Hermansky-Pudlak Syndrome 2

A number sign (#) is used with this entry because Hermansky-Pudlak syndrome-2 (HPS2) is caused by homozygous or compound heterozygous mutation in the gene encoding the beta-3A subunit of the AP3 complex (AP3B1; 603401) on chromosome 5q14.

For a general phenotypic description and a discussion of genetic heterogeneity of Hermansky-Pudlak syndrome, see HPS1 (203300).

Description

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. HPS2 differs from the other forms of HPS in that it includes immunodeficiency, and patients with HPS2 have an increased susceptibility to infections due to congenital neutropenia (Jung et al., 2006).

Clinical Features

Kotzot et al. (1994) reported a boy and girl with tyrosinase (TYR; 606933)-positive oculocutaneous albinism, recurrent bacterial infections, granulocytopenia, intermittent thrombocytopenia, microcephaly, protruding midface, rough and projecting hair, and mild mental retardation. The patients were first cousins born in a consanguineous Turkish family; the parents were related as first cousins in both cases, and all 4 parents had a number of common ancestors. In a follow-up of the patients reported by Kotzot et al. (1994), Jung et al. (2006) noted that both patients had severe dental decay with bacterial periodontitis. One patient had recurrent skin abscesses and the other had 2 episodes of pneumonia. Neither had prolonged bleeding, although both had thrombocytopenia and splenomegaly. Immunologic studies by Jung et al. (2006) detected no functional neutrophil aberrations despite ultrastructural changes suggestive of aberrant vesicular maturation. However, natural killer (NK) cells were decreased.

Huizing et al. (2002) reported a 5-year-old boy of Native American ancestry who had oculocutaneous albinism, recurrent infections, hepatosplenomegaly, neutropenia, and thrombocytopenia. He presented during the first year of life with severe respiratory infections and neutropenia. Recurrent respiratory infections resulted in nonspecific interstitial pneumonitis. He had dysmorphic facies with epicanthal folds, low-set and posteriorly rotated ears, broad nasal root, long philtrum, retrognathia, and thin upper lip. He also had mild developmental delay, bilateral mild conductive hearing loss, and nystagmus. Laboratory studies showed an absence of dense bodies in the patient's platelets.

Enders et al. (2006) reported a 2-year-old patient with oculocutaneous albinism and immunodeficiency originally thought to have Griscelli syndrome type 2 (607624). Genetic analysis identified a homozygous mutation in the AP3B1 gene (603401.0006). During preparation for hematopoietic stem cell transplantation, the patient was found to have neutropenia, disturbed platelet aggregation, reduced platelet dense granules, and impaired platelet degranulation. Stem cell transplant was withheld, and granulocyte-colony-stimulating factor (GCSF; 138970) therapy was initiated, thereby preventing further bacterial infections. At 3 years of age, the patient developed therapy-resistant fulminant hemophagocytic lymphohistiocytosis (see HLH, 267700). Enders et al. (2006) suggested that the genetic defect in this child may have predisposed to the development of HLH and concluded that HPS2 belongs to the group of familial hemophagocytic syndromes and may represent an indication for hematopoietic stem cell transplant.

Inheritance

The transmission pattern of Hermansky-Pudlak syndrome in the family reported by Kotzot et al. (1994) was consistent with autosomal recessive inheritance.

Pathogenesis

Adaptor protein-3 (AP3) is a ubiquitous cytoplasmic complex that shuttles cargo proteins from the trans-Golgi and a tubular-endosomal compartment to endosome-lysosome-related organelles. Lack of the beta-3A subunit of this complex causes Hermansky-Pudlak syndrome type 2 (Fontana et al., 2006).

Dell'Angelica et al. (1999) found that the fibroblasts of 2 brothers with HPS2 exhibited drastically reduced levels of AP3 due to enhanced degradation of mutant beta-3A. AP3 deficiency resulted in increased surface expression of the lysosomal membrane proteins CD63 (155740), LAMP1 (153330), and LAMP2 (309060), but not of nonlysosomal proteins. These differential effects were considered consistent with the preferential interaction of the AP3 mu-3A subunit with tyrosine-based signals involved in lysosomal targeting. Dell'Angelica et al. (1999) suggested that AP3 functions in protein sorting to lysosomes and that HPS provides an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machinery.

Sugita et al. (2002) showed that CD1B (188360), but not other CD1 isoforms, binds the AP3 adaptor protein complex. In AP3-deficient cells from patients with HPS2, CD1B failed to gain access to lysosomes efficiently and was mislocalized to the plasma membrane and early endosomes. The failure in CD1B trafficking resulted in a profound failure to present microbial lipid antigens efficiently. Since MHC class II traffics normally in AP3-deficient cells, Sugita et al. (2002) proposed that defects in CD1B antigen presentation may account for the recurrent bacterial infections in HPS2 patients. They concluded that there is an AP3-dependent pathway for antigen presentation by CD1B molecules.

By studying CD8 (see 186910)-positive cytotoxic T lymphocytes (CTLs) from an HPS2 patient, Clark et al. (2003) determined that AP3 deficiency results in loss of microtubule-mediated movement of enlarged perforin- and granzyme-containing lytic granules toward the immunologic synapse and a profound loss of CTL-mediated killing.

In 2 previously unreported sibs affected by HPS2, Fontana et al. (2006) observed a dramatic reduction of cytolytic activity of freshly isolated and of IL2-activated natural killer cells. Levels of perforin (170280) were reduced in unstimulated NK cells, thereby accounting for the impairment of NK cytolytic activity. In addition, analysis of neutrophils in these patients demonstrated that intracellular elastase content was largely reduced, whereas CD63 expression on plasma membrane was substantially increased. Taken together, these observations suggested that type 2 Hermansky-Pudlak syndrome is characterized by defects of innate immunity.

Molecular Genetics

Dell'Angelica et al. (1999) identified mutations in the AP3B1 gene (603401.0001-603401.0002) in 2 brothers with HPS2.

In a patient with a severe form of HPS2, Huizing et al. (2002) identified compound heterozygosity for 2 nonsense mutations in the AP3B1 gene (603401.0007; 603401.0008). Northern blot analysis detected no AP3B1 mRNA transcript, consistent with nonsense-mediated mRNA decay.

Clark et al. (2003) found that CD8-positive CTLs from an immunodeficient HPS patient lacked the beta-3A, gamma, and mu-3A subunits of AP3, consistent with HPS2. By PCR analysis, they identified compound heterozygosity for mutations in the AP3B1 gene (see 603401.0003).

In 2 Turkish patients with HPS2 from a large consanguineous family originally reported by Kotzot et al. (1994), Jung et al. (2006) identified a homozygous deletion in the AP3B1 gene (603401.0005).

Nomenclature

In a review of the trafficking of organellar-specific proteins to melanosomes, lysosomes, and cytoplasmic granules, Spritz (1999) proposed that HPS due to mutations in the AP3B1 gene be named HPS2 and the original syndrome be called HPS1.