago Borrero et al. 2006).  Sequencing the entire HPS3 coding region may be indicated in individuals who are clinically affected and have either one or no alleles with the exon 1 deletion. Complete HPS3 gene sequencing is available from PreventionGenetics (Test #4847).

Testing is accomplished by amplifying patient and control DNAs with PCR primers that flank or lie within the 3,904 bp deletion, essentially as described by Anikster et al (Anikster et al. 2001). This test permits the identification of patients with normal genotypes, patients who are homozygous for the deletion, and patients who are heterozygous carriers.