Hermansky–Pudlak syndrome type 1 in patients of Indian descent

https://doi.org/10.1016/j.ymgme.2009.03.011Get rights and content

Abstract

Hermansky–Pudlak syndrome (HPS) develops from defects in the biogenesis and/or function of lysosome-related organelles essential to membrane and protein trafficking. Of the eight known human subtypes, only HPS-1 and HPS-4 develop pulmonary fibrosis in addition to the general clinical manifestations of oculocutaneous albinism and bleeding diathesis. We identified HPS-1 in three unrelated patients from different regions of India, who presented with iris transillumination, pale fundi, hypopigmentation, nystagmus, decreased visual acuity, and a bleeding diathesis. Two of these patients carried the homozygous mutation c.398+5G>A (IVS5+5G>A) in HPS1, resulting in skipping of exon 5 in HPS1 mRNA. The third patient carried a novel homozygous c.988−1G>T mutation that resulted in in-frame skipping of HPS1 exon 12 and removes 56 amino acids from the HPS1 protein. Given the discovery of HPS-1 in an ethnic group where oculocutaneous albinism (OCA) is highly prevalent, it is possible that HPS in India is under-diagnosed. We recommend that unconfirmed OCA patients in this ethic group be considered for mutational screening of known HPS genes, in particular c.398+5G>A and c.980−1G>T, to ensure that patients can be monitored and treated for clinical complications unique to HPS.

Introduction

Hermansky–Pudlak syndrome (HPS; MIM #203300) is an autosomal recessive disorder characterized by oculocutaneous albinism and a bleeding diathesis; some patients exhibit lysosomal accumulation of ceroid lipofuscin, granulomatous colitis, or pulmonary fibrosis that is fatal in the fourth or fifth decade [1], [2], [3], [4], [5]. Genetic heterogeneity is supported by the existence of at least 15 HPS mouse models [6], and mutations in eight different genes have been identified in humans with HPS [7], [8]. The HPS genes with known function have roles in the biogenesis and/or function of intracellular organelles required in membrane and protein trafficking [8]. The genetic heterogeneity of HPS gives rise to clinical heterogeneity. For example, only patients with mutations in HPS1 or HPS4 develop pulmonary fibrosis [8], [9], [10].

HPS is a rare disorder that has been identified in patients worldwide, including Puerto Rico, Japan, Northern Europe, and Israel [3], [7], [8], [11], [12], [13], [14], [15]. In addition, HPS-1, the most common HPS subtype, was recently reported in two African American siblings [16]. HPS-1 results from mutations in the HPS1 gene located on 10q23.1–q23.3 [17] and occurs largely as a genetic isolate in individuals from northwest Puerto Rico [11]. Among non-Puerto Ricans, HPS-1 accounts for ∼50% of all HPS cases [7], [18]. Here, we report the first diagnosis of HPS in patients of Indian descent arising from two different mutations in HPS1.

Section snippets

Patients and cells

Written, informed consent was obtained for enrollment in a protocol approved by the National Human Genome Research Institute (NHGRI) institutional review board to evaluate the clinical and molecular aspects of HPS. Patient numbers conformed to a master list of NIH subjects with HPS. The diagnosis was based upon the absence of platelet dense bodies on whole-mount electron microscopy and the presence of hypopigmentation, decreased visual acuity, and nystagmus. Primary skin fibroblast and

Case reports

Patient HPS152 was a female adopted from Hyderbad, India at 14 months of age, and was 8 years old at the time of our initial evaluation. At the time of adoption, an ophthalmologist diagnosed oculocutaneous albinism (Fig. 1A–C). Frequent bruising and epistaxis occurred, with bleeding for up to 1 h. These findings and the absence of platelet dense bodies on electron microscopy (Fig. 1D) led to the diagnosis of HPS at age 7. No transfusions, DDAVP (1-deamino-8-d-arginine vasopressin), or cautery were

Discussion

Our mutation analysis of unclassified patients with Hermansky–Pudlak syndrome revealed three apparently unrelated patients from different regions of India with mutations in the HPS1 gene. All three patients displayed iris transillumination, pale fundi, hypopigmentation, nystagmus, decreased visual acuity, and absence of platelet dense bodies. None of the patients had developed pulmonary fibrosis or a decrease of pulmonary function at the time of evaluation, likely because all three patients

Acknowledgments

Isa Bernardini, Roxanne Fischer, Heidi Dorward, and Wendy Westbroek provided excellent technical assistance. This work was supported by the Intramural Research programs of the National Human Genome Research Institute and National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

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